Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH)

In the paper

“Other sources of myofibroblasts include vascular smooth muscle cells, mesothelial cells, and portal fibroblasts, out of which portal myofibroblasts marked by thymocyte differentiation antigen 1 (THY1) may play an outsized role in biliary fibrosis due to their physical localization in the portal region (53, 55-57) (58).”

What the sources say

• Partly supported

  The Results identify portal fibroblast-like cells as myofibroblasts located around portal tracts, and the Discussion suggests their location may give them specialized functions in biliary disease. But the paper does not identify them by THY1 or support an outsized contribution to biliary fibrosis; it says they are less abundant than hepatic stellate cells and probably do not make a major contribution to organ fibrosis. It also says mesothelial cells do not give rise to intrahepatic myofibroblasts. (LLM, conf=0.86)

  cites [53] Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, Dapito DH, Pradere J-P, Schwabe RF, Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nature communications 4, 2823 (2013). PMC4059406 24264436 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section (“Vim-CreER marks myofibroblasts”; page unavailable) identifies vascular smooth muscle cells and portal fibroblasts as liver cell populations that may express vimentin, a marker used here to track myofibroblasts. It does not identify mesothelial cells as a source or address THY1, biliary fibrosis, or an outsized role for portal myofibroblasts due to their location. (LLM, conf=0.78)

  cites [55] Troeger JS, Mederacke I, Gwak GY, Dapito DH, Mu X, Hsu CC, Pradere JP, Friedman RA, Schwabe RF, Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 143, 1073– 1083 e1022 (2012). 22750464 PMC3848328 sourceExperimental — accuracy not yet measured
• Supported

  The Results section ('Portal Fibroblasts—Not HSCs—Are the Major Source…'; page unavailable) identifies Thy1 as a portal-fibroblast marker and finds that portal fibroblasts are the principal collagen-producing cells in bile-duct-ligated mouse livers. The paper also locates these cells in the portal triad and describes collagen deposition in the portal area, supporting the citing sentence’s hedged explanation of their importance in biliary fibrosis. (LLM, conf=0.89)

  cites [56] Yang W, He H, Wang T, Su N, Zhang F, Jiang K, Zhu J, Zhang C, Niu K, Wang L, Yuan X, Liu N, Li L, Wei W, Hu J, Single-Cell Transcriptomic Analysis Reveals a Hepatic Stellate Cell–Activation Roadmap and Myofibroblast Origin During Liver Fibrosis in Mice. Hepatology 74, 2774– 2790 (2021). 34089528 PMC8597108 source
• Not checked yetcites [57] Lei L, Bruneau A, El Mourabit H, Guegan J, Folseraas T, Lemoinne S, Karlsen TH, Hoareau B, Morichon R, Gonzalez-Sanchez E, Goumard C, Ratziu V, Charbord P, Gautheron J, Tacke F, Jaffredo T, Cadoret A, Housset C, Portal fibroblasts with mesenchymal stem cell features form a reservoir of proliferative myofibroblasts in liver fibrosis. Hepatology 76, 1360– 1375 (2022). 35278227 source
• Supported

  The Introduction identifies portal fibroblasts as myofibroblast precursors particularly relevant to biliary fibrosis. The Discussion identifies Thy1-expressing mesenchymal cells as portal fibroblasts and explains that their portal location is compatible with the site of cholestatic injury in mouse models. The claim's hedged wording reflects this proposed role; the paper notes that their relative contribution remains controversial. (LLM, conf=0.86)

  cites [58] Katsumata LW, Miyajima A, Itoh T, Portal fibroblasts marked by the surface antigen Thy1 contribute to fibrosis in mouse models of cholestatic liver injury. Hepatol Commun 1, 198– 214 (2017). 29404454 PMC5721447 source

In the paper

“Single-cell studies have also revealed remarkable heterogeneity within different cell types in health and disease, identifying multiple HSC clusters in murine models of MASH fibrosis and human cirrhosis.”

What the sources say

• Partly supported

  The Results section reports multiple HSC clusters in a mouse model of NASH (now also termed MASH) with fibrosis, supporting that part of the claim. The paper does not report HSC clusters in human cirrhosis; its References section lists a separate study of human cirrhosis, but does not describe its cluster findings in the passages found. Page numbers were not available in our copy. (LLM, conf=0.88)

  cites [42] Rosenthal SB, Liu X, Ganguly S, Dhar D, Pasillas MP, Ricciardelli E, Li RZ, Troutman TD, Kisseleva T, Glass CK, Brenner DA, Heterogeneity of HSCs in a Mouse Model of NASH. Hepatology 74, 667– 685 (2021). 33550587 PMC8346581 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section reports two distinct human HSC clusters, supporting the general point that single-cell studies reveal HSC heterogeneity. It identifies the comparison dataset as healthy liver, while the Discussion mentions murine HSC subpopulations in CCl4-induced fibrosis—not MASH fibrosis. Our copy does not report multiple HSC clusters in human cirrhosis. (LLM, conf=0.88)

  cites [99] Payen VL, Lavergne A, Alevra Sarika N, Colonval M, Karim L, Deckers M, Najimi M, Coppieters W, Charloteaux B, Sokal EM, El Taghdouini A, Single-cell RNA sequencing of human liver reveals hepatic stellate cell heterogeneity. JHEP Rep 3, 100278 (2021). 34027339 PMC8121977 sourceExperimental — accuracy not yet measured
• Partly supported

  In “Ten Thousand Points of Light – Heterogeneity Among the Stars of NASH Fibrosis” (page unavailable), the paper describes single-cell evidence of HSC heterogeneity and multiple HSC subclusters in a murine NASH model. Our copy does not report multiple HSC clusters in human cirrhosis, so that part of the attributed claim is unsupported. (LLM, conf=0.87)

  cites [126] Carter J, Wang S, Friedman SL, Ten Thousand Points of Light: Heterogeneity Among the Stars of NASH Fibrosis. Hepatology 74, (2021). PMC8390430 33724489 sourceExperimental — accuracy not yet measured

In the paper

“Moreover, certain patterns of DNA methylation at fibrosis-related genes, such as those encoding TGFβ1, COL1A1, PDGFα, peroxisome proliferator-activated receptor alpha (PPARα), and peroxisome proliferator-activated receptor delta (PPARδ), can not only distinguish between patients with mild versus advanced MASLD, but also predict future fibrosis progression (169-172).”

What the sources say

• Partly supported

  The Results section reports different methylation in mild versus advanced NAFLD, including at COL1A1 and PDGFA. It does not establish the claimed differences for TGFβ1, PPARα, or PPARδ. The Discussion says the groups were selected by fibrosis severity at biopsy; their expected future outcomes were based on that severity, not on a demonstrated ability of methylation patterns to predict progression. (LLM, conf=0.88)

  cites [169] Murphy SK, Yang H, Moylan CA, Pang H, Dellinger A, Abdelmalek MF, Garrett ME, Ashley–Koch A, Suzuki A, Tillmann HL, Hauser MA, Diehl AM, Relationship Between Methylome and Transcriptome in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 145, 1076– 1087 (2013). 23916847 PMC3805742 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results and discussion section reports methylation differences at specific CpGs between mild and severe NAFLD, supporting the distinction between fibrosis stages, though the COL1A1 difference was not statistically significant. The Conclusions section describes predicting future progression as a possibility, not a demonstrated capability; the study was too small to calculate a predictive algorithm. Page numbers were not provided in our copy. (LLM, conf=0.90)

  cites [170] Hardy T, Zeybel M, Day CP, Dipper C, Masson S, McPherson S, Henderson E, Tiniakos D, White S, French J, Mann DA, Anstee QM, Mann J, Plasma DNA methylation: a potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease. Gut 66, 1321 (2017). 27002005 PMC5031527 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results and discussion report methylation differences at specific CpGs between mild and severe NAFLD, although the COL1A1 difference was not statistically significant. The Conclusions propose that a methylation panel might predict future progression, but say the study was too small to test such a prediction. Page numbers were not provided in our copy. (LLM, conf=0.91)

  cites [171] Zeybel M, Hardy T, Robinson SM, Fox C, Anstee QM, Ness T, Masson S, Mathers JC, French J, White S, Mann J, Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease. Clinical Epigenetics 7, 25 (2015). 25859289 PMC4391139 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results sections on fibrosis profiles and prediction report methylation differences across existing NAFLD fibrosis stages and a model that classified current fibrosis status in a held-out test set. Table 2 identifies different genes from those listed in the claim, and the paper does not show that methylation at the named genes predicts future fibrosis progression. (LLM, conf=0.89)

  cites [172] Johnson ND, Wu X, Still CD, Chu X, Petrick AT, Gerhard GS, Conneely KN, DiStefano JK, Differential DNA methylation and changing cell-type proportions as fibrotic stage progresses in NAFLD. Clinical Epigenetics 13, 152 (2021). 34353365 PMC8340447 sourceExperimental — accuracy not yet measured

In the paper

“Our profiling of FAT-MASH macrophages using single nucleus RNA-seq showed no enrichment of ECM-related pathways, only induction of a few select matrix metalloproteinases (MMP2, matrix metalloproteinase 12 (MMP12), matrix metalloproteinase 14 (MMP14)) and decreased collagen type 18 alpha 1 (COL18A1) (48).”

