Distinct hepatocyte identities in liver homeostasis and regeneration

May combine two claims.

Metabolic zonation is dynamic and requires active activation and repression of metabolic gene expression.

“Zonal reprogramming observed by spatial transcriptomics22 and molecular cartography25 combined with perturbation of WNT/β-catenin signalling further indicate that metabolic zonation is dynamic and requires active activation and repression of metabolic gene expression.”

• cites [22] Sun T. Annunziato S. Bergling S. Sheng C. Orsini V. Forcella P. ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation Cell Stem Cell 28 2021 1822 1837 e1810 34129813 sourceNot checked — no full text of the source
• cites [25] Hu S. Liu S. Bian Y. Poddar M. Singh S. Cao C. Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b Cell Rep Med 3 2022 100754 PMC9588996 36220068 sourceSupported

May combine two claims.

Due to high levels of WNT/β-catenin signalling, pericentral hepatocytes express the β-catenin target gene Lgr5, which confers tissue stem cell identity in the gut, but not in the liver.

“Due to high levels of WNT/β-catenin signalling, pericentral hepatocytes express the β-catenin target gene Lgr5, which confers tissue stem cell identity in the gut, but not in the liver.44,50”

• cites [44] Planas-Paz L. Orsini V. Boulter L. Calabrese D. Pikiolek M. Nigsch F. The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size Nat Cell Biol 18 2016 467 479 27088858 sourcePartly supported

  The main text (page unavailable) identifies LGR5 as a Wnt target gene expressed in pericentral hepatocytes with high Wnt activity. The Discussion (page unavailable) reports that these cells did not show the proliferation or outward lineage expansion seen in other LGR5-positive tissue stem-cell compartments. It does not establish that LGR5 itself confers stem-cell identity in the gut; it describes LGR5 as expressed in those stem cells. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [50] Ang C.H. Hsu S.H. Guo F. Tan C.T. Yu V.C. Visvader J.E. Lgr5(+) pericentral hepatocytes are self-maintained in normal liver regeneration and susceptible to hepatocarcinogenesis Proc Natl Acad Sci U S A 116 2019 19530 19540 31488716 PMC6765306 sourcePartly supported

  The Discussion (page unavailable) identifies Lgr5 as a Wnt target gene expressed in hepatocytes adjacent to central veins, and the Abstract reports that these cells mainly maintain their own lineage during normal liver regeneration. The Results call Lgr5 a stem-cell marker in epithelial tissues, but this paper does not establish that Lgr5 confers stem-cell identity in the gut or that high Wnt signalling causes its expression in pericentral hepatocytes. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The expression of WNT ligands is influenced by diurnal mRNA fluctuations, suggesting that WNT signalling may fluctuate throughout the day.

“Further, the expression of WNT ligands is influenced by diurnal mRNA fluctuations, suggesting that WNT signalling may fluctuate throughout the day.26”

• cites [26] Droin C. Kholtei J.E. Bahar Halpern K. Hurni C. Rozenberg M. Muvkadi S. Space-time logic of liver gene expression at sub-lobular scale Nat Metab 3 2021 43 58 33432202 PMC7116850 sourceSupported

May combine two claims.

YAP promotes SRY-box transcription factor 9 (SOX9) expression in hepatocytes and may confer the hybrid hepatocyte-biliary identity of periportal SOX9+ hepatocytes.

“However, YAP promotes SRY-box transcription factor 9 (SOX9) expression in hepatocytes59 and may confer the hybrid hepatocyte-biliary identity of periportal SOX9+ hepatocytes.60”

• cites [59] Yimlamai D. Christodoulou C. Galli G.G. Yanger K. Pepe-Mooney B. Gurung B. Hippo pathway activity influences liver cell fate Cell 157 2014 1324 1338 24906150 PMC4136468 sourceSupported
• cites [60] Font-Burgada J. Shalapour S. Ramaswamy S. Hsueh B. Rossell D. Umemura A. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer Cell 162 2015 766 779 26276631 PMC4545590 sourcePartly supported

  The Results (‘HybHP Exhibit a Unique Transcriptome’; page unavailable) show that periportal hybrid hepatocytes express SOX9 and have some bile-duct characteristics. But the cited paper does not link YAP to that hybrid identity; the Discussion instead suggests that proximity to ductal cells and factors such as Notch ligands may contribute to their partial ductal character. Citation 59, not this source, is attached to the separate claim that YAP promotes SOX9 expression. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

May combine two claims.

Higher ploidies (>8n) appear in injured livers, likely due to alterations to cell cycles caused by cellular damage.

“Higher ploidies (>8n) appear in injured livers, likely due to alterations to cell cycles caused by cellular damage.29”

• cites [29] Gentric G. Desdouets C. Polyploidization in liver tissue Am J Pathol 184 2014 322 331 24140012 sourcePartly supported

  The “Polyploidy in the Liver” section (page unavailable) says liver injury modifies the ploidy profile and that some hepatocytes undergo incomplete cell cycles during regeneration. It does not establish that injured livers develop ploidies above 8n, and it says the mechanisms generating polyploid hepatocytes under cellular stress remain unknown. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Higher periportal availability of hormones, such as insulin and glucagon, play important opposing roles in spatial metabolic zonation and interact with the WNT/β-catenin pathway.

“Higher periportal availability of hormones, such as insulin and glucagon, play important opposing roles in spatial metabolic zonation and interact with the WNT/β-catenin pathway.54”

• cites [54] Cheng X. Kim S.Y. Okamoto H. Xin Y. Yancopoulos G.D. Murphy A.J. Glucagon contributes to liver zonation Proc Natl Acad Sci U S A 115 2018 E4111 E4119 29555772 PMC5924920 sourcePartly supported

  The Discussion (page not available in our copy) says glucagon acts more strongly in the periportal zone and counteracts WNT/β-catenin signaling in liver metabolic zonation. The Results call insulin a counterregulatory hormone of glucagon, but the paper does not establish higher periportal insulin availability or an insulin interaction with WNT/β-catenin. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

At birth, all hepatocytes are diploid, with accumulation of polyploid hepatocytes, mostly 4n and some 8n, occurring during post-natal development until polyploid hepatocytes account for ∼90% of hepatocytes in rodent livers and 30% in human livers.

“Curiously, at birth, all hepatocytes are diploid, with accumulation of polyploid hepatocytes, mostly 4n and some 8n, occurring during post-natal development (further reviewed in[29], [30], [31]), until polyploid hepatocytes account for ∼90% of hepatocytes in rodent livers and 30% in human livers.[32], [33], [34], [35]”

• cites [32] Duncan A.W. Taylor M.H. Hickey R.D. Hanlon Newell A.E. Lenzi M.L. Olson S.B. The ploidy conveyor of mature hepatocytes as a source of genetic variation Nature 467 2010 707 710 20861837 PMC2967727 sourcePartly supported

  The Main Text (page not provided) says hepatocyte polyploidization begins at weaning in rodents and increases with age, and identifies 4n and 8n hepatocytes. It does not give the claimed ∼90% prevalence in rodent livers or 30% in human livers. Its 90 ± 2% figure refers to marker expression in transplanted octaploid cells, not the proportion of polyploid hepatocytes. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [33] Gandillet A. Alexandre E. Holl V. Royer C. Bischoff P. Cinqualbre J. Hepatocyte ploidy in normal young rat Comp Biochem Physiol A Mol Integr Physiol 134 2003 665 673 12600676 sourceNot checked — no full text of the source
• cites [34] Guidotti J.E. Bregerie O. Robert A. Debey P. Brechot C. Desdouets C. Liver cell polyploidization: a pivotal role for binuclear hepatocytes J Biol Chem 278 2003 19095 19101 12626502 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Although a porto-central Yes-associated protein (YAP) expression gradient has been reported, the role of YAP/HIPPO signalling in metabolic zonation is unclear.

“Although a porto-central Yes-associated protein (YAP) expression gradient has been reported,55 the role of YAP/HIPPO signalling in metabolic zonation is unclear.”

• cites [55] Fitamant J. Kottakis F. Benhamouche S. Tian H.S. Chuvin N. Parachoniak C.A. YAP inhibition restores hepatocyte differentiation in advanced HCC, leading to tumor regression Cell Rep 10 2015 1692 1707 25772357 PMC4565791 sourceSupported

May combine two claims.

Mechanisms regulating hepatocyte ploidy include insulin signalling through the P13K-AKT pathway, which is influenced by weaning and induces formation of binucleate tetraploid hepatocytes during postnatal liver growth.

“Mechanisms regulating hepatocyte ploidy include insulin signalling through the P13K-AKT pathway, which is influenced by weaning67 and induces formation of binucleate tetraploid hepatocytes during postnatal liver growth.68,69”

• cites [67] Margall-Ducos G. Celton-Morizur S. Couton D. Bregerie O. Desdouets C. Liver tetraploidization is controlled by a new process of incomplete cytokinesis J Cell Sci 120 2007 3633 3639 17895361 sourceNot checked — no full text of the source
• cites [68] Celton-Morizur S. Merlen G. Couton D. Desdouets C. Polyploidy and liver proliferation: central role of insulin signaling Cell Cycle 9 2010 460 466 20090410 sourceSupported
• cites [69] Celton-Morizur S. Merlen G. Couton D. Margall-Ducos G. Desdouets C. The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents J Clin Invest 119 2009 1880 1887 19603546 PMC2701880 sourceSupported

May combine two claims.