What the sources say

• Not checked yetcites [48] Wang S, Li K, Pickholz E, Dobie R, Matchett KP, Henderson NC, Carrico C, Driver I, Borch Jensen M, Chen L, Petitjean M, Bhattacharya D, Fiel MI, Liu X, Kisseleva T, Alon U, Adler M, Medzhitov R, Friedman SL, An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Science Translational Medicine 15, eadd3949 (2023). 36599008 PMC10686705 source

In the paper

“Among these features, the extent of fibrosis is the strongest predictor of patient mortality, and is therefore the focus of drug development efforts (13-16).”

What the sources say

• Not checked yetcites [13] Ekstedt M, Hagström H, Nasr P, Fredrikson M, Stål P, Kechagias S, Hultcrantz R, Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 61, 1547– 1554 (2015). 25125077 source
• Not checked yetcites [14] Hagström H, Nasr P, Ekstedt M, Hammar U, Stål P, Hultcrantz R, Kechagias S, Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. Journal of Hepatology 67, 1265– 1273 (2017). 28803953 source
• Not checked yetcites [15] Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, Mills PR, Keach JC, Lafferty HD, Stahler A, Haflidadottir S, Bendtsen F, Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 149, 389– 397.e310 (2015). 25935633 PMC4516664 source
• Not checked yetcites [16] Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, Sebastiani G, Ekstedt M, Hagstrom H, Nasr P, Stal P, Wong VW-S, Kechagias S, Hultcrantz R, Loomba R, Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology 65, 1557– 1565 (2017). 28130788 PMC5397356 source

In the paper

“Despite the scale and urgency of the disease, there are currently no approved drugs for MASH, making it a major unmet need (3, 12).”

What the sources say

• Not checked yetcites [3] Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ, Mechanisms of NAFLD development and therapeutic strategies. Nature Medicine 24, 908– 922 (2018). PMC6553468 29967350 source
• Not checked yetcites [12] Rowe IA, Wong VW, Loomba R, Treatment Candidacy for Pharmacologic Therapies for NASH. Clin Gastroenterol Hepatol 20, 1209– 1217 (2022). 33711479 PMC8908435 source

In the paper

“Microscopically, the enhanced stiffness of the pericellular milieu affects all cells, most notably by activating hepatic stellate cells (HSCs) to increase their fibrogenic activity (19).”

What the sources say

• Not checked yetcites [19] Georges PC, Hui JJ, Gombos Z, McCormick ME, Wang AY, Uemura M, Mick R, Janmey PA, Furth EE, Wells RG, Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis. Am J Physiol Gastrointest Liver Physiol 293, G1147– 1154 (2007). 17932231 source

In the paper

“metabolic dysfunction-associated steatohepatitis (MASH or previously non-alcoholic steatohepatitis/NASH), which is associated with inflammation and fibrosis (1-4).”

What the sources say

• Not checked yetcites [1] Hossain P, Kawar B, El Nahas M, Obesity and Diabetes in the Developing World — A Growing Challenge. New England Journal of Medicine 356, 213– 215 (2007). 17229948 source
• Not checked yetcites [2] Diehl AM, Day C, Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. New England Journal of Medicine 377, 2063– 2072 (2017). 29166236 source
• Not checked yetcites [3] Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ, Mechanisms of NAFLD development and therapeutic strategies. Nature Medicine 24, 908– 922 (2018). PMC6553468 29967350 source
• Not checked yetcites [4] Loomba R, Friedman SL, Shulman GI, Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 184, 2537– 2564 (2021). 33989548 PMC12168897 source

In the paper

“ECM may also generate a physical barrier to trans-sinusoidal transport (‘capillarization’) and concurrently disrupt the function of other resident liver cells besides hepatocytes, in particular sinusoidal endothelial cells.”

In the paper

“There likely are progressive functional changes throughout the course of MASH progression, but current diagnostic tests are not sufficiently sensitive to detect them until they are accompanied by marked architectural disruption.”

In the paper

“Progressive changes in the composition of the matrisome affect all families of ECM molecules (17, 18), leading to altered biochemical and mechanical features of the liver.”

What the sources say

• Not checked yetcites [17] Dolin CE, Arteel GE, The Matrisome, Inflammation, and Liver Disease. Semin Liver Dis 40, 180– 188 (2020). 31910448 PMC7195244 source
• Not checked yetcites [18] Massey VL, Dolin CE, Poole LG, Hudson SV, Siow DL, Brock GN, Merchant ML, Wilkey DW, Arteel GE, The hepatic “matrisome” responds dynamically to injury: Characterization of transitional changes to the extracellular matrix in mice. Hepatology 65, 969– 982 (2017). 28035785 PMC5319876 source

In the paper

“In non-cirrhotic stages, soluble signals from the changing ECM composition or fibrogenic cells can impede regeneration, disrupt immune homeostasis, and alter the clearance of systemic and hepatic metabolites.”

In the paper

“Similar to other tissues, myofibroblasts are the main fibrogenic cells in fibrotic liver. In liver they are derived from resident mesenchymal pericytes, or HSCs.”

In the paper

“Hepatic progenitor cells are typically present within ductular reactions and represent a potential source of transforming growth factor beta (TGFβ and platelet-derived growth factor (PDGF), potent activating stimuli (34-36).”

What the sources say

• Not checked yetcites [34] Ramm GA, Nair VG, Bridle KR, Shepherd RW, Crawford DHG, Contribution of Hepatic Parenchymal and Nonparenchymal Cells to Hepatic Fibrogenesis in Biliary Atresia. The American Journal of Pathology 153, 527– 535 (1998). 9708812 PMC1852970 source
• Not checked yetcites [35] Grappone C, Pinzani M, Parola M, Pellegrini G, Caligiuri A, DeFranco R, Marra F, Herbst H, Alpini G, Milani S, Expression of platelet-derived growth factor in newly formed cholangiocytes during experimental biliary fibrosis in rats. Journal of Hepatology 31, 100– 109 (1999). 10424289 source
• Not checked yetcites [36] Malizia G, Brunt EM, Peters MG, Rizzo A, Broekelmann TJ, McDonald JA, Growth factor and procollagen type I gene expression in human liver disease. Gastroenterology 108, 145– 156 (1995). 7806036 source

In the paper

“Thus far only drugs targeting upstream hepatic lipid accumulation pathways but none of the downstream mediators of cell injury and cell death show signs of efficacy in the clinic.”

In the paper

“Ductular reaction in MASH is frequent and strongly correlates with fibrosis severity in patients for unclear reasons (32, 33).”

What the sources say

• Not checked yetcites [32] Richardson MM, Jonsson JR, Powell EE, Brunt EM, Neuschwander–Tetri BA, Bhathal PS, Dixon JB, Weltman MD, Tilg H, Moschen AR, Purdie DM, Demetris AJ, Clouston AD, Progressive Fibrosis in Nonalcoholic Steatohepatitis: Association With Altered Regeneration and a Ductular Reaction. Gastroenterology 133, 80– 90 (2007). 17631134 source
• Not checked yetcites [33] Zhao L, Westerhoff M, Pai RK, Choi W-T, Gao Z-H, Hart J, Centrilobular ductular reaction correlates with fibrosis stage and fibrosis progression in non-alcoholic steatohepatitis. Modern Pathology 31, 150– 159 (2018). 28862262 source

In the paper

“These functions normally contribute to tissue repair under homeostatic conditions, but sustained activation in chronic liver diseases drives fibrosis, especially in MASH (41) where they are detectable by expression of desmin and alpha smooth muscle actin (αSMA) using immunofluorescence, and by conservation of gene expression based on single-cell RNA-seq (42-46).”

What the sources say

• Not checked yetcites [41] Schuster R, Younesi F, Ezzo M, Hinz B, The Role of Myofibroblasts in Physiological and Pathological Tissue Repair. Cold Spring Harbor Perspectives in Biology, (2022). PMC9808581 36123034 source
• Not checked yetcites [42] Rosenthal SB, Liu X, Ganguly S, Dhar D, Pasillas MP, Ricciardelli E, Li RZ, Troutman TD, Kisseleva T, Glass CK, Brenner DA, Heterogeneity of HSCs in a Mouse Model of NASH. Hepatology 74, 667– 685 (2021). 33550587 PMC8346581 source
• Not checked yetcites [43] Ganguly S, Muench GA, Shang L, Rosenthal SB, Rahman G, Wang R, Wang Y, Kwon HC, Diomino AM, Kisseleva T, Soorosh P, Hosseini M, Knight R, Schnabl B, Brenner DA, Dhar D, Nonalcoholic Steatohepatitis and HCC in a Hyperphagic Mouse Accelerated by Western Diet. Cellular and Molecular Gastroenterology and Hepatology 12, 891– 920 (2021). 34062281 PMC8342972 source
• Not checked yetcites [44] Marcher A-B, Bendixen SM, Terkelsen MK, Hohmann SS, Hansen MH, Larsen BD, Mandrup S, Dimke H, Detlefsen S, Ravnskjaer K, Transcriptional regulation of Hepatic Stellate Cell activation in NASH. Sci Rep-Uk 9, 2324 (2019). PMC6382845 30787418 source
• Not checked yetcites [45] Tsuchida T, Lee YA, Fujiwara N, Ybanez M, Allen B, Martins S, Fiel MI, Goossens N, Chou H-I, Hoshida Y, Friedman SL, A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. Journal of Hepatology 69, 385– 395 (2018). 29572095 PMC6054570 source
• Not checked yetcites [46] Xiong X, Kuang H, Ansari S, Liu T, Gong J, Wang S, Zhao X-Y, Ji Y, Li C, Guo L, Zhou L, Chen Z, Leon-Mimila P, Chung MT, Kurabayashi K, Opp J, Campos-Pérez F, Villamil-Ramírez H, Canizales-Quinteros S, Lyons R, Lumeng CN, Zhou B, Qi L, Huertas-Vazquez A, Lusis AJ, Xu XZS, Li S, Yu Y, Li JZ, Lin JD, Landscape of Intercellular Crosstalk in Healthy and NASH Liver Revealed by Single-Cell Secretome Gene Analysis. Molecular Cell 75, 644– 660.e645 (2019). 31398325 PMC7262680 source

In the paper

“The majority of myofibroblasts in chemically-injured mouse models also derive from HSCs, and their depletion reduces liver fibrosis (52-54).”