E2F7 and E2F8 are cell cycle factors expressed at low levels in adult livers but at high levels during the first 7 weeks after birth in mice; they are also responsible for postnatal polyploidisation.

“E2F7 and E2F8 are cell cycle factors expressed at low levels in adult livers but at high levels during the first 7 weeks after birth in mice; they are also responsible for postnatal polyploidisation.38,70”

• cites [38] Wilkinson P.D. Delgado E.R. Alencastro F. Leek M.P. Roy N. Weirich M.P. The polyploid state restricts hepatocyte proliferation and liver regeneration in mice Hepatology 69 2019 1242 1258 30244478 PMC6532408 sourceSupported
• cites [70] Pandit S.K. Westendorp B. Nantasanti S. van Liere E. Tooten P.C. Cornelissen P.W. E2F8 is essential for polyploidization in mammalian cells Nat Cell Biol 14 2012 1181 1191 23064264 sourceNot checked — no full text of the source

May combine two claims.

The human liver exhibits differential DNA methylation between the periportal and pericentral zone at binding sites of around 50 transcription factors, which may lead to distinct binding preferences along the centro-portal axis.

“Furthermore, the human liver exhibits differential DNA methylation between the periportal and pericentral zone at binding sites of around 50 transcription factors, which may lead to distinct binding preferences along the centro-portal axis.63”

• cites [63] Brosch M. Kattler K. Herrmann A. von Schonfels W. Nordstrom K. Seehofer D. Epigenomic map of human liver reveals principles of zonated morphogenic and metabolic control Nat Commun 9 2018 4150 30297808 PMC6175862 sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

In injured livers, oxidative stress through induction of ATR/p53/p21 signalling has been reported to induce hepatocyte polyploidy.

“In injured livers, oxidative stress through induction of ATR/p53/p21 signalling has been reported to induce hepatocyte polyploidy72 (further reviewed in31).”

• cites [72] Gentric G. Maillet V. Paradis V. Couton D. L'Hermitte A. Panasyuk G. Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease J Clin Invest 125 2015 981 992 25621497 PMC4362240 sourcePartly supported

  The Results report ATR activation, p53 activation and p21 accumulation in NAFLD hepatocytes; antioxidant treatment reduced ATR activation and restored a normal ploidy profile. The Discussion links oxidative stress to an ATR/p53/p21-controlled checkpoint but says the precise mechanism connecting genomic stress to pathological polyploidy remains to be established. The claim extends this NAFLD finding to injured livers generally and states the signaling pathway more definitively than the paper does. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Normal ploidies observed among adult mouse hepatocytes are diploid (2n), tetraploid (4n) and octaploid (8n); and 4n and 8n hepatocytes often have two nuclei (bi-nucleated).

“Normal ploidies observed among adult mouse hepatocytes are diploid (2n), tetraploid (4n) and octaploid (8n); and 4n and 8n hepatocytes often have two nuclei (bi-nucleated).28”

• cites [28] Morales-Navarrete H. Segovia-Miranda F. Klukowski P. Meyer K. Nonaka H. Marsico G. A versatile pipeline for the multi-scale digital reconstruction and quantitative analysis of 3D tissue architecture Elife 4 2015 PMC4764584 26673893 sourceSupported

May combine two claims.

In uninjured mouse livers, 2n mononuclear diploid and 2x2n binuclear tetraploid hepatocytes are more frequent in zone 1 and zone 3, while 2x4n binuclear octaploid hepatocytes are more frequent in zone 2, with 4n mononuclear hepatocytes distributed evenly across the lobule.

“In uninjured mouse livers, there is some correlation between hepatocyte size and ploidy and their location within the lobule. 2n mononuclear diploid and 2x2n binuclear tetraploid hepatocytes are more frequent in zone 1 and zone 3, while 2x4n binuclear octaploid hepatocytes are more frequent in zone 2, with 4n mononuclear hepatocytes distributed evenly across the lobule.28”

• cites [28] Morales-Navarrete H. Segovia-Miranda F. Klukowski P. Meyer K. Nonaka H. Marsico G. A versatile pipeline for the multi-scale digital reconstruction and quantitative analysis of 3D tissue architecture Elife 4 2015 PMC4764584 26673893 sourceSupported

May combine two claims.

HIF1α promotes glycolysis and HIF2α suppresses gluconeogenesis in pericentral hepatocytes.

“For example, HIF1α promotes glycolysis and HIF2α suppresses gluconeogenesis in pericentral hepatocytes.41”

• cites [41] Kietzmann T. Metabolic zonation of the liver: the oxygen gradient revisited Redox Biol 11 2017 622 630 28126520 PMC5257182 sourcePartly supported

  The “Hypoxia-inducible transcription factors (HIFs)” section (page unavailable) says HIFα proteins are more abundant in the perivenous zone and that deleting their shared ARNT subunit increases gluconeogenesis. The “Hypoxia, HIFs, and hedgehog signaling” section links HIF-1α to glycolysis during a liver-injury response, but describes a stellate-cell-to-myofibroblast transition, not pericentral hepatocytes. The copy does not establish that HIF-2α specifically suppresses gluconeogenesis in those hepatocytes. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Indirect regulation of hepatocyte identity is mediated by competition of HNF4α and β-catenin for binding to TCF. Without nuclear β-catenin, the HNF4α/TCF complex promotes periportal gene expression, whereas nuclear translocation of β-catenin forms a β-catenin/TCF complex that favours pericentral gene expression.

“This indirect regulation of hepatocyte identity is mediated by the competition of HNF4α and β-catenin for binding to TCF. Without nuclear β-catenin, the HNF4α/TCF complex promotes periportal gene expression, whereas nuclear translocation of β-catenin forms a β-catenin/TCF complex that favours pericentral gene expression.52”

• cites [52] Gougelet A. Torre C. Veber P. Sartor C. Bachelot L. Denechaud P.D. T-cell factor 4 and beta-catenin chromatin occupancies pattern zonal liver metabolism in mice Hepatology 59 2014 2344 2357 24214913 sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

A single-nucleus RNA sequencing study found differences between 2n and 4n hepatocytes with regards to their expression of genes associated with metabolism, which shows crosstalk with the hepatocyte's position within the lobule.

“Recently, a single-nucleus RNA sequencing study found differences between 2n and 4n hepatocytes with regards to their expression of genes associated with metabolism, which shows crosstalk with the hepatocyte’s position within the lobule.40”

• cites [40] Richter M.L. Deligiannis I.K. Yin K. Danese A. Lleshi E. Coupland P. Single-nucleus RNA-seq2 reveals functional crosstalk between liver zonation and ploidy Nat Commun 12 2021 4264 34253736 PMC8275628 sourceSupported

May combine two claims.

Periportal Hedgehog signalling contributes to defining hepatocyte identity and metabolic zonation by partially counteracting WNT/β-catenin signalling and regulating glucose homeostasis.

“In addition, periportal Hedgehog signalling contributes to defining hepatocyte identity and metabolic zonation by partially counteracting WNT/β-catenin signalling and regulating glucose homeostasis.53”

• cites [53] Matz-Soja M. Aleithe S. Marbach E. Bottger J. Arnold K. Schmidt-Heck W. Hepatic Hedgehog signaling contributes to the regulation of IGF1 and IGFBP1 serum levels Cell Commun Signal 12 2014 11 24548465 PMC3946028 sourcePartly supported

  The Discussion (page unavailable) says Hedgehog disruption appeared to affect liver zonation and that the findings indicate an effect on WNT/β-catenin signalling. It also reports an influence on glucose homeostasis through the IGF axis. It does not establish that the signalling is periportal, defines hepatocyte identity, or counteracts WNT/β-catenin; the zonation finding is more tentative than the citing sentence suggests. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

Activation of WNT/β-catenin signalling reprogrammed periportal into pericentral hepatocytes, while pathway blockage induced widespread periportal metabolic enzyme expression.

“While activation of WNT/β-catenin signalling reprogrammed periportal into pericentral hepatocytes, pathway blockage induced widespread periportal metabolic enzyme expression.22,42,44,45,51”

• cites [22] Sun T. Annunziato S. Bergling S. Sheng C. Orsini V. Forcella P. ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation Cell Stem Cell 28 2021 1822 1837 e1810 34129813 sourceNot checked — no full text of the source
• cites [42] Benhamouche S. Decaens T. Godard C. Chambrey R. Rickman D.S. Moinard C. Apc tumor suppressor gene is the "zonation-keeper" of mouse liver Dev Cell 10 2006 759 770 16740478 sourceNot checked — no full text of the source
• cites [44] Planas-Paz L. Orsini V. Boulter L. Calabrese D. Pikiolek M. Nigsch F. The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size Nat Cell Biol 18 2016 467 479 27088858 sourcePartly supported

  The results section (page unavailable) reports that RSPO1 expanded WNT/β-catenin signalling into periportal hepatocytes and increased the pericentral markers GS and CYP2E1, but does not establish that those cells were fully reprogrammed. Another results passage reports increased periportal metabolic genes after β-catenin knockout or DKK1 overexpression, but says they were not increased after LGR4/5 deletion. Thus the effect of pathway blockage depends on how it was blocked, and the copy does not establish widespread periportal enzyme expression for blockage generally. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Knocking CreERT2 into the endogenous Axin2 locus increases proliferation of hepatocytes due to heterozygous Axin2 deletion.