What the sources say

• Not checked yetcites [52] Troeger JS, Mederacke I, Gwak GY, Dapito DH, Mu X, Hsu CC, Pradere JP, Friedman RA, Schwabe RF, Deactivation of Hepatic Stellate Cells During Liver Fibrosis Resolution in Mice. Gastroenterology 143, 1073– 1083.e1022 (2012). 22750464 PMC3848328 source
• Not checked yetcites [53] Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, Dapito DH, Pradere J-P, Schwabe RF, Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nature communications 4, 2823 (2013). PMC4059406 24264436 source
• Not checked yetcites [54] Puche JE, Lee YA, Jiao J, Aloman C, Fiel MI, Muñoz U, Kraus T, Lee T, Yee HF Jr, Friedman SL, A novel murine model to deplete hepatic stellate cells uncovers their role in amplifying liver damage in mice. Hepatology 57, 339– 350 (2013). 22961591 PMC3522764 source

In the paper

“NK cytotoxicity may be enhanced by mucosal invariant T (MAIT) cells (95).”

What the sources say

• Not checked yetcites [95] Jiang X, Peng Y, Liu L, Wang Y, Li M, Li W, Huang F, Zheng C, Xu F, Hu Q, Wei W, Dong S, Zhao Q, MAIT cells ameliorate liver fibrosis by enhancing the cytotoxicity of NK cells in cholestatic murine models. Liver international: official journal of the International Association for the Study of the Liver 42, 2743– 2758 (2022). 36181707 source

In the paper

“In the presence of signals from the damaged and inflammatory liver, quiescent HSCs “activate” into proliferative, contractile, ECM-remodeling myofibroblasts that also harbor inflammatory features through the secretion of cytokines and chemokines (96) (97, 98).”

What the sources say

• Not checked yetcites [96] Tsuchida T, Friedman SL, Mechanisms of hepatic stellate cell activation. Nature Reviews Gastroenterology & Hepatology 14, 397– 411 (2017). 28487545 source
• Not checked yetcites [97] Filliol A, Saito Y, Nair A, Dapito DH, Yu LX, Ravichandra A, Bhattacharjee S, Affo S, Fujiwara N, Su H, Sun Q, Savage TM, Wilson-Kanamori JR, Caviglia JM, Chin L, Chen D, Wang X, Caruso S, Kang JK, Amin AD, Wallace S, Dobie R, Yin D, Rodriguez-Fiallos OM, Yin C, Mehal A, Izar B, Friedman RA, Wells RG, Pajvani UB, Hoshida Y, Remotti HE, Arpaia N, Zucman-Rossi J, Karin M, Henderson NC, Tabas I, Schwabe RF, Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis. Nature 610, 356– 365 (2022). 36198802 PMC9949942 source
• Not checked yetcites [98] Affo S, Nair A, Brundu F, Ravichandra A, Bhattacharjee S, Matsuda M, Chin L, Filliol A, Wen W, Song X, Decker A, Worley J, Caviglia JM, Yu L, Yin D, Saito Y, Savage T, Wells RG, Mack M, Zender L, Arpaia N, Remotti HE, Rabadan R, Sims P, Leblond AL, Weber A, Riener MO, Stockwell BR, Gaublomme J, Llovet JM, Kalluri R, Michalopoulos GK, Seki E, Sia D, Chen X, Califano A, Schwabe RF, Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations. Cancer Cell 39, 866– 882 e811 (2021). 33930309 PMC8241235 source

In the paper

“In fatty liver, a novel subset of lipid-associated macrophages (LAMs) display a unique ability to metabolize lipids, but their contribution to fibrosis is unknown (70, 76).”

What the sources say

• Not checked yetcites [70] Remmerie A, Martens L, Thoné T, Castoldi A, Seurinck R, Pavie B, Roels J, Vanneste B, De Prijck S, Vanhockerhout M, Binte Abdul Latib M, Devisscher L, Hoorens A, Bonnardel J, Vandamme N, Kremer A, Borghgraef P, Van Vlierberghe H, Lippens S, Pearce E, Saeys Y, Scott CL, Osteopontin Expression Identifies a Subset of Recruited Macrophages Distinct from Kupffer Cells in the Fatty Liver. Immunity 53, 641– 657.e614 (2020). 32888418 PMC7501731 source
• Not checked yetcites [76] Jaitin DA, Adlung L, Thaiss CA, Weiner A, Li B, Descamps H, Lundgren P, Bleriot C, Liu Z, Deczkowska A, Keren-Shaul H, David E, Zmora N, Eldar SM, Lubezky N, Shibolet O, Hill DA, Lazar MA, Colonna M, Ginhoux F, Shapiro H, Elinav E, Amit I, Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner. Cell 178, 686– 698.e614 (2019). 31257031 PMC7068689 source

In the paper

“HSCs normally exist as quiescent pericyte-like cells that wrap around the vasculature, promote homeostatic hepatocyte turnover through the secretion of growth factors such as hepatocyte growth factor (HGF), and serve as a major storage site for vitamin A.”

In the paper

“Macrophages, both the liver resident Kupffer cells and bone marrow monocyte-derived cells recruited in response to injury, secrete cytokines that activate HSCs into myofibroblasts, the most potent of which being TGFβ.”

In the paper

“The HSC-NK cell crosstalk is bidirectional, as activated HSCs can also disrupt cancer dormancy in liver through their secretion of C-X-C motif chemokine 12 (CXCL12) to induce NK cell quiescence that reduces cancer cell killing (94).”

What the sources say

• Not checked yetcites [94] Correia AL, Guimaraes JC, Auf der Maur P, De Silva D, Trefny MP, Okamoto R, Bruno S, Schmidt A, Mertz K, Volkmann K, Terracciano L, Zippelius A, Vetter M, Kurzeder C, Weber WP, Bentires-Alj M, Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy. Nature 594, 566– 571 (2021). 34079127 source

In the paper

“Second, monocyte-derived macrophages replace liver resident Kupffer cells that normally clear iron, resulting in iron overload, oxidative stress, and activation of HSCs into myofibroblasts (70, 74-77).”

What the sources say

• Not checked yetcites [70] Remmerie A, Martens L, Thoné T, Castoldi A, Seurinck R, Pavie B, Roels J, Vanneste B, De Prijck S, Vanhockerhout M, Binte Abdul Latib M, Devisscher L, Hoorens A, Bonnardel J, Vandamme N, Kremer A, Borghgraef P, Van Vlierberghe H, Lippens S, Pearce E, Saeys Y, Scott CL, Osteopontin Expression Identifies a Subset of Recruited Macrophages Distinct from Kupffer Cells in the Fatty Liver. Immunity 53, 641– 657.e614 (2020). 32888418 PMC7501731 source
• Not checked yetcites [74] Gao H, Jin Z, Bandyopadhyay G, Wang G, Zhang D, Rocha K. C. e., Liu X, Zhao H, Kisseleva T, Brenner DA, Karin M, Ying W, Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis. Cell Metabolism 34, 1201– 1213.e1205 (2022). 35921818 PMC9365100 source
• Not checked yetcites [75] Tran S, Baba I, Poupel L, Dussaud S, Moreau M, Gélineau A, Marcelin G, Magréau-Davy E, Ouhachi M, Lesnik P, Boissonnas A, Le Goff W, Clausen BE, Yvan-Charvet L, Sennlaub F, Huby T, Gautier EL, Impaired Kupffer Cell Self-Renewal Alters the Liver Response to Lipid Overload during Non-alcoholic Steatohepatitis. Immunity 53, 627– 640.e625 (2020). 32562600 source
• Not checked yetcites [76] Jaitin DA, Adlung L, Thaiss CA, Weiner A, Li B, Descamps H, Lundgren P, Bleriot C, Liu Z, Deczkowska A, Keren-Shaul H, David E, Zmora N, Eldar SM, Lubezky N, Shibolet O, Hill DA, Lazar MA, Colonna M, Ginhoux F, Shapiro H, Elinav E, Amit I, Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner. Cell 178, 686– 698.e614 (2019). 31257031 PMC7068689 source
• Not checked yetcites [77] Seidman JS, Troutman TD, Sakai M, Gola A, Spann NJ, Bennett H, Bruni CM, Ouyang Z, Li RZ, Sun X, Vu BT, Pasillas MP, Ego KM, Gosselin D, Link VM, Chong L-W, Evans RM, Thompson BM, McDonald JG, Hosseini M, Witztum JL, Germain RN, Glass CK, Niche-Specific Reprogramming of Epigenetic Landscapes Drives Myeloid Cell Diversity in Nonalcoholic Steatohepatitis. Immunity 52, 1057– 1074.e1057 (2020). 32362324 PMC7305990 source

In the paper

“Inhibiting hedgehog signaling can attenuate HSC activation and MASH fibrosis (112, 113).”