“Instead, EdU incorporation suggested that knocking CreERT2 into the endogenous Axin2 locus increases proliferation of hepatocytes due to heterozygous Axin2 deletion.86”

• cites [86] Wei Y. Wang Y.G. Jia Y. Li L. Yoon J. Zhang S. Liver homeostasis is maintained by midlobular zone 2 hepatocytes Science 2021 371 PMC8496420 33632817 sourcePartly supported

  In “Zone 3 cells near the CV do not repopulate during normal homeostasis” (page unavailable), EdU labeling shows that Axin2-CreER mice had the highest relative proliferation rate in zone 3, unlike the comparison strains. The passage does not establish that hepatocyte proliferation increased overall or that heterozygous Axin2 deletion caused the difference. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Zone 2 hepatocytes expand during homeostasis, with a corresponding contraction of the areas originally occupied by zone 1 or 3 hepatocytes.

“A comprehensive study using several new mouse transgenic lines to label different portions of the lobule also demonstrated that zone 2 hepatocytes expand during homeostasis, with a corresponding contraction of the areas originally occupied by zone 1 or 3 hepatocytes.86”

• cites [86] Wei Y. Wang Y.G. Jia Y. Li L. Yoon J. Zhang S. Liver homeostasis is maintained by midlobular zone 2 hepatocytes Science 2021 371 PMC8496420 33632817 sourceSupported

May combine two claims.

Dnmt1 deletion was accompanied by liver fibrosis and inflammation, and a reduced hepatocyte proliferative capacity in response to injury.

“This was accompanied by liver fibrosis and inflammation, and a reduced hepatocyte proliferative capacity in response to injury.”

• cites [96] Kaji K. Factor V.M. Andersen J.B. Durkin M.E. Tomokuni A. JU Marquardt DNMT1 is a required genomic regulator for murine liver histogenesis and regeneration Hepatology 64 2016 582 598 26999257 PMC5841553 sourceSupported

May combine two claims.

The hepatostat is set such that the liver regenerates back to 100% of what is required for homeostasis, unlike other solid organs with more limited regenerative potential.

“This is necessary to adapt the size of the liver and number of hepatocytes to the body`s needs, and the “hepatostat” is set such that the liver regenerates back to 100% of what is required for homeostasis, unlike other solid organs with more limited regenerative potential.73,74”

• cites [73] Michalopoulos G.K. Hepatostat: liver regeneration and normal liver tissue maintenance Hepatology 65 2017 1384 1392 27997988 sourceSupported
• cites [74] Michalopoulos G.K. Bhushan B. Liver regeneration: biological and pathological mechanisms and implications Nat Rev Gastroenterol Hepatol 18 2021 40 55 32764740 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Whether specialised liver stem cells maintain hepatocyte numbers during homeostasis remains controversial.

“Whether specialised liver stem cells maintain hepatocyte numbers during homeostasis remains controversial.13,77”

• cites [13] Sun T. Annunziato S. Tchorz J.S. Prometheus revisited: liver homeostasis and repair Aging (Albany NY) 12 2020 4685 4687 32205468 PMC7138553 sourceSupported
• cites [77] Monga S.P. No zones left behind: democratic hepatocytes contribute to liver homeostasis and repair Cell Stem Cell 26 2020 2 3 31951586 sourceCould not verify

  The only passage retrieved from our copy is the title and publication metadata; it does not address whether specialised liver stem cells maintain hepatocyte numbers or whether that question is controversial. Searches for stem cells, homeostasis, hepatocytes, and related terms found no substantive passage. (LLM, conf=0.70)

  Experimental — accuracy not yet measured

May combine two claims.

Sparsely labelled hepatocytes, marked by novel Cre-expressing transgenes from the Hamp2 and Mup3 promoters, also expanded during homeostasis, demonstrating that proliferation is not limited to the high telomerase-expressing population.

“Additionally, sparsely labelled hepatocytes, marked by novel Cre-expressing transgenes from the Hamp2 and Mup3 promoters, also expanded during homeostasis, demonstrating that proliferation is not limited to the high telomerase-expressing population.86”

• cites [86] Wei Y. Wang Y.G. Jia Y. Li L. Yoon J. Zhang S. Liver homeostasis is maintained by midlobular zone 2 hepatocytes Science 2021 371 PMC8496420 33632817 sourcePartly supported

  The sections on Hamp2-positive clones and Mup3-CreER tracing report that sparsely labeled hepatocyte clones expanded during homeostasis. However, the section on hepatocytes marked in other ways says Tert-positive cells may overlap with the Hamp2 and Mup3 populations, so these results do not establish that proliferation occurs outside the high-telomerase-expressing population. Page numbers were not available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Periportal hepatocytes do not expand towards zone 3 under homeostatic conditions, and may reduce over time.

“Alternative methods based on tracing of periportal hepatocytes showed that periportal hepatocytes do not expand towards zone 360 under homeostatic conditions, and may reduce over time.84”

• cites [60] Font-Burgada J. Shalapour S. Ramaswamy S. Hsueh B. Rossell D. Umemura A. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer Cell 162 2015 766 779 26276631 PMC4545590 sourcePartly supported

  The Results section reports that uninjured littermates did not show expansion of hybrid periportal hepatocytes, supporting the claim that they do not expand toward zone 3 under homeostatic conditions. It does not support a reduction over time: the same section says GFP-positive periportal hepatocytes were stable throughout life and YFP-positive cells remained stable for at least nine months. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [84] Pu W. Zhang H. Huang X. Tian X. He L. Wang Y. Mfsd2a+ hepatocytes repopulate the liver during injury and regeneration Nat Commun 7 2016 13369 PMC5120209 27857132 sourceSupported

May combine two claims.

Activated YAP signalling reversibly increased liver size, but its deletion did not affect liver size during homeostasis.

“While activated YAP signalling reversibly increased liver size,93 its deletion did not affect liver size during homeostasis.57,58,94”

• cites [93] Camargo F.D. Gokhale S. Johnnidis J.B. Fu D. Bell G.W. Jaenisch R. YAP1 increases organ size and expands undifferentiated progenitor cells Curr Biol 17 2007 2054 2060 17980593 sourceNot checked — no full text of the source
• cites [57] Planas-Paz L. Sun T. Pikiolek M. Cochran N.R. Bergling S. Orsini V. YAP, but not RSPO-LGR4/5, signaling in biliary epithelial cells promotes a ductular reaction in response to liver injury Cell Stem Cell 25 2019 39 53 e10 31080135 sourceCould not verify

  Citation 94 is attached to the claim that YAP deletion did not affect liver size during homeostasis. The Results describe naive YapDEL mice as having comparable bilirubin levels to controls and no significant hepatocyte damage, but do not report liver size in those mice. Searches for liver size, liver weight, and liver-to-body-weight ratio did not locate a measurement that settles the claim. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [58] Verboven E. Moya I.M. Sansores-Garcia L. Xie J. Hillen H. Kowalczyk W. Regeneration defects in yap and taz mutant mouse livers are caused by bile duct disruption and cholestasis Gastroenterology 160 2021 847 862 33127392 sourceSupported

May combine two claims.

RSPO injections reversibly increased liver size by inducing hepatocyte proliferation, whereas WNT/β-catenin signalling blockade resulted in smaller livers.

“RSPO injections reversibly increased liver size by inducing hepatocyte proliferation, whereas WNT/β-catenin signalling blockade resulted in smaller livers.44,90,91”

• cites [44] Planas-Paz L. Orsini V. Boulter L. Calabrese D. Pikiolek M. Nigsch F. The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size Nat Cell Biol 18 2016 467 479 27088858 sourceSupported
• cites [90] Annunziato S. Sun T. Tchorz J.S. The RSPO-LGR4/5-ZNRF3/RNF43 module in liver homeostasis, regeneration, and disease Hepatology 76 2022 888 899 35006616 sourceNot checked — no full text of the source
• cites [91] Russell J.O. Monga S.P. Wnt/beta-Catenin signaling in liver development, homeostasis, and pathobiology Annu Rev Pathol 13 2018 351 378 29125798 PMC5927358 sourcePartly supported

  The 'Wnt/β-Catenin Signaling in Hepatocytes' section (page unavailable) reports significantly reduced liver weight in mice lacking hepatocyte LGR4/LGR5 or Wnt coreceptors, supporting the smaller-liver part. Our copy does not report that RSPO injections reversibly increased liver size through hepatocyte proliferation; its reported proliferation-related increase followed liver-specific β-catenin overexpression instead. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Hepatocytes do not proliferate equally over time, as results obtained via three independent experimental approaches have led to the same conclusion, namely that zone 2 hepatocytes proliferate more than hepatocytes from the other zones.

“Nevertheless, hepatocytes do not proliferate equally over time, as results obtained via three independent experimental approaches have led to the same conclusion, namely that zone 2 hepatocytes proliferate more than hepatocytes from the other zones.75,86,88”

• cites [75] He L. Pu W. Liu X. Zhang Z. Han M. Li Y. Proliferation tracing reveals regional hepatocyte generation in liver homeostasis and repair Science 2021 371 33632818 sourceNot checked — no full text of the source
• cites [86] Wei Y. Wang Y.G. Jia Y. Li L. Yoon J. Zhang S. Liver homeostasis is maintained by midlobular zone 2 hepatocytes Science 2021 371 PMC8496420 33632817 sourceSupported
• cites [88] Chen F. Jimenez R.J. Sharma K. Luu H.Y. Hsu B.Y. Ravindranathan A. Broad distribution of hepatocyte proliferation in liver homeostasis and regeneration Cell Stem Cell 26 2020 27 33 e24 31866223 PMC8009755 sourcePartly supported

  The Discussion (page unavailable) reports proliferation throughout the normal liver lobule, with a slight predominance in the midlobular zone, supporting the zone 2 comparison in that setting. It does not establish that three independent experimental approaches reached that conclusion, and the Results (page unavailable) report uniform proliferation across zones after repeated CCl4 injury. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Hepatocyte renewal is not driven by zone 3, no hepatocytes formed particularly large clones, and hepatocyte proliferation was distributed throughout the lobule with larger hepatocyte clones more frequently found in zone 2.

“3D imaging of labelled cells and their progeny showed that hepatocyte renewal is not driven by zone 3, no hepatocytes formed particularly large clones, and hepatocyte proliferation was distributed throughout the lobule with larger hepatocyte clones more frequently found in zone 2.88”

• cites [88] Chen F. Jimenez R.J. Sharma K. Luu H.Y. Hsu B.Y. Ravindranathan A. Broad distribution of hepatocyte proliferation in liver homeostasis and regeneration Cell Stem Cell 26 2020 27 33 e24 31866223 PMC8009755 sourceSupported

May combine two claims.

ZNRF3 and RNF43 cooperate to restrict WNT/β-catenin signalling during homeostasis to prevent uncontrolled proliferation and tumour formation, while enabling metabolic zonation.

“ZNRF3 and RNF43 cooperate to restrict WNT/β-catenin signalling during homeostasis to prevent uncontrolled proliferation and tumour formation, while enabling metabolic zonation.22,92”

• cites [22] Sun T. Annunziato S. Bergling S. Sheng C. Orsini V. Forcella P. ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation Cell Stem Cell 28 2021 1822 1837 e1810 34129813 sourceNot checked — no full text of the source
• cites [92] Belenguer G. Mastrogiovanni G. Pacini C. Hall Z. Dowbaj A.M. Arnes-Benito R. RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state Nat Commun 13 2022 334 35039505 PMC8764073 sourcePartly supported

  The Introduction identifies RNF43 and ZNRF3 as negative regulators of WNT signalling, and the Results and Discussion link their loss to increased hepatocyte proliferation and disrupted lipid zonation. The claim overstates the homeostasis finding: the Discussion reports progression to liver cancer following chronic injury, not tumour formation during homeostasis, and describes metabolic and regeneration defects alongside increased WNT sensitivity. Page numbers are not provided in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Hepatocytes display remarkable plasticity and under some conditions can transdifferentiate into BECs.

“Hepatocytes display remarkable plasticity and under some conditions can transdifferentiate into BECs, epithelial cells of the bile ducts with completely different morphology, gene expression and function59,[97], [98], [99]”

• cites [59] Yimlamai D. Christodoulou C. Galli G.G. Yanger K. Pepe-Mooney B. Gurung B. Hippo pathway activity influences liver cell fate Cell 157 2014 1324 1338 24906150 PMC4136468 sourceSupported
• cites [97] Michalopoulos G.K. Barua L. Bowen W.C. Transdifferentiation of rat hepatocytes into biliary cells after bile duct ligation and toxic biliary injury Hepatology 41 2005 535 544 15726663 PMC1821079 sourceSupported
• cites [98] Schaub J.R. Huppert K.A. Kurial S.N.T. Hsu B.Y. Cast A.E. Donnelly B. De novo formation of the biliary system by TGFbeta-mediated hepatocyte transdifferentiation Nature 557 2018 247 251 29720662 PMC6597492 sourceSupported

May combine two claims.

Dnmt1 deletion was accompanied by loss of the perivenous enzyme CYP2E1, causing unresponsiveness to CCl4.

“Intriguingly, deletion of Dnmt1 was accompanied by the loss of the perivenous enzyme cytochrome CYP2E1, which is responsible for the bioactivation of carbon tetrachloride (CCl4), thus causing unresponsiveness to this drug.96”

• cites [96] Kaji K. Factor V.M. Andersen J.B. Durkin M.E. Tomokuni A. JU Marquardt DNMT1 is a required genomic regulator for murine liver histogenesis and regeneration Hepatology 64 2016 582 598 26999257 PMC5841553 sourcePartly supported

  The Results section (“Differentiation Defects in Postnatal Hepatocytes Caused by Dnmt1 Deletion”; page not provided) reports that Dnmt1-deleted mice resisted CCl4 liver injury during their first eight postnatal weeks, alongside strong repression of CYP2E1, the major enzyme responsible for CCl4 bioactivation. It describes the findings as coincident, not as proof that CYP2E1 loss caused complete unresponsiveness; the claim also omits the age limit. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Deletion of Dnmt1 in postnatal hepatocytes using Alb-Cre transgenic mice caused global hypomethylation, enhanced the DNA damage response, and induced a senescent state.

“deletion of Dnmt1 in postnatal hepatocytes using Alb-Cre transgenic mice caused global hypomethylation, enhanced the DNA damage response, and induced a senescent state.”

• cites [96] Kaji K. Factor V.M. Andersen J.B. Durkin M.E. Tomokuni A. JU Marquardt DNMT1 is a required genomic regulator for murine liver histogenesis and regeneration Hepatology 64 2016 582 598 26999257 PMC5841553 sourceSupported

May combine two claims.

Not all hepatocytes transdifferentiate with the same capacity; zone 1 periportal hepatocytes transdifferentiated readily to BECs, but even with NOTCH activation, zone 3 hepatocytes did not transdifferentiate.

“Curiously, not all hepatocytes transdifferentiate with the same capacity; zone 1 periportal hepatocytes transdifferentiated readily to BECs, but even with activation of NOTCH signalling, which is a strong inducer of biliary fate in hepatocytes, zone 3 hepatocytes did not transdifferentiate.99”

• cites [99] Yanger K. Zong Y. Maggs L.R. Shapira S.N. Maddipati R. Aiello N.M. Robust cellular reprogramming occurs spontaneously during liver regeneration Genes Dev 27 2013 719 724 23520387 PMC3639413 sourceSupported

May combine two claims.

Reprogrammed zone 1 hepatocytes exhibited reduced metabolic function, upregulated tissue stem cell markers and increased proliferative capacity, contributing to regeneration.

“These reprogrammed zone 1 hepatocytes exhibited reduced metabolic function, upregulated tissue stem cell markers and increased proliferative capacity, contributing to regeneration.59,60,100,101”

• cites [59] Yimlamai D. Christodoulou C. Galli G.G. Yanger K. Pepe-Mooney B. Gurung B. Hippo pathway activity influences liver cell fate Cell 157 2014 1324 1338 24906150 PMC4136468 sourcePartly supported

  The Results sections on the liver progenitor cell program and single-hepatocyte de-differentiation report loss of hepatocyte-specific gene expression, acquisition of progenitor markers, and proliferation after YAP activation (page numbers unavailable). The paper does not identify the reprogrammed cells specifically as zone 1 hepatocytes or demonstrate reduced metabolic function. Its Discussion describes a possible role in liver repair, rather than showing that these cells contributed to regeneration. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [60] Font-Burgada J. Shalapour S. Ramaswamy S. Hsueh B. Rossell D. Umemura A. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer Cell 162 2015 766 779 26276631 PMC4545590 sourcePartly supported

  The Results ('HybHP Exhibit a Unique Transcriptome') report lower expression of oxidative drug-metabolism genes and expression of ductal markers including Sox9 and Opn. The Discussion reports that these periportal hepatocytes proliferate to restore liver mass after chronic injury. But the paper describes them as a pre-existing population in healthy liver, not hepatocytes reprogrammed during regeneration; it also does not establish a general reduction in metabolic function or characterize the ductal markers as upregulated tissue stem-cell markers. Page numbers were not available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [100] Tarlow B.D. Pelz C. Naugler W.E. Wakefield L. Wilson E.M. Finegold M.J. Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes Cell Stem Cell 15 2014 605 618 25312494 PMC4254170 sourceNot checked — no full text of the source

May combine two claims.

Following partial hepatectomy, a subset of hepatocytes transiently acquired an early-postnatal-like gene expression programme to proliferate, while other hepatocytes became metabolically hyperactive to compensate for temporary deficits in liver function.

“Following partial hepatectomy, a subset of hepatocytes transiently acquired an early-postnatal-like gene expression programme to proliferate, while other hepatocytes became metabolically hyperactive to compensate for any temporary deficits in liver function.106”

• cites [106] Chembazhi U.V. Bangru S. Hernaez M. Kalsotra A. Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver Genome Res 31 2021 576 591 33649154 PMC8015853 sourceSupported

May combine two claims.

Some hepatocytes retained chromatin landscapes and transcriptomics of metabolically active uninjured hepatocytes, while others showed changing chromatin and expression signatures suggesting transient fetal reprogramming.

“Interestingly, some hepatocytes retained chromatin landscapes and transcriptomics of metabolically active uninjured hepatocytes, while others showed changing chromatin and expression signatures suggesting transient fetal reprogramming.107”

• cites [107] Chen T. Oh S. Gregory S. Shen X. Diehl A.M. Single-cell omics analysis reveals functional diversification of hepatocytes during liver regeneration JCI Insight 5 2020 PMC7710279 33208554 sourceSupported

May combine two claims.