What the sources say

• Not checked yetcites [112] Wang X, Zheng Z, Caviglia JM, Corey KE, Herfel TM, Cai B, Masia R, Chung RT, Lefkowitch JH, Schwabe RF, Tabas I, Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis. Cell Metabolism 24, 848– 862 (2016). 28068223 PMC5226184 source
• Not checked yetcites [113] Wang X, Cai B, Yang X, Sonubi OO, Zheng Z, Ramakrishnan R, Shi H, Valenti L, Pajvani UB, Sandhu J, Infante RE, Radhakrishnan A, Covey DF, Guan K-L, Buck J, Levin LR, Tontonoz P, Schwabe RF, Tabas I, Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis. Cell Metabolism 31, 969– 986.e967 (2020). 32259482 PMC7313619 source

In the paper

“For example, in experimental MASH and human disease a subset of hepatocytes that express the Ephrin B2 receptor can induce cell-autonomous inflammation that provokes fibrosis, establishing these cells as a potential therapeutic target (49).”

What the sources say

• Not checked yetcites [49] Xiao Y, Batmanov K, Hu W, Zhu K, Tom AY, Guan D, Jiang C, Cheng L, McCright SJ, Yang EC, Lanza MR, Liu Y, Hill DA, Lazar MA, Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis. Science Translational Medicine 15, eadc9653 (2023). 36753562 PMC10234568 source

In the paper

“Reactivation of notch signaling in hepatocytes in MASH can increase SPP1 expression, which activates HSCs in a paracrine manner.”

In the paper

“Through the use of bulk RNA-seq, liver gene signatures were derived from whole liver, isolated hepatocytes, isolated non-parenchymal cells, or plasma that correlated with various disease features and, in some cases, predicted the transition from MASLD to MASH (44, 116-122).”

What the sources say

• Not checked yetcites [44] Marcher A-B, Bendixen SM, Terkelsen MK, Hohmann SS, Hansen MH, Larsen BD, Mandrup S, Dimke H, Detlefsen S, Ravnskjaer K, Transcriptional regulation of Hepatic Stellate Cell activation in NASH. Sci Rep-Uk 9, 2324 (2019). PMC6382845 30787418 source
• Not checked yetcites [116] Govaere O, Cockell S, Tiniakos D, Queen R, Younes R, Vacca M, Alexander L, Ravaioli F, Palmer J, Petta S, Boursier J, Rosso C, Johnson K, Wonders K, Day CP, Ekstedt M, Orešič M, Darlay R, Cordell HJ, Marra F, Vidal-Puig A, Bedossa P, Schattenberg JM, Clément K, Allison M, Bugianesi E, Ratziu V, Daly AK, Anstee QM, Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis. Science Translational Medicine 12, eaba4448 (2020). 33268509 source
• Not checked yetcites [117] Vandel J, Dubois-Chevalier J, Gheeraert C, Derudas B, Raverdy V, Thuillier D, Gaal L, Francque S, Pattou F, Staels B, Eeckhoute J, Lefebvre P, Hepatic Molecular Signatures Highlight the Sexual Dimorphism of Nonalcoholic Steatohepatitis (NASH). Hepatology 73, 920– 936 (2021). 32394476 PMC8048532 source
• Not checked yetcites [118] Santhekadur PK, Kumar DP, Sanyal AJ, Preclinical models of non-alcoholic fatty liver disease. Journal of Hepatology 68, 230– 237 (2018). 29128391 PMC5775040 source
• Not checked yetcites [119] Cazanave S, Podtelezhnikov A, Jensen K, Seneshaw M, Kumar DP, Min H-K, Santhekadur PK, Banini B, Mauro AG, Oseini AM, Vincent R, Tanis KQ, Webber AL, Wang L, Bedossa P, Mirshahi F, Sanyal AJ, The Transcriptomic Signature Of Disease Development And Progression Of Nonalcoholic Fatty Liver Disease. Sci Rep-Uk 7, 17193 (2017). PMC5722878 29222421 source
• Not checked yetcites [120] Lake AD, Novak P, Fisher CD, Jackson JP, Hardwick RN, Billheimer DD, Klimecki WT, Cherrington NJ, Analysis of Global and Absorption, Distribution, Metabolism, and Elimination Gene Expression in the Progressive Stages of Human Nonalcoholic Fatty Liver Disease. Drug Metabolism and Disposition 39, 1954 (2011). 21737566 PMC3186211 source
• Not checked yetcites [121] van Koppen A, Verschuren L, van den Hoek AM, Verheij J, Morrison MC, Li K, Nagabukuro H, Costessi A, Caspers MPM, van den Broek TJ, Sagartz J, Kluft C, Beysen C, Emson C, van Gool AJ, Goldschmeding R, Stoop R, Bobeldijk-Pastorova I, Turner SM, Hanauer G, Hanemaaijer R, Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model. Cellular and Molecular Gastroenterology and Hepatology 5, 83– 98.e10 (2018). 29276754 PMC5738456 source
• Not checked yetcites [122] Lefebvre P, Lalloyer F, Baugé E, Pawlak M, Gheeraert C, Dehondt H, Vanhoutte J, Woitrain E, Hennuyer N, Mazuy C, Bobowski-Gérard M, Zummo FP, Derudas B, Driessen A, Hubens G, Vonghia L, Kwanten WJ, Michielsen P, Vanwolleghem T, Eeckhoute J, Verrijken A, Van Gaal L, Francque S, Staels B, Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin. JCI Insight 2, (2017). PMC5499370 28679947 source

In the paper

“Notable among these pathways are yes-associated protein 1 (YAP)/tafazzin (TAZ), hedgehog, and, notch, as well as others (111).”

What the sources say

• Not checked yetcites [111] Loft A, Alfaro AJ, Schmidt SF, Pedersen FB, Terkelsen MK, Puglia M, Chow KK, Feuchtinger A, Troullinaki M, Maida A, Wolff G, Sakurai M, Berutti R, Ekim Üstünel B, Nawroth P, Ravnskjaer K, Diaz MB, Blagoev B, Herzig S, Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication. Cell Metabolism 33, 1685– 1700.e1689 (2021). 34237252 source

In the paper

“Although activated HSCs are the primary fibrogenic cells in MASH, these methods have identified an expanded list of fibrogenic drivers expressed by activated HSCs that could represent antifibrotic drug targets (42, 48, 49, 125).”

What the sources say

• Not checked yetcites [42] Rosenthal SB, Liu X, Ganguly S, Dhar D, Pasillas MP, Ricciardelli E, Li RZ, Troutman TD, Kisseleva T, Glass CK, Brenner DA, Heterogeneity of HSCs in a Mouse Model of NASH. Hepatology 74, 667– 685 (2021). 33550587 PMC8346581 source
• Not checked yetcites [48] Wang S, Li K, Pickholz E, Dobie R, Matchett KP, Henderson NC, Carrico C, Driver I, Borch Jensen M, Chen L, Petitjean M, Bhattacharya D, Fiel MI, Liu X, Kisseleva T, Alon U, Adler M, Medzhitov R, Friedman SL, An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Science Translational Medicine 15, eadd3949 (2023). 36599008 PMC10686705 source
• Not checked yetcites [49] Xiao Y, Batmanov K, Hu W, Zhu K, Tom AY, Guan D, Jiang C, Cheng L, McCright SJ, Yang EC, Lanza MR, Liu Y, Hill DA, Lazar MA, Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis. Science Translational Medicine 15, eadc9653 (2023). 36753562 PMC10234568 source
• Not checked yetcites [125] Fred RG, Steen Pedersen J, Thompson JJ, Lee J, Timshel PN, Stender S, Opseth Rygg M, Gluud LL, Bjerregaard Kristiansen V, Bendtsen F, Hansen T, Pers TH, Single-cell transcriptome and cell type-specific molecular pathways of human non-alcoholic steatohepatitis. Sci Rep-Uk 12, 13484 (2022). PMC9355943 35931712 source

In the paper

“Conversely, a recent study has identified a subset of hepatocytes that express annexin A2 that preferentially repopulate damaged tissue in acute liver injury (115) – the relevance of this finding to MASH injury is not clear yet.”

What the sources say

• Not checked yetcites [115] Matchett KP, Wilson-Kanamori JR, Portman JR, Kapourani CA, Fercoq F, May SB, Mackey JBG, Brice M, Zajdel E, Beltran MS, Sutherland EF, Wilson JC, Wallace SJ, Kitto L, Younger NT, Dobie R, Oniscu GC, Wigmore SJ, Ramachandiran P, Vallejos CA, Carragher NO, Simpson KJ, Kendall TJ, Rule JA, Lee WM, Hoare M, Weston CJ, Marioni JC, Teichmann ST, Bird TG, Carlin LM, Henderson NC, Multimodal decoding of human liver regeneration. bioRxiv, (2023). PMC11153152 38693268 source

In the paper

“Some monocyte-derived macrophages resemble Kupffer cells, the homeostatic liver resident macrophage, whereas others acquire a classical “M2-like” polarization and promote resolution of inflammation through production of proresolvin mediators such as maresin 1.”