MET or EGFR signalling alone can compensate for one another, but blocking both results in deficient liver regeneration and animal death after partial hepatectomy.

“While MET or EGFR signalling alone can compensate for one another, blocking both signalling pathways results in deficient liver regeneration, with respect to original liver mass, and animal death after partial hepatectomy.[127], [128], [129]”

• cites [127] Tsagianni A. Mars W.M. Bhushan B. Bowen W.C. Orr A. Stoops J. Combined systemic disruption of MET and epidermal growth factor receptor signaling causes liver failure in normal mice Am J Pathol 188 2018 2223 2235 30031724 PMC6168971 sourcePartly supported

  The paper's opening summary reports that combined MET and EGFR inhibition abolished regeneration after hepatectomy and led to liver failure and death 15–18 days later. Its Results show that mice with either pathway disrupted alone maintained liver/body weight ratios in the resting-liver experiment, but do not establish that the pathways compensate for one another during regeneration after hepatectomy or address recovery of the original liver mass. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [128] Lopez-Luque J. Caballero-Diaz D. Martinez-Palacian A. Roncero C. Moreno-Caceres J. Garcia-Bravo M. Dissecting the role of epidermal growth factor receptor catalytic activity during liver regeneration and hepatocarcinogenesis Hepatology 63 2016 604 619 26313466 sourcePartly supported

  The Discussion (page not provided) reports that mice with impaired EGFR signaling recovered liver mass after partial hepatectomy and had increased c-Met activation, suggesting partial compensation. It does not report the reverse compensation or test whether blocking both pathways causes deficient regeneration and death; it also says some EGFR functions are not compensated by c-Met. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [129] Paranjpe S. Bowen W.C. Mars W.M. Orr A. Haynes M.M. DeFrances M.C. Combined systemic elimination of MET and epidermal growth factor receptor signaling completely abolishes liver regeneration and leads to liver decompensation Hepatology 64 2016 1711 1724 27397846 PMC5074871 sourceSupported

May combine two claims.

Several studies suggest that hepatocyte proliferation leads to metabolic remodelling and that hepatocytes across the liver can adapt dynamically to changes during regeneration.

“Several studies suggest that hepatocyte proliferation leads to metabolic remodelling and that hepatocytes across the liver can adapt dynamically to changes during regeneration106,107,[131], [132], [133], [134], [135]”

• cites [106] Chembazhi U.V. Bangru S. Hernaez M. Kalsotra A. Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver Genome Res 31 2021 576 591 33649154 PMC8015853 sourcePartly supported

  The Results (Cell type composition, heterogeneity, and metabolic dynamics) describe transient changes in metabolic pathways alongside increased proliferation-related activity after partial hepatectomy. The Discussion describes dynamic hepatocyte states in different liver regions. The paper does not establish that proliferation itself causes the metabolic remodelling; it presents both as coordinated responses during regeneration. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [107] Chen T. Oh S. Gregory S. Shen X. Diehl A.M. Single-cell omics analysis reveals functional diversification of hepatocytes during liver regeneration JCI Insight 5 2020 PMC7710279 33208554 sourcePartly supported

  The Results section reports changes in hepatocyte-specific gene expression when proliferation was maximal, and the Discussion describes dynamic changes in hepatocyte states during regeneration. But the paper does not establish that proliferation causes metabolic remodelling: it describes heterogeneous responses, with some hepatocytes retaining metabolic functions while others change state to become more proliferative. The findings concern regenerating mouse liver after partial hepatectomy. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [131] Bangru S. Arif W. Seimetz J. Bhate A. Chen J. Rashan E.H. Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote liver regeneration Nat Struct Mol Biol 25 2018 928 939 30250226 PMC6173981 sourcePartly supported

  The Results section, “Regenerating hepatocytes reactivate neonatal gene expression patterns” (page not provided), reports increased proliferation and reduced expression of transcripts associated with metabolic processes in toxin-injured mouse hepatocytes. It describes these changes as responses to injury, not evidence that proliferation causes metabolic remodelling. The cited passages also do not establish that hepatocytes across the liver adapt dynamically. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

May combine two claims.

When hepatocyte-mediated regeneration is impaired, following chronic injury and induction of hepatocyte senescence, BECs can transdifferentiate into zone 1 hepatocytes which subsequently proliferate and repopulate other lobular zones.

“When hepatocyte-mediated regeneration is impaired, following chronic injury and induction of hepatocyte senescence, BECs can transdifferentiate into zone 1 hepatocytes which subsequentially proliferate and repopulate other lobular zones[112], [113], [114], [115], [116], [117], [118]”

• cites [112] Pu W. Zhu H. Zhang M. Pikiolek M. Ercan C. Li J. Bipotent transitional liver progenitor cells contribute to liver regeneration Nat Genet 2023 PMC10101857 36914834 sourcePartly supported

  The Main section states that, when hepatocytes become senescent and hepatocyte-mediated regeneration is impaired in mice, BECs can become replication-competent hepatocytes. Results (“Generation of a model for BEC-to-hepatocyte conversion”; page unavailable) place BEC-derived hepatocyte clones near portal veins, but do not show that they subsequently proliferate and repopulate other lobular zones. The zone-to-zone repopulation part is therefore unsupported by this paper. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [113] Deng X. Zhang X. Li W. Feng R.X. Li L. Yi G.R. Chronic liver injury induces conversion of biliary epithelial cells into hepatocytes Cell Stem Cell 23 2018 114 122.e113 29937200 sourceNot checked — no full text of the source
• cites [114] Espanol-Suner R. Carpentier R. Van Hul N. Legry V. Achouri Y. Cordi S. Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice Gastroenterology 143 2012 1564 1575.e1567 22922013 sourcePartly supported

  The Discussion (page unavailable) reports that LPC and biliary-cell precursors produced a small proportion of hepatocytes after CDE-induced chronic injury. The section “LPC-Derived Hepatocytes Are Fully Differentiated” (page unavailable) locates those cells in zones 1 and 2 and shows that they proliferated after partial hepatectomy. Our copy does not establish that hepatocyte senescence triggered this process or that the new hepatocytes subsequently proliferated to repopulate other lobular zones. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

During two distinct phases of regeneration, macrophage-derived WNT ligands were required for functional compensation and induction of metabolic gene expression, whereas endothelium-derived WNT ligands were more important for inducing hepatocyte proliferation.

“During two distinct phases of regeneration, macrophage-derived WNT ligands were required for functional compensation and induction of metabolic gene expression, whereas endothelium-derived WNT ligands were more important for inducing hepatocyte proliferation.134”

• cites [134] Walesky C.M. Kolb K.E. Winston C.L. Henderson J. Kruft B. Fleming I. Functional compensation precedes recovery of tissue mass following acute liver injury Nat Commun 11 2020 5785 33214549 PMC7677389 sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

New hepatocytes from BEC transdifferentiation are reported to persist long-term and through chronic injury.

“and the new hepatocytes are reported to persist long-term and through chronic injury.113,119”

• cites [113] Deng X. Zhang X. Li W. Feng R.X. Li L. Yi G.R. Chronic liver injury induces conversion of biliary epithelial cells into hepatocytes Cell Stem Cell 23 2018 114 122.e113 29937200 sourceNot checked — no full text of the source
• cites [119] Lu W.Y. Bird T.G. Boulter L. Tsuchiya A. Cole A.M. Hay T. Hepatic progenitor cells of biliary origin with liver repopulation capacity Nat Cell Biol 17 2015 971 983 26192438 PMC4612439 sourceSupported

May combine two claims.

Many CYP450 enzymes responsible for metabolising drugs and xenobiotics are expressed in pericentral hepatocytes, so associated toxic metabolites predominantly damage hepatocytes in this zone.

“Many of the CYP450 enzymes, which are responsible for metabolising drugs and xenobiotics, are expressed in pericentral hepatocytes. Associated toxic metabolites therefore predominantly damage hepatocytes in this zone.147”

• cites [147] Zanger U.M. Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation Pharmacol Ther 138 2013 103 141 23333322 sourcePartly supported

  The Introduction states that CYP enzymes metabolize most drugs and other xenobiotics, and section 4.5.2 links CYP2E1 activity to liver-cell damage. Neither passage establishes that these enzymes are concentrated in pericentral hepatocytes or that toxic metabolites predominantly damage that zone. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Zone 2 hepatocytes traced by Igfbp2-CreER proliferate more during regeneration after partial hepatectomy and during pregnancy, can replace zone 3 and 1 hepatocytes after CCl4- or DDC-induced injury, and their proliferation is nutritionally regulated.

“A recent study shows that zone 2 hepatocytes traced by Igfbp2-CreER proliferate more during regeneration after partial hepatectomy and during pregnancy. Additionally, they can replace zone 3 and 1 hepatocytes after CCl4- or DDC-induced injury, and their proliferation is nutritionally regulated136”

• cites [136] Lin Y.-H. Wei Y. Wang Y. Pagani C.A. Li L. Zhu M. IGFBP2 expressing midlobular hepatocytes preferentially contribute to liver homeostasis and regeneration bioRxiv 2022 2022.2010.2012.511675 PMC10580294 37146585 sourcePartly supported

  Split into 3 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

Activating mutations in the WNT/β-catenin pathway are frequently found in liver tumours, and hepatocytes with high WNT/β-catenin activity are highly susceptible to malignant transformation in experimental tumour models.