In the paper

“LAMs are identified by the expression of TREM2, Tetraspanin CD9 (CD9), and SPP1, which also represent markers of scar-associated macrophages (SAMs) in cirrhotic patients, suggesting a common macrophage lineage in different liver injury models (51).”

What the sources say

• Not checked yetcites [51] Ramachandran P, Dobie R, Wilson-Kanamori JR, Dora EF, Henderson BEP, Luu NT, Portman JR, Matchett KP, Brice M, Marwick JA, Taylor RS, Efremova M, Vento-Tormo R, Carragher NO, Kendall TJ, Fallowfield JA, Harrison EM, Mole DJ, Wigmore SJ, Newsome PN, Weston CJ, Iredale JP, Tacke F, Pollard JW, Ponting CP, Marioni JC, Teichmann SA, Henderson NC, Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512– 518 (2019). 31597160 PMC6876711 source

In the paper

“This activation involves the expression of adhesion proteins such as vascular cell adhesion molecule 1 (VCAM-1), which directly recruits pro-inflammatory and pro-fibrogenic immune cells into the liver, while also disrupting the quiescent state of HSCs (104) (105-109).”

What the sources say

• Not checked yetcites [104] Hammoutene A, Rautou P-E, Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease. Journal of Hepatology 70, 1278– 1291 (2019). 30797053 source
• Not checked yetcites [105] DeLeve LD, Wang X, Guo Y, Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology 48, 920– 930 (2008). 18613151 PMC2695448 source
• Not checked yetcites [106] Xie G, Wang X, Wang L, Wang L, Atkinson RD, Kanel GC, Gaarde WA, DeLeve LD, Role of Differentiation of Liver Sinusoidal Endothelial Cells in Progression and Regression of Hepatic Fibrosis in Rats. Gastroenterology 142, 918– 927.e916 (2012). 22178212 PMC3618963 source
• Not checked yetcites [107] Chen L, Gu T, Li B, Li F, Ma Z, Zhang Q, Cai X, Lu L, Delta-like ligand 4/DLL4 regulates the capillarization of liver sinusoidal endothelial cell and liver fibrogenesis. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1866, 1663– 1675 (2019). 31233801 source
• Not checked yetcites [108] Furuta K, Guo Q, Pavelko KD, Lee J-H, Robertson KD, Nakao Y, Melek J, Shah VH, Hirsova P, Ibrahim SH, Lipid-induced endothelial vascular cell adhesion molecule 1 promotes nonalcoholic steatohepatitis pathogenesis. The Journal of Clinical Investigation 131, (2021). PMC7954604 33476308 source
• Not checked yetcites [109] Hammoutene A, Biquard L, Lasselin J, Kheloufi M, Tanguy M, Vion A-C, Mérian J, Colnot N, Loyer X, Tedgui A, Codogno P, Lotersztajn S, Paradis V, Boulanger CM, Rautou P-E, A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis. Journal of Hepatology 72, 528– 538 (2020). 31726115 source

In the paper

“Single-cell RNA-seq has enabled researchers to attribute differentially expressed genes to specific cell types.”

In the paper

“Seminal work from the Henderson group first profiled hepatic cells, including HSCs from fibrotic mouse and patient livers (50, 51), which has since been expanded to MASH by several other groups including ours.”

What the sources say

• Not checked yetcites [50] Dobie R, Wilson-Kanamori JR, Henderson BEP, Smith JR, Matchett KP, Portman JR, Wallenborg K, Picelli S, Zagorska A, Pendem SV, Hudson TE, Wu MM, Budas GR, Breckenridge DG, Harrison EM, Mole DJ, Wigmore SJ, Ramachandran P, Ponting CP, Teichmann SA, Marioni JC, Henderson NC, Single-Cell Transcriptomics Uncovers Zonation of Function in the Mesenchyme during Liver Fibrosis. Cell Reports 29, 1832– 1847.e1838 (2019). 31722201 PMC6856722 source
• Not checked yetcites [51] Ramachandran P, Dobie R, Wilson-Kanamori JR, Dora EF, Henderson BEP, Luu NT, Portman JR, Matchett KP, Brice M, Marwick JA, Taylor RS, Efremova M, Vento-Tormo R, Carragher NO, Kendall TJ, Fallowfield JA, Harrison EM, Mole DJ, Wigmore SJ, Newsome PN, Weston CJ, Iredale JP, Tacke F, Pollard JW, Ponting CP, Marioni JC, Teichmann SA, Henderson NC, Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512– 518 (2019). 31597160 PMC6876711 source

In the paper

“This process is influenced by the liver microenvironment (101), leading to the identification of several different subsets of monocyte-derived macrophages based on their gene expression.”

What the sources say

• Not checked yetcites [101] Lavin Y, Mortha A, Rahman A, Merad M, Regulation of macrophage development and function in peripheral tissues. Nature Reviews Immunology 15, 731– 744 (2015). PMC4706379 26603899 source

In the paper

“In MASH, liver sinusoidal endothelial cells (LSECs) undergo a morphological transition characterized by the loss of fenestration, lower prevalence of autophagic vacuoles, and the acquisition of an”

In the paper

“Although studies have long implicated TGFβ1 as the dominant fibrogenic driver, a recent study also implicates TGFβ2 and TGFβ3 as potent fibrogenic stimuli, but which lack the pro-inflammatory effects of TGFβ1 antagonism that have limited the latter’s appeal as a therapeutic target (147).”

What the sources say

• Not checked yetcites [147] Sun T, Huang Z, Liang WC, Yin J, Lin WY, Wu J, Vernes JM, Lutman J, Caplazi P, Jeet S, Wong T, Wong M, DePianto DJ, Morshead KB, Sun KH, Modrusan Z, Vander Heiden JA, Abbas AR, Zhang H, Xu M, N'Diaye EN, Roose-Girma M, Wolters PJ, Yadav R, Sukumaran S, Ghilardi N, Corpuz R, Emson C, Meng YG, Ramalingam TR, Lupardus P, Brightbill HD, Seshasayee D, Wu Y, Arron JR, TGFbeta2 and TGFbeta3 isoforms drive fibrotic disease pathogenesis. Sci Transl Med 13, (2021). 34349032 source

In the paper

“These findings may explain the overrepresentation of Hispanic and underrepresentation of African Americans in MASH clinics.”

In the paper

“Although these findings provide valuable insights into the mechanisms underlying MASH, overall, few genetic variants have been mechanistically linked to MASH pathogenesis (145), and each exerts only a modest effect on disease outcome at the population level, suggesting that environmental determinants play a more important role in driving the disease.”

What the sources say

• Not checked yetcites [145] Vujkovic M, Ramdas S, Lorenz KM, Guo X, Darlay R, Cordell HJ, He J, Gindin Y, Chung C, Myers RP, Schneider CV, Park J, Lee KM, Serper M, Carr RM, Kaplan DE, Haas ME, MacLean MT, Witschey WR, Zhu X, Tcheandjieu C, Kember RL, Kranzler HR, Verma A, Giri A, Klarin DM, Sun YV, Huang J, Huffman JE, Creasy KT, Hand NJ, Liu CT, Long MT, Yao J, Budoff M, Tan J, Li X, Lin HJ, Chen YI, Taylor KD, Chang RK, Krauss RM, Vilarinho S, Brancale J, Nielsen JB, Locke AE, Jones MB, Verweij N, Baras A, Reddy KR, Neuschwander-Tetri BA, Schwimmer JB, Sanyal AJ, Chalasani N, Ryan KA, Mitchell BD, Gill D, Wells AD, Ma source

In the paper

“Absence of the HSD17B13 protein due to a truncation variant is protective against fibrosis, suggesting that this enzyme generates a potential lipotoxic species, which is absent from those with the variant, however the native substrate and product of this protein have not been established.”

In the paper

“Furthermore, the splice variant rs72613567 in the Hydroxysteroid 17-beta Dehydrogenase 13 (HSD17B13) gene has been identified as protective against MASH, with HSD17B13 potentially contributing to MASH fibrosis by promoting pyrimidine catabolism (134, 140-142).”

What the sources say

• Not checked yetcites [134] Anstee QM, Darlay R, Cockell S, Meroni M, Govaere O, Tiniakos D, Burt AD, Bedossa P, Palmer J, Liu Y-L, Aithal GP, Allison M, Yki-Järvinen H, Vacca M, Dufour J-F, Invernizzi P, Prati D, Ekstedt M, Kechagias S, Francque S, Petta S, Bugianesi E, Clement K, Ratziu V, Schattenberg JM, Valenti L, Day CP, Cordell HJ, Daly AK, Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort☆. Journal of Hepatology 73, 505– 515 (2020). 32298765 source
• Not checked yetcites [140] Liu Y-L, Reeves HL, Burt AD, Tiniakos D, McPherson S, Leathart JBS, Allison MED, Alexander GJ, Piguet A-C, Anty R, Donaldson P, Aithal GP, Francque S, Van Gaal L, Clement K, Ratziu V, Dufour J-F, Day CP, Daly AK, Anstee QM, TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nature communications 5, 4309 (2014). PMC4279183 24978903 source
• Not checked yetcites [141] Dongiovanni P, Petta S, Maglio C, Fracanzani AL, Pipitone R, Mozzi E, Motta BM, Kaminska D, Rametta R, Grimaudo S, Pelusi S, Montalcini T, Alisi A, Maggioni M, Kärjä V, Borén J, Käkelä P, Di Marco V, Xing C, Nobili V, Dallapiccola B, Craxi A, Pihlajamäki J, Fargion S, Sjöström L, Carlsson LM, Romeo S, Valenti L, Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 61, 506– 514 (2015). 25251399 source
• Not checked yetcites [142] Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjærg-Hansen A, Vogt TF, Hobbs HH, Cohen JC, Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nature Genetics 46, 352– 356 (2014). 24531328 PMC3969786 source

In the paper

“The rs58542926 minor allele of transmembrane 6 superfamily member 2 (TM6SF2) is also reportedly associated with MASLD and sometimes MASH (134, 140-142).”