“Activating mutations in the WNT/β-catenin pathway are frequently found in liver tumours and hepatocytes with high WNT/β-catenin activity are highly susceptible to malignant transformation in experimental tumour models.50,90,91,85”

• cites [50] Ang C.H. Hsu S.H. Guo F. Tan C.T. Yu V.C. Visvader J.E. Lgr5(+) pericentral hepatocytes are self-maintained in normal liver regeneration and susceptible to hepatocarcinogenesis Proc Natl Acad Sci U S A 116 2019 19530 19540 31488716 PMC6765306 sourcePartly supported

  The Discussion reports constitutive WNT-pathway activation in approximately 50% of HCC patients. The Results and Discussion show that Lgr5+ pericentral hepatocytes, which express WNT target genes, are highly susceptible to transformation in the DEN and Neu/Her2 mouse models. The paper does not establish that hepatocytes with high WNT/β-catenin activity generally share that susceptibility; the tested population was the narrower Lgr5+ subset. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [90] Annunziato S. Sun T. Tchorz J.S. The RSPO-LGR4/5-ZNRF3/RNF43 module in liver homeostasis, regeneration, and disease Hepatology 76 2022 888 899 35006616 sourceNot checked — no full text of the source
• cites [91] Russell J.O. Monga S.P. Wnt/beta-Catenin signaling in liver development, homeostasis, and pathobiology Annu Rev Pathol 13 2018 351 378 29125798 PMC5927358 sourcePartly supported

  The “Wnt/β-catenin signaling in liver tumors” discussion reports β-catenin activation in 20–35% of hepatocellular carcinomas and says mice with activated signaling are more susceptible to DEN-induced liver cancer. It does not establish that high-activity hepatocytes are generally *highly* susceptible to malignant transformation: β-catenin activation alone did not produce spontaneous liver cancer in the mouse models described. No page number is supplied in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

Treatment with RSPO ligands or tetravalent FZD-LRP antibodies enhanced WNT/β-catenin signalling, accelerated liver regeneration and increased metabolic function in diverse injury models.

“Treatment with RSPO ligands44,158 or tetravalent FZD-LRP antibodies25 enhanced WNT/β-catenin signalling, accelerated liver regeneration and increased metabolic function in diverse injury models.”

• cites [44] Planas-Paz L. Orsini V. Boulter L. Calabrese D. Pikiolek M. Nigsch F. The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size Nat Cell Biol 18 2016 467 479 27088858 sourcePartly supported

  The RSPO1-treatment passages report increased hepatic WNT/β-catenin signalling and faster liver regrowth after partial hepatectomy. They also report changes in metabolic-zonation markers, but not improved metabolic function; the treatment experiment uses one regeneration model, not diverse injury models. The tetravalent-antibody claim is attached to a different citation in the citing sentence. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [158] Zhang Z. Broderick C. Nishimoto M. Yamaguchi T. Lee S.J. Zhang H. Tissue-targeted R-spondin mimetics for liver regeneration Sci Rep 10 2020 13951 PMC7435267 32811902 sourcePartly supported

  The Results section (“Liver-targeted RSPO mimetics improves liver function in diseased mouse models”; page unavailable) reports increased Wnt-target gene expression, a proliferation marker, and faster recovery of a liver-function measure after RSPO treatment. It also reports increased expression of metabolic enzymes, but only suggests a potential metabolic benefit. The experiments use a chronic thioacetamide injury model, not diverse injury models, and do not directly demonstrate accelerated liver regeneration. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [25] Hu S. Liu S. Bian Y. Poddar M. Singh S. Cao C. Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b Cell Rep Med 3 2022 100754 PMC9588996 36220068 sourcePartly supported

  The Results (pages not provided) show that the tetravalent FZD-LRP6 antibody FL6.13 activated WNT/β-catenin signalling, rescued delayed regeneration after partial hepatectomy in Wnt-deficient mice, and promoted repair when given late after APAP injury. They report restoration of metabolic-zonation markers, while the Discussion says metabolic function was maintained—not increased. The APAP Results also report worse injury when FL6.13 was given early, so the benefit depends on treatment timing. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Alcohol and paracetamol damage pericentral hepatocytes and are responsible for the majority of fatal acute liver injury cases.

“Examples include alcohol148 and paracetamol,149 which damage pericentral hepatocytes and are responsible for the majority of fatal acute liver injury cases.”

• cites [148] Massey V.L. Arteel G.E. Acute alcohol-induced liver injury Front Physiol 3 2012 193 22701432 PMC3372892 sourcePartly supported

  The Introduction identifies the liver as a major target of alcohol-induced injury, and the Summary describes how acute alcohol exposure can cause inflammatory liver damage. Neither passage specifies pericentral hepatocytes or says alcohol accounts for a majority of fatal acute liver injury cases. Citation 148 is attached to alcohol, not paracetamol. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [149] Yoon E. Babar A. Choudhary M. Kutner M. Pyrsopoulos N. Acetaminophen-induced hepatotoxicity: a comprehensive update J Clin Transl Hepatol 4 2016 131 142 27350943 PMC4913076 sourcePartly supported

  The General approach and diagnostic tools section says acetaminophen causes its greatest liver injury in zone 3, consistent with damage to pericentral hepatocytes. Epidemiology identifies it as the most common cause of acute liver failure in the United States, but estimates it accounts for approximately 48% of diagnoses; it does not establish that paracetamol accounts for a majority of fatal acute liver injury cases. The separate citation attached to alcohol is not assessed here. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Many patients with chronic liver disease are at increased risk of developing HCC or cholangiocellular carcinoma.

“Many patients with chronic liver disease are at an increased risk of developing hepatocellular carcinoma (HCC) or cholangiocellular carcinoma.159,160”

• cites [159] Deeb M. Karlsen T.H. Hirschfield G.M. The 6 C's of primary sclerosing cholangitis J Hepatol 73 2020 1255 1256 32649970 sourcePartly supported

  The CHOLANGITIS figure (pp. 1255–1256) says patients with primary sclerosing cholangitis are at increased risk of hepatocellular carcinoma and cholangiocarcinoma. The source concerns this specific chronic liver disease; it does not establish the claim for patients with chronic liver disease more broadly. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [160] Zhu C. Tabas I. Schwabe R.F. Pajvani U.B. Maladaptive regeneration - the reawakening of developmental pathways in NASH and fibrosis Nat Rev Gastroenterol Hepatol 18 2021 131 142 33051603 PMC7854502 sourcePartly supported

  The Abstract (page unavailable) states that fibrosis in patients with NAFLD–NASH increases the risk of HCC, and “Future directions — NASH-driven HCC?” reports HCC in a small percentage of patients with NAFLD. This supports the HCC-risk portion, but the paper does not establish increased risk of cholangiocellular carcinoma or make the same risk claim for patients with chronic liver disease generally. The latter cancer appears only in a reference title. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

Small hepatocytes found in retrorsine-treated rat livers and small Thy1+ hepatocytes observed in rat livers following galactosamine-induced injury have robust regenerative properties.

“An interesting but less well understood population of hepatocytes are the small hepatocytes found in retrorsine-treated rat livers[138], [139], [140] and the small Thy1+ hepatocytes observed in rat livers following galactosamine-induced injury141 (Fig. 3F). These small hepatocytes were reported to have robust regenerative properties.”

• cites [138] Gordon G.J. Coleman W.B. Hixson D.C. Grisham J.W. Liver regeneration in rats with retrorsine-induced hepatocellular injury proceeds through a novel cellular response Am J Pathol 156 2000 607 619 10666390 PMC1850042 sourceSupported
• cites [139] Best D.H. Coleman W.B. Liver regeneration by small hepatocyte-like progenitor cells after necrotic injury by carbon tetrachloride in retrorsine-exposed rats Exp Mol Pathol 89 2010 92 98 20599936 sourceNot checked — no full text of the source
• cites [140] Katayama S. Tateno C. Asahara T. Yoshizato K. Size-dependent in vivo growth potential of adult rat hepatocytes Am J Pathol 158 2001 97 105 11141483 PMC1850269 sourceSupported

May combine two claims.

HCC is more frequent in patients with zone 3 injury, such as NASH or alcohol-related liver disease, while cholangiocellular carcinoma risk is dramatically increased in patients with persistent periportal injury.

“While HCC is more frequent in patients with zone 3 injury, such as NASH or alcohol-related liver disease,160 cholangiocellular carcinoma risk is dramatically increased in patients with persistent periportal injury, e.g. in those with primary sclerosing cholangitis.159”

• cites [160] Zhu C. Tabas I. Schwabe R.F. Pajvani U.B. Maladaptive regeneration - the reawakening of developmental pathways in NASH and fibrosis Nat Rev Gastroenterol Hepatol 18 2021 131 142 33051603 PMC7854502 sourcePartly supported

  Citation 160 is attached to the HCC clause, not the subsequent cholangiocellular-carcinoma clause. In “Future directions — NASH-driven HCC?” (page unavailable), the review links NASH to HCC, but it does not establish that HCC is more frequent with zone 3 injury or address alcohol-related liver disease as another example. Searches for those terms found no supporting passage. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [159] Deeb M. Karlsen T.H. Hirschfield G.M. The 6 C's of primary sclerosing cholangitis J Hepatol 73 2020 1255 1256 32649970 sourcePartly supported

  The CHOLANGITIS figure (pp. 1255–1256) identifies cholangiocarcinoma among cancers for which patients with primary sclerosing cholangitis have increased risk, and depicts portal fibrosis. It does not establish that persistent periportal injury generally confers a dramatically increased risk. The HCC comparison is attached to a different citation in the citing sentence. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Cholestatic injury activates YAP signalling and thereby reprogrammes periportal hepatocytes, reducing the amount of metabolically active workers in this zone.