What the sources say

• Not checked yetcites [134] Anstee QM, Darlay R, Cockell S, Meroni M, Govaere O, Tiniakos D, Burt AD, Bedossa P, Palmer J, Liu Y-L, Aithal GP, Allison M, Yki-Järvinen H, Vacca M, Dufour J-F, Invernizzi P, Prati D, Ekstedt M, Kechagias S, Francque S, Petta S, Bugianesi E, Clement K, Ratziu V, Schattenberg JM, Valenti L, Day CP, Cordell HJ, Daly AK, Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort☆. Journal of Hepatology 73, 505– 515 (2020). 32298765 source
• Not checked yetcites [140] Liu Y-L, Reeves HL, Burt AD, Tiniakos D, McPherson S, Leathart JBS, Allison MED, Alexander GJ, Piguet A-C, Anty R, Donaldson P, Aithal GP, Francque S, Van Gaal L, Clement K, Ratziu V, Dufour J-F, Day CP, Daly AK, Anstee QM, TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nature communications 5, 4309 (2014). PMC4279183 24978903 source
• Not checked yetcites [141] Dongiovanni P, Petta S, Maglio C, Fracanzani AL, Pipitone R, Mozzi E, Motta BM, Kaminska D, Rametta R, Grimaudo S, Pelusi S, Montalcini T, Alisi A, Maggioni M, Kärjä V, Borén J, Käkelä P, Di Marco V, Xing C, Nobili V, Dallapiccola B, Craxi A, Pihlajamäki J, Fargion S, Sjöström L, Carlsson LM, Romeo S, Valenti L, Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 61, 506– 514 (2015). 25251399 source
• Not checked yetcites [142] Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjærg-Hansen A, Vogt TF, Hobbs HH, Cohen JC, Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nature Genetics 46, 352– 356 (2014). 24531328 PMC3969786 source

In the paper

“Iron can be shuttled by extracellular vesicles from hepatocytes to HSCs in MASH, stimulating fibrogenesis through iron overload and oxidative stress, an effect that is further exacerbated by TGFβ-mediated suppression of the antioxidant protein cytoglobin (CYGB) (74) (149).”

What the sources say

• Not checked yetcites [74] Gao H, Jin Z, Bandyopadhyay G, Wang G, Zhang D, Rocha K. C. e., Liu X, Zhao H, Kisseleva T, Brenner DA, Karin M, Ying W, Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis. Cell Metabolism 34, 1201– 1213.e1205 (2022). 35921818 PMC9365100 source
• Not checked yetcites [149] Okina Y, Sato-Matsubara M, Matsubara T, Daikoku A, Longato L, Rombouts K, Thanh Thuy LT, Ichikawa H, Minamiyama Y, Kadota M, Fujii H, Enomoto M, Ikeda K, Yoshizato K, Pinzani M, Kawada N, TGF-β1-driven reduction of cytoglobin leads to oxidative DNA damage in stellate cells during non-alcoholic steatohepatitis. Journal of Hepatology 73, 882– 895 (2020). 32330605 source

In the paper

“Among these polymorphisms, carriers of the Patatin Like Phospholipase Domain Containing 3 (PNPLA3) allele rs738409[G] (encoding I148M) are most prevalent in Hispanics and display an increased susceptibility to MASLD and MASH.”

What the sources say

• Not checked yetcites [132] Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH, Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nature Genetics 40, 1461– 1465 (2008). 18820647 PMC2597056 source
• Not checked yetcites [133] Valenti L, Al-Serri A, Daly AK, Galmozzi E, Rametta R, Dongiovanni P, Nobili V, Mozzi E, Roviaro G, Vanni E, Bugianesi E, Maggioni M, Fracanzani AL, Fargion S, Day CP, Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 51, 1209– 1217 (2010). 20373368 source
• Not checked yetcites [134] Anstee QM, Darlay R, Cockell S, Meroni M, Govaere O, Tiniakos D, Burt AD, Bedossa P, Palmer J, Liu Y-L, Aithal GP, Allison M, Yki-Järvinen H, Vacca M, Dufour J-F, Invernizzi P, Prati D, Ekstedt M, Kechagias S, Francque S, Petta S, Bugianesi E, Clement K, Ratziu V, Schattenberg JM, Valenti L, Day CP, Cordell HJ, Daly AK, Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort☆. Journal of Hepatology 73, 505– 515 (2020). 32298765 source

In the paper

“These different communication networks are reflected in the differential expression of ligand-receptor signaling pairs, suggesting that the repertoire of disease drivers – and therefore the underlying signaling events – may change as the disease advances, such that advanced fibrotic stages may respond to different pharmacotherapies than earlier stages (48, 49).”

What the sources say

• Not checked yetcites [48] Wang S, Li K, Pickholz E, Dobie R, Matchett KP, Henderson NC, Carrico C, Driver I, Borch Jensen M, Chen L, Petitjean M, Bhattacharya D, Fiel MI, Liu X, Kisseleva T, Alon U, Adler M, Medzhitov R, Friedman SL, An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Science Translational Medicine 15, eadd3949 (2023). 36599008 PMC10686705 source
• Not checked yetcites [49] Xiao Y, Batmanov K, Hu W, Zhu K, Tom AY, Guan D, Jiang C, Cheng L, McCright SJ, Yang EC, Lanza MR, Liu Y, Hill DA, Lazar MA, Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis. Science Translational Medicine 15, eadc9653 (2023). 36753562 PMC10234568 source

In the paper

“High concentrations of cholesterol and free cholesterol accumulate in HSCs in methionine-choline deficient (MCD) MASH mice, which increases toll-like receptor 4 (TLR4) and sensitizes the cells to TGFβ–induced activation (148).”

What the sources say

• Not checked yetcites [148] Tomita K, Teratani T, Suzuki T, Shimizu M, Sato H, Narimatsu K, Okada Y, Kurihara C, Irie R, Yokoyama H, Shimamura K, Usui S, Ebinuma H, Saito H, Watanabe C, Komoto S, Kawaguchi A, Nagao S, Sugiyama K, Hokari R, Kanai T, Miura S, Hibi T, Free cholesterol accumulation in hepatic stellate cells: Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. Hepatology 59, 154– 169 (2014). 23832448 source

In the paper

“Furthermore, HSD17B13 is not expressed by HSCs, indicating that the impact of the gene in promoting or protecting from fibrosis is indirect and due to changes in hepatocytes.”

In the paper

“From a mechanistic perspective, the I148M single nucleotide polymorphism (SNP) drives injury and fibrosis by promoting fat accumulation in hepatocytes (135) and enhancing fibrogenic activity of HSCs (136), respectively.”

What the sources say

• Not checked yetcites [135] BasuRay S, Smagris E, Cohen JC, Hobbs HH, The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology 66, 1111– 1124 (2017). 28520213 PMC5605398 source
• Not checked yetcites [136] Bruschi FV, Claudel T, Tardelli M, Caligiuri A, Stulnig TM, Marra F, Trauner M, The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells. Hepatology 65, 1875– 1890 (2017). 28073161 source

In the paper

“Another ligand of the TGFβ-bone morphogenetic protein (BMP) superfamily, bone morphogenetic protein 8B (BMP8B), is upregulated in MASH and signals through mothers against decapentaplegic (SMADs) to drive HSC activation in animal models, reinforcing TGFβ's vital role as a fibrogenic stimulus (150).”

What the sources say

• Not checked yetcites [150] Vacca M, Leslie J, Virtue S, Lam BYH, Govaere O, Tiniakos D, Snow S, Davies S, Petkevicius K, Tong Z, Peirce V, Nielsen MJ, Ament Z, Li W, Kostrzewski T, Leeming DJ, Ratziu V, Allison MED, Anstee QM, Griffin JL, Oakley F, Vidal-Puig A, Bone morphogenetic protein 8B promotes the progression of non-alcoholic steatohepatitis. Nature Metabolism 2, 514– 531 (2020). PMC7617436 32694734 source

In the paper

“On the other hand, genetic depletion of Indian hedgehog from hepatocytes reduces MASH fibrosis and hepatocellular carcinoma in a dietary mouse model, suggesting that different hedgehog ligands may have distinct activities (158).”

What the sources say

• Not checked yetcites [158] Chong YC, Lim TE, Fu Y, Shin EM, Tergaonkar V, Han W, Indian Hedgehog links obesity to development of hepatocellular carcinoma. Oncogene 38, 2206– 2222 (2019). 30470823 source

In the paper

“Furthermore, HSCs synthesize hyaluronic acid through the expression of hyaluronic acid synthase 2, which promotes fibrogenicity in a NOTCH1-dependent manner by stimulating TLR4 and CD44 expressed on HSCs themselves (154).”