“Such cholestatic injury also activates YAP signalling and thereby reprogrammes periportal hepatocytes, reducing the amount of metabolically active workers in this zone.57,94,102”

• cites [57] Planas-Paz L. Sun T. Pikiolek M. Cochran N.R. Bergling S. Orsini V. YAP, but not RSPO-LGR4/5, signaling in biliary epithelial cells promotes a ductular reaction in response to liver injury Cell Stem Cell 25 2019 39 53 e10 31080135 sourcePartly supported

  The Results report YAP activation in periportal hepatocytes after DDC-induced injury and a YAP-dependent increase in SOX9-positive periportal hepatocytes (page not provided). This supports a change in hepatocyte state, but the cited passages do not show that it reduces the number of metabolically active hepatocytes in that zone. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [94] Pepe-Mooney B.J. Dill M.T. Alemany A. Ordovas-Montanes J. Matsushita Y. Rao A. Single-cell analysis of the liver epithelium reveals dynamic heterogeneity and an essential role for YAP in homeostasis and regeneration Cell Stem Cell 25 2019 23 38 e28 31080134 PMC6814390 sourcePartly supported

  The Results section, “YAP is Essential in Hepatocytes for the Regenerative Ductular Response to Injury” (page unavailable), reports YAP activation primarily in periportal hepatocytes after DDC injury and finds that YAP is crucial for their reprogramming toward a biliary-like fate. It does not report a reduction in the number of metabolically active hepatocytes in that zone. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [102] Li W. Yang L. He Q. Hu C. Zhu L. Ma X. A homeostatic arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling Cell Stem Cell 25 2019 54 68.e55 31271748 sourcePartly supported

  The Introduction and the section on Arid1a-dependent YAP activation describe periportal injury, YAP-responsive hepatocytes, and their conversion into liver-progenitor-like cells. The DDC-injury results also show that some hepatocyte-derived cells acquire ductal-like features and diminish expression of the mature hepatocyte gene Fah. The paper does not establish a reduction in the number of metabolically active hepatocytes in the periportal zone, so that consequence goes beyond its findings. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

May combine two claims.

Approximately 80% of hepatocytes randomly labelled by AAV8-TBG-Cre gave rise to expanding hepatocyte clones in mouse livers subjected to repeated CCl4 injury, indicating that proliferative hepatocytes are relatively abundant.

“However, ∼80% of hepatocytes randomly labelled by AAV8-TBG-Cre gave rise to expanding hepatocyte clones in mouse livers subjected to repeated CCl4 injury, indicating that proliferative hepatocytes are relatively abundant.88”

• cites [88] Chen F. Jimenez R.J. Sharma K. Luu H.Y. Hsu B.Y. Ravindranathan A. Broad distribution of hepatocyte proliferation in liver homeostasis and regeneration Cell Stem Cell 26 2020 27 33 e24 31866223 PMC8009755 sourceSupported

May combine two claims.

Highly polyploid mononucleated hepatocytes observed in mouse models of NAFLD arise via activation of the ATR-p53-p21 pathway from oxidative stress, delaying the S to G2 transition and leading to endoreplication.

“For example, highly polyploid mononucleated hepatocytes observed in mouse models of NAFLD arise via activation of the ATR-p53-p21 pathway from oxidative stress, delaying the S to G2 transition and leading to endoreplication.72”

• cites [72] Gentric G. Maillet V. Paradis V. Couton D. L'Hermitte A. Panasyuk G. Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease J Clin Invest 125 2015 981 992 25621497 PMC4362240 sourcePartly supported

  The Discussion reports enrichment of highly polyploid mononuclear hepatocytes in NAFLD mouse models and links oxidative stress to activation of the ATR/p53/p21 checkpoint. However, the Results locate the arrest at G2/M rather than specifically at the S-to-G2 transition, and the Discussion says the observed successive S phases suggest endoreplication, rather than establishing it as the mechanism. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Telomere deprotection and infection by HBV or HCV promote polyploidisation via unknown mechanisms.

“Telomere deprotection162 and infection by HBV or HCV163,164 were also reported to promote polyploidisation via unknown mechanisms.”

• cites [162] Lazzerini Denchi E. Celli G. de Lange T. Hepatocytes with extensive telomere deprotection and fusion remain viable and regenerate liver mass through endoreduplication Genes Dev 20 2006 2648 2653 17015429 PMC1578691 sourcePartly supported

  The Conclusions (page not provided) report that TRF2-deficient hepatocytes become highly polyploid, supporting the telomere-deprotection part of the claim. But the paper describes a mechanism—joined telomeres prevent chromatid segregation, while repeated DNA replication continues—so it does not support describing that mechanism as unknown. The HBV/HCV part is attached to other citations and is not judged here. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [163] Toyoda H. Bregerie O. Vallet A. Nalpas B. Pivert G. Brechot C. Changes to hepatocyte ploidy and binuclearity profiles during human chronic viral hepatitis Gut 54 2005 297 302 15647198 PMC1774850 sourcePartly supported

  The Results and Conclusion (page not provided) report that the polyploid hepatocyte fraction increased with the severity of chronic hepatitis and suggest that HBV and HCV may modulate liver ploidy through different mechanisms. The Discussion (page not provided) calls for investigation of those mechanisms; it does not establish that infection itself promotes polyploidisation. The telomere-deprotection clause is attached to a different citation and is not judged here. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [164] Ahodantin J. Bou-Nader M. Cordier C. Megret J. Soussan P. Desdouets C. Hepatitis B virus X protein promotes DNA damage propagation through disruption of liver polyploidization and enhances hepatocellular carcinoma initiation Oncogene 38 2019 2645 2657 30538294 sourceNot checked — no full text of the source

May combine two claims.

Transient changes in hepatocyte identity are required when hepatocytes re-enter the cell cycle in response to injury, while others increase metabolic function to maintain hepatic metabolism.

“Transient changes in hepatocyte identity are required when hepatocytes re-enter the cell cycle in response to injury, while others increase metabolic function to maintain hepatic metabolism.25,104,106,107,134”

• cites [25] Hu S. Liu S. Bian Y. Poddar M. Singh S. Cao C. Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b Cell Rep Med 3 2022 100754 PMC9588996 36220068 sourcePartly supported

  The Results section on liver regeneration after partial hepatectomy reports hepatocyte proliferation, and the Discussion describes dynamic changes in zonal gene expression and identity. Neither establishes that transient identity changes are required for cell-cycle re-entry after injury, or that other hepatocytes increase metabolic function to maintain hepatic metabolism. Page numbers are unavailable in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [104] Ben-Moshe S. Veg T. Manco R. Dan S. Papinutti D. Lifshitz A. The spatiotemporal program of zonal liver regeneration following acute injury Cell Stem Cell 29 2022 973 989 e910 35659879 sourceNot checked — no full text of the source
• cites [106] Chembazhi U.V. Bangru S. Hernaez M. Kalsotra A. Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver Genome Res 31 2021 576 591 33649154 PMC8015853 sourcePartly supported

  The Discussion (page not available) reports transient changes in hepatocyte gene programs before cell-cycle entry after partial hepatectomy, while other hepatocytes enter a metabolically hyperactive state. The Results, “Division of labor balances the proliferation and metabolic demands of a regenerating liver” (page not available), reports increased metabolic-gene expression in that subset. The paper does not establish that these identity changes are required across liver injuries generally; it studies partial hepatectomy and says whether the pattern occurs in other injury models remains unknown. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Lost hepatocytes must be replaced during homeostatic turnover or following injury to maintain a full work force.

“Yet, lost hepatocytes must be replaced during homeostatic turnover or following injury to maintain a full work force.”

May combine two claims.

A modular regenerative response by hepatocytes repairs different types of local or pan-zonal injuries, and the enormous regenerative potential and plasticity of hepatocytes is sufficient to restore liver mass and function.

“Instead, a modular regenerative response by hepatocytes repairs different types of local or pan-zonal injuries, and the enormous regenerative potential and plasticity of hepatocytes is sufficient to restore liver mass and function.”

Probably not a substantial claim: may not pass S4 (based).

Changes in hepatocyte identity are associated with severe liver disease.

“Changes in hepatocyte identity are associated with severe liver disease.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Impaired metabolic function is associated with severe hepatic and systemic diseases.

“Impaired metabolic function is associated with severe hepatic and systemic diseases (reviewed in9).”

• cites [9] Martini T. Naef F. Tchorz J.S. Spatiotemporal metabolic liver zonation and consequences on pathophysiology Annu Rev Pathol 18 2023 439 466 36693201 sourceNot checked — no full text of the source

May combine two claims.

Many end-stage liver diseases are characterised by insufficient functional hepatocytes or maladaptive repair processes that can have fatal consequences.

“Many end-stage liver diseases are characterised by insufficient functional hepatocytes or maladaptive repair processes that can have fatal consequences.9”

• cites [9] Martini T. Naef F. Tchorz J.S. Spatiotemporal metabolic liver zonation and consequences on pathophysiology Annu Rev Pathol 18 2023 439 466 36693201 sourceNot checked — no full text of the source

May combine two claims.