What the sources say

• Not checked yetcites [154] Yang YM, Noureddin M, Liu C, Ohashi K, Kim SY, Ramnath D, Powell EE, Sweet MJ, Roh YS, Hsin IF, Deng N, Liu Z, Liang J, Mena E, Shouhed D, Schwabe RF, Jiang D, Lu SC, Noble PW, Seki E, Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis. Sci Transl Med 11, (2019). PMC6589184 31189722 source

In the paper

“In hepatocytes, activation of TLR4 increases the expression of jagged 1 (JAG1), a well-established notch receptor 1 (NOTCH1) ligand, which leads to SRY-box transcription factor 9 (SOX9)-dependent transcription and secretion of SPP1, stimulating HSC activation (114).”

What the sources say

• Not checked yetcites [114] Zhu C, Kim K, Wang X, Bartolome A, Salomao M, Dongiovanni P, Meroni M, Graham MJ, Yates KP, Diehl AM, Schwabe RF, Tabas I, Valenti L, Lavine JE, Pajvani UB, Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis. Science Translational Medicine 10, eaat0344 (2018). 30463916 PMC6822168 source

In the paper

“Epigenetic regulation plays a critical role in conveying environmental information that influences gene expression and cellular behavior.”

In the paper

“NOTCH expression has also been detected in endothelial cells of patients with MASH, and its selective depletion or overexpression can reduce or aggravate MASH fibrosis in murine models, respectively, possibly by modulating nitric oxide synthase 3 (eNOS) (155).”

What the sources say

• Not checked yetcites [155] Fang Z-Q, Ruan B, Liu J-J, Duan J-L, Yue Z-S, Song P, Xu H, Ding J, Xu C, Dou G-R, Wang L, Notch-triggered maladaptation of liver sinusoidal endothelium aggravates nonalcoholic steatohepatitis through endothelial nitric oxide synthase. Hepatology 76, 742– 758 (2022). 35006626 source

In the paper

“SPP1, a downstream target of hedgehog signaling, is induced in myofibroblasts in MASH, and its antagonism reduces fibrosis in the MCD mouse model (38, 159).”

What the sources say

• Not checked yetcites [38] Syn W-K, Choi SS, Liaskou E, Karaca GF, Agboola KM, Oo YH, Mi Z, Pereira TA, Zdanowicz M, Malladi P, Chen Y, Moylan C, Jung Y, Bhattacharya SD, Teaberry V, Omenetti A, Abdelmalek MF, Guy CD, Adams DH, Kuo PC, Michelotti GA, Whitington PF, Diehl AM, Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology 53, 106– 115 (2011). 20967826 PMC3025083 source
• Not checked yetcites [159] Sahai A, Malladi P, Melin-Aldana H, Green RM, Whitington PF, Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model. Am J Physiol-Gastr L 287, G264– G273 (2004). 15044174 source

In the paper

“SPP1 expression and secretion is also promoted by nuclear factor of activated T cells 4 (NFATc4) and coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), transcription factors activated in MASH mice and patients (160, 161).”

What the sources say

• Not checked yetcites [160] Du M, Wang X, Yuan L, Liu B, Mao X, Huang D, Yang L, Huang K, Zhang F, Wang Y, Luo X, Wang C, Peng J, Liang M, Huang D, Huang K, Targeting NFATc4 attenuates non-alcoholic steatohepatitis in mice. Journal of Hepatology 73, 1333– 1346 (2020). 32717288 source
• Not checked yetcites [161] Li Y, Xiu W, Xu J, Chen X, Wang G, Duan J, Sun L, Liu B, Xie W, Pu G, Wang Q, Wang C, Increased CHCHD2 expression promotes liver fibrosis in nonalcoholic steatohepatitis via Notch/osteopontin signaling. JCI Insight 7, (2022). PMC9746920 36477358 source

In the paper

“Ballooning of hepatocytes is a prominent pathologic hallmark of MASH that distinguishes MASH from MASLD and is thought to represent a unique type of cell injury that is associated with lipotoxicity and release of inflammatory and fibrogenic signals.”

In the paper

“Other major sources of hedgehog ligands may be reactive-appearing ductular cells that strongly correlate with fibrosis in patients with MASH or in MASH-associated hepatocytes where increased cholesterol intake activate TAZ to drive Indian hedgehog expression and secretion (112, 113, 163).”

What the sources say

• Not checked yetcites [112] Wang X, Zheng Z, Caviglia JM, Corey KE, Herfel TM, Cai B, Masia R, Chung RT, Lefkowitch JH, Schwabe RF, Tabas I, Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis. Cell Metabolism 24, 848– 862 (2016). 28068223 PMC5226184 source
• Not checked yetcites [113] Wang X, Cai B, Yang X, Sonubi OO, Zheng Z, Ramakrishnan R, Shi H, Valenti L, Pajvani UB, Sandhu J, Infante RE, Radhakrishnan A, Covey DF, Guan K-L, Buck J, Levin LR, Tontonoz P, Schwabe RF, Tabas I, Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis. Cell Metabolism 31, 969– 986.e967 (2020). 32259482 PMC7313619 source
• Not checked yetcites [163] Machado MV, Michelotti GA, Pereira TA, Xie G, Premont R, Cortez-Pinto H, Diehl AM, Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease. Journal of Hepatology 63, 962– 970 (2015). 26070409 PMC4575842 source

In the paper

“In addition to generation of intermediary metabolites through glycolysis, lipolysis, and glutaminolysis, the cells rely on activation of autophagy to release fatty acids through hydrolysis of retinyl esters (183) linked to endoplasmic reticulum stress (184).”

What the sources say

• Not checked yetcites [183] Hernandez-Gea V, Ghiassi-Nejad Z, Rozenfeld R, Gordon R, Fiel MI, Yue Z, Czaja MJ, Friedman SL, Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142, 938– 946 (2012). 22240484 PMC3439519 source
• Not checked yetcites [184] Hernandez-Gea V, Hilscher M, Rozenfeld R, Lim MP, Nieto N, Werner S, Devi LA, Friedman SL, Endoplasmic reticulum stress induces fibrogenic activity in hepatic stellate cells through autophagy. J Hepatol 59, 98– 104 (2013). 23485523 PMC3686909 source

In the paper

“Mechanistically, lipoprotein lipase promotes free cholesterol accumulation in HSCs, which in turn activates TLR4 signaling and reduces Bambi expression that together sensitizes HSCs to TGFβ-driven activation (188).”

What the sources say

• Not checked yetcites [188] Teratani T, Tomita K, Furuhashi H, Sugihara N, Higashiyama M, Nishikawa M, Irie R, Takajo T, Wada A, Horiuchi K, Inaba K, Hanawa Y, Shibuya N, Okada Y, Kurihara C, Nishii S, Mizoguchi A, Hozumi H, Watanabe C, Komoto S, Nagao S, Yamamoto J, Miura S, Hokari R, Kanai T, Lipoprotein Lipase Up-regulation in Hepatic Stellate Cells Exacerbates Liver Fibrosis in Nonalcoholic Steatohepatitis in Mice. Hepatology Communications 3, 1098– 1112 (2019). 31388630 PMC6671781 source

In the paper

“However, for MASH, only cholesterol and lipid metabolism have been linked to HSC fibrogenicity in vivo.”

In the paper

“These findings implicate the microbiota in driving this critical transition, but fecal transplant studies have yielded mixed results and no single bacterium has emerged as a pathogenic agent across different studies.”

In the paper

“Transplant of fecal microbiota from lean healthy donors into obese patients improved lipid profiles and reduced liver stiffness in one study (200), whereas in another a synbiotic formation (probiotics + prebiotics) failed to alter fibrosis (201).”

What the sources say

• Not checked yetcites [200] Ng SC, Xu Z, Mak JWY, Yang K, Liu Q, Zuo T, Tang W, Lau L, Lui RN, Wong SH, Tse YK, Li AYL, Cheung K, Ching JYL, Wong VWS, Kong APS, Ma RCW, Chow EYK, Wong SKH, Ho ICH, Chan PKS, Chan FKL, Microbiota engraftment after faecal microbiota transplantation in obese subjects with type 2 diabetes: a 24-week, double-blind, randomised controlled trial. Gut 71, 716 (2022). 33785557 source

In the paper

“Studies on different strains of mice have shown that plasma cholesterol strongly correlates with the extent of fibrosis, and mice supplemented with high cholesterol develop increased fibrosis (148, 186).”

What the sources say

• Not checked yetcites [148] Tomita K, Teratani T, Suzuki T, Shimizu M, Sato H, Narimatsu K, Okada Y, Kurihara C, Irie R, Yokoyama H, Shimamura K, Usui S, Ebinuma H, Saito H, Watanabe C, Komoto S, Kawaguchi A, Nagao S, Sugiyama K, Hokari R, Kanai T, Miura S, Hibi T, Free cholesterol accumulation in hepatic stellate cells: Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. Hepatology 59, 154– 169 (2014). 23832448 source
• Not checked yetcites [186] Hui ST, Kurt Z, Tuominen I, Norheim F, Davis RC, Pan C, Dirks DL, Magyar CE, French SW, Chella Krishnan K, Sabir S, Campos-Pérez F, Méndez-Sánchez N, Macías-Kauffer L, León-Mimila P, Canizales-Quinteros S, Yang X, Beaven SW, Huertas-Vazquez A, Lusis AJ, The Genetic Architecture of Diet-Induced Hepatic Fibrosis in Mice. Hepatology 68, (2018). PMC6269199 29907965 source

In the paper

“Co-housing wildtype mice with mice prone to MASH led to increased disease severity in wildtype mice, presumably due to a transfer of fecal microbiota (204).”