In the classic description of the liver lobule, hepatocytes reside in three zones defined according to their location along the porto-central axis, and carry out different metabolic functions.

“In the classic description of the liver lobule (Fig. 1A), hepatocytes reside in three zones defined according to their location along the porto-central axis, and carry out different metabolic functions.18”

• cites [18] Jungermann K. Katz N. Functional hepatocellular heterogeneity Hepatology 2 1982 385 395 7042508 sourceNot checked — no full text of the source

May combine two claims.

Hepatocytes across all lobular zones exhibit high plasticity and support liver regeneration on demand.

“Hepatocytes across all lobular zones exhibit high plasticity and support liver regeneration on demand.”

May combine two claims.

Location, gene expression, cell size and ploidy are associated with differences in proliferation and contribution to the hepatocyte pool, as well as with assigning metabolic functions.

“These factors have been associated with differences in proliferation and contribution to the hepatocyte pool, as well as with assigning metabolic functions.”

May combine two claims.

Zone 1 (periportal) hepatocytes carry out oxidative energy metabolism, beta-oxidation, AA catabolism, ureagenesis from AAs, gluconeogenesis, bile acid and bilirubin excretion; zone 3 (pericentral) hepatocytes primarily perform glycolysis, liponeogenesis, ureagenesis from ammonia, and biotransformation.

“Zone 1 (periportal) hepatocytes carry out functions such as oxidative energy metabolism, beta-oxidation, AA catabolism, ureagenesis from AAs, gluconeogenesis, as well as bile acid and bilirubin excretion; while glycolysis, liponeogenesis, ureagenesis from ammonia, and biotransformation are primarily performed by zone 3 (pericentral) hepatocytes.”

• cites [18] Jungermann K. Katz N. Functional hepatocellular heterogeneity Hepatology 2 1982 385 395 7042508 sourceNot checked — no full text of the source

May combine two claims.

Core clock genes undergo rhythmic H3 histone acetylation, which can be explained by the rhythmic interaction of p300 with CLOCK.

“Interestingly, core clock genes undergo rhythmic H3 histone acetylation, which can be explained by the rhythmic interaction of p300 with CLOCK.66”

• cites [66] Etchegaray J.P. Lee C. Wade P.A. Reppert S.M. Rhythmic histone acetylation underlies transcription in the mammalian circadian clock Nature 421 2003 177 182 12483227 sourceNot checked — no full text of the source

May combine two claims.

Hepatocyte identity is controlled by epigenetic mechanisms, including chromatin remodelling, DNA methylation, post-translational modifications of histones, and non-coding RNAs; however, epigenetic regulation of zonal hepatocyte identity and regeneration are not well understood.

“In addition to these signalling pathways, hepatocyte identity is controlled by epigenetic mechanisms. This includes chromatin remodelling, DNA methylation, post-translational modifications of histones, and non-coding RNAs, however, epigenetic regulation of zonal hepatocyte identity and regeneration are not well understood.61”

• cites [61] Monga S.P. Sadler K.C. An epigenetic perspective on liver regeneration Epigenomics 12 2020 381 384 32090611 sourceNot checked — no full text of the source

May combine two claims.

Some hepatocytes with ZNRF3/RNF43 deletion increased metabolic gene expression, whereas others proliferated.

“A curious and still unresolved finding was that some hepatocytes with ZNRF3/RNF43 deletion increased metabolic gene expression, whereas others proliferated.22”

• cites [22] Sun T. Annunziato S. Bergling S. Sheng C. Orsini V. Forcella P. ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation Cell Stem Cell 28 2021 1822 1837 e1810 34129813 sourceNot checked — no full text of the source

May combine two claims.

Midzonal hepatocytes generally express lower levels of metabolic genes, while periportal and pericentral hepatocytes express higher levels of their respective zone-specific metabolic genes.

“Given the generally lower expression of metabolic genes in midzonal hepatocytes, along with higher expression of periportal and pericentral metabolic genes in their respective zones”

• cites [9] Martini T. Naef F. Tchorz J.S. Spatiotemporal metabolic liver zonation and consequences on pathophysiology Annu Rev Pathol 18 2023 439 466 36693201 sourceNot checked — no full text of the source

May combine two claims.

Since the same pathways that induce and maintain metabolic function also control hepatocyte proliferation, restricting unnecessary proliferation while maintaining the metabolic identity of hepatocytes in the different zones is an important balancing act for the liver.

“Since the same pathways that induce and maintain metabolic function also control hepatocyte proliferation, restricting unnecessary proliferation while maintaining the metabolic identity of hepatocytes in the different zones is an important balancing act for the liver.22,76”

• cites [22] Sun T. Annunziato S. Bergling S. Sheng C. Orsini V. Forcella P. ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation Cell Stem Cell 28 2021 1822 1837 e1810 34129813 sourceNot checked — no full text of the source
• cites [76] Tchorz J.S. The conundrum of the pericentral hepatic niche: WNT/-Catenin signaling, metabolic zonation, and many open questions Gene Expr 20 2020 119 124 32962796 PMC7650010 sourceNot checked — no full text of the source

May combine two claims.

Transient fetal reprogramming of peri-injury hepatocytes, which subsequently adopted a zone 3 fate and contributed to local repair, suggests that hepatocytes in this zone have high plasticity.

“Transient fetal reprogramming of peri-injury hepatocytes, which subsequently adopted a zone 3 fate and contributed to local repair, suggests that hepatocytes in this zone have high plasticity104”

• cites [104] Ben-Moshe S. Veg T. Manco R. Dan S. Papinutti D. Lifshitz A. The spatiotemporal program of zonal liver regeneration following acute injury Cell Stem Cell 29 2022 973 989 e910 35659879 sourceNot checked — no full text of the source

May combine two claims.

HGF and EGFR ligands are direct mitogens on hepatocytes.

“For example, HGF (ligand of the MET receptor) and ligands of EGFR are direct mitogens on hepatocytes.”

May combine two claims.

Bipotential CK19+/HNF4α+ transient LPCs emerge from BECs following severe liver injury and transdifferentiate into hepatocytes or differentiate back into BECs.

“Only recently, such studies identified bipotential CK19+/HNF4α+ transient LPCs (TLPCs) that emerge from BECs following severe liver injury and transdifferentiate into hepatocytes or differentiate back into BECs.”

May combine two claims.

SFSS is associated with a liver remnant or graft to body weight ratio <0.8% or a remnant to total liver volume of less than 25%-30%.

“SFSS is associated with a liver remnant or graft to body weight ratio <0.8% or a remnant to total liver volume of less than 25%–30%, where the liver is too small to handle post-operative metabolic demands.157”

• cites [157] Tucker O.N. Heaton N. The 'small for size' liver syndrome Curr Opin Crit Care 11 2005 150 155 15758596 sourceNot checked — no full text of the source

May combine two claims.

Persistent injury and induction of a pro-proliferative programme in hepatocytes reduces the availability of metabolically active hepatocytes and increases the risk of tumour formation.

“Persistent injury and induction of a pro-proliferative programme in hepatocytes not only reduces the availability of metabolically active hepatocytes, but also increases the risk of tumour formation.”

May combine two claims.

Lipotoxicity-induced hepatocyte injury leads to loss of hepatocyte identity and reprogramming, causing loss of metabolic function and induction of profibrotic and proinflammatory factors.

“Lipotoxicity-induced hepatocyte injury further leads to a loss of hepatocyte identity and reprogramming, causing loss of metabolic function and the induction of profibrotic and proinflammatory factors.155”

• cites [155] Loft A. Alfaro A.J. Schmidt S.F. Pedersen F.B. Terkelsen M.K. Puglia M. Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication Cell Metab 33 2021 1685 1700.e1689 34237252 sourceNot checked — no full text of the source

May combine two claims.

Primary hepatocytes retain some metabolic function in short-term experiments, but prolonged culture or use of hepatocyte-like cell systems dramatically changes their metabolic identity.

“While primary hepatocytes retain some metabolic function in short-term experiments, prolonged culture or use of hepatocyte-like cell systems dramatically changes their metabolic identity.”

May combine two claims.

Despite differences in gene expression, hepatocytes appear to be the same cell type and can adopt gene expression characteristics of each zone depending on their surrounding environment.

“Despite differences in gene expression, hepatocytes appear to be the same cell type and can adopt gene expression characteristics of each zone depending on their surrounding environment.”

May combine two claims.

The majority of routine liver function tests only measure the function of periportal hepatocytes or assess hepatocyte damage.

“However, the majority of routine liver function tests only measure the function of periportal hepatocytes (e.g. serum albumin detection, prothrombin time or lactate dehydrogenase measurements) or assess hepatocyte damage (e.g. measurement of transaminases).166”

• cites [166] Lala V. Zubair M. Minter D.A. Liver function tests 2022 StatPearls. Treasure Island (FL) 29494096Not checked yet

  Not checked in the free run.

May combine two claims.

Persistent changes in hepatocyte identity are associated with most liver diseases and are often accompanied by severe hepatic and systemic consequences.

“Unfortunately, persistent changes in hepatocyte identity are associated with most liver diseases and are often accompanied by severe hepatic and systemic consequences.9”

• cites [9] Martini T. Naef F. Tchorz J.S. Spatiotemporal metabolic liver zonation and consequences on pathophysiology Annu Rev Pathol 18 2023 439 466 36693201 sourceNot checked — no full text of the source