What the sources say

• Not checked yetcites [204] Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez J-P, Shulman GI, Gordon JI, Hoffman HM, Flavell RA, Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179– 185 (2012). 22297845 PMC3276682 source

In the paper

“Lipoprotein lipase abundance also increases in HSCs in patients with MASLD and MASH, and depletion of lipoprotein lipase selectively in HSCs reduces their activation and liver fibrosis progression in a rodent model of MASLD (188).”

What the sources say

• Not checked yetcites [188] Teratani T, Tomita K, Furuhashi H, Sugihara N, Higashiyama M, Nishikawa M, Irie R, Takajo T, Wada A, Horiuchi K, Inaba K, Hanawa Y, Shibuya N, Okada Y, Kurihara C, Nishii S, Mizoguchi A, Hozumi H, Watanabe C, Komoto S, Nagao S, Yamamoto J, Miura S, Hokari R, Kanai T, Lipoprotein Lipase Up-regulation in Hepatic Stellate Cells Exacerbates Liver Fibrosis in Nonalcoholic Steatohepatitis in Mice. Hepatology Communications 3, 1098– 1112 (2019). 31388630 PMC6671781 source

In the paper

“Autophagy also provokes the release of miR-29a, which can stimulate fibrogenesis in neighboring cells through paracrine signaling (185).”

What the sources say

• Not checked yetcites [185] Yu X, Elfimova N, Muller M, Bachurski D, Koitzsch U, Drebber U, Mahabir E, Hansen HP, Friedman SL, Klein S, Dienes HP, Hosel M, Buettner R, Trebicka J, Kondylis V, Mannaerts I, Odenthal M, Autophagy-Related Activation of Hepatic Stellate Cells Reduces Cellular miR-29a by Promoting Its Vesicular Secretion. Cell Mol Gastroenterol Hepatol 13, 1701– 1716 (2022). 35219894 PMC9046234 source

In the paper

“Mice overexpressing both ACC1 and ACC2 display increased de novo lipogenesis in the liver and spontaneously develop MASH-like symptoms (189).”

What the sources say

• Not checked yetcites [189] Fullerton MD, Galic S, Marcinko K, Sikkema S, Pulinilkunnil T, Chen Z-P, O'Neill HM, Ford RJ, Palanivel R, O'Brien M, Hardie DG, Macaulay SL, Schertzer JD, Dyck JRB, van Denderen BJ, Kemp BE, Steinberg GR, Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nature Medicine 19, 1649– 1654 (2013). PMC4965268 24185692 source

In the paper

“However, these mice do not become obese and therefore fail to develop associated metabolic defects, including insulin resistance.”

In the paper

“The degree of fibrosis ranged from non-detectable to robust, indicating a major contribution of genetic background to MASH pathology (186).”

What the sources say

• Not checked yetcites [186] Hui ST, Kurt Z, Tuominen I, Norheim F, Davis RC, Pan C, Dirks DL, Magyar CE, French SW, Chella Krishnan K, Sabir S, Campos-Pérez F, Méndez-Sánchez N, Macías-Kauffer L, León-Mimila P, Canizales-Quinteros S, Yang X, Beaven SW, Huertas-Vazquez A, Lusis AJ, The Genetic Architecture of Diet-Induced Hepatic Fibrosis in Mice. Hepatology 68, (2018). PMC6269199 29907965 source

In the paper

“The Oz mouse harbors a spontaneous mutation within the Alstrom syndrome 1 (Alms1) gene, similar to patients with Alstrom syndrome, which, when combined with a Western diet on a C57BL/6 background, leads to obesity and diabetes, then MASH, with advanced fibrosis by 12 weeks of age (43, 229, 230).”

What the sources say

• Not checked yetcites [43] Ganguly S, Muench GA, Shang L, Rosenthal SB, Rahman G, Wang R, Wang Y, Kwon HC, Diomino AM, Kisseleva T, Soorosh P, Hosseini M, Knight R, Schnabl B, Brenner DA, Dhar D, Nonalcoholic Steatohepatitis and HCC in a Hyperphagic Mouse Accelerated by Western Diet. Cellular and Molecular Gastroenterology and Hepatology 12, 891– 920 (2021). 34062281 PMC8342972 source
• Not checked yetcites [229] Farrell GC, Mridha AR, Yeh MM, Arsov T, Van Rooyen DM, Brooling J, Nguyen T, Heydet D, Delghingaro-Augusto V, Nolan CJ, Shackel NA, McLennan SV, Teoh NC, Larter CZ, Strain dependence of diet-induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype. Liver International 34, 1084– 1093 (2014). 24107103 source
• Not checked yetcites [230] Arsov T, Silva DG, O’Bryan MK, Sainsbury A, Lee NJ, Kennedy C, Manji SSM, Nelms K, Liu C, Vinuesa CG, de Kretser DM, Goodnow CC, Petrovsky N, Fat Aussie—A New Alström Syndrome Mouse Showing a Critical Role for ALMS1 in Obesity, Diabetes, and Spermatogenesis. Molecular Endocrinology 20, 1610– 1622 (2006). 16513793 source

In the paper

“A different adipocyte secreted hormone, adiponectin, has antifibrotic properties but has not yet emerged as a therapeutic, although increased adiponectin is emerging as an indication of therapeutic benefit in clinical trials of metabolic therapy for MASH (220).”

What the sources say

• Not checked yetcites [220] Marques V, Afonso MB, Bierig N, Duarte-Ramos F, Santos-Laso A, Jimenez-Aguero R, Eizaguirre E, Bujanda L, Pareja MJ, Luis R, Costa A, Machado MV, Alonso C, Arretxe E, Alustiza JM, Krawczyk M, Lammert F, Tiniakos DG, Flehmig B, Cortez-Pinto H, Banales JM, Castro RE, Normann A, Rodrigues CMP, Adiponectin, Leptin, and IGF-1 Are Useful Diagnostic and Stratification Biomarkers of NAFLD. Front Med (Lausanne) 8, 683250 (2021). 34249975 PMC8260936 source

In the paper

“Rodent models of MASH have been extensively reviewed and comprise 3 broad categories: 1) diet-based; 2) genetic; or 3) mixed, which refers to combined diet, genetic, or chemical perturbations (118, 210-213).”

What the sources say

• Not checked yetcites [118] Santhekadur PK, Kumar DP, Sanyal AJ, Preclinical models of non-alcoholic fatty liver disease. Journal of Hepatology 68, 230– 237 (2018). 29128391 PMC5775040 source
• Not checked yetcites [210] Hunter H, de Gracia Hahn D, Duret A, Im YR, Cheah Q, Dong J, Fairey M, Hjalmarsson C, Li A, Lim HK, McKeown L, Mitrofan C-G, Rao R, Utukuri M, Rowe IA, Mann JP, Weight loss, insulin resistance, and study design confound results in a meta-analysis of animal models of fatty liver. eLife 9, e56573 (2020). 33063664 PMC7647398 source
• Not checked yetcites [211] Ibrahim SH, Hirsova P, Malhi H, Gores GJ, Animal Models of Nonalcoholic Steatohepatitis: Eat, Delete, and Inflame. Digest Dis Sci 61, 1325– 1336 (2016). 26626909 PMC4838538 source
• Not checked yetcites [212] Brenner DA, Of Mice and Men and Nonalcoholic Steatohepatitis. Hepatology 68, 2059– 2061 (2018). 30033687 PMC6398944 source
• Not checked yetcites [213] Im YR, Hunter H, de Gracia Hahn D, Duret A, Cheah Q, Dong J, Fairey M, Hjalmarsson C, Li A, Lim HK, McKeown L, Mitrofan C-G, Rao R, Utukuri M, Rowe IA, Mann JP, A Systematic Review of Animal Models of NAFLD Finds High-Fat, High-Fructose Diets Most Closely Resemble Human NAFLD. Hepatology 74, 1884– 1901 (2021). 33973269 source

In the paper

“The prevalence of co-morbid diabetes and MASH is high, with up to 75% of type II diabetes patients also developing MASLD (3).”

What the sources say

• Not checked yetcites [3] Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ, Mechanisms of NAFLD development and therapeutic strategies. Nature Medicine 24, 908– 922 (2018). PMC6553468 29967350 source

In the paper

“MASH dysbiosis also incorporates an altered fungal flora, with some efficacy of antifungals in reducing disease severity and fibrosis in germ-free mice (209).”

What the sources say

• Not checked yetcites [209] Demir M, Lang S, Hartmann P, Duan Y, Martin A, Miyamoto Y, Bondareva M, Zhang X, Wang Y, Kasper P, Bang C, Roderburg C, Tacke F, Steffen H-M, Goeser T, Kruglov A, Eckmann L, Stärkel P, Fouts DE, Schnabl B, The fecal mycobiome in non-alcoholic fatty liver disease☆. Journal of Hepatology 76, 788– 799 (2022). 34896404 PMC8981795 source

In the paper

“Although MASH development in both Oz and Agouti yellow mice follow the natural history of disease progression in humans, both models require mice with specific genetic backgrounds.”

In the paper

“Among the most often used genetic models of MASLD are mice genetically deficient for leptin (ob/ob) or the leptin receptor (db/db) (216-219).”

What the sources say

• Not checked yetcites [216] Polyzos SA, Kountouras J, Mantzoros CS, Leptin in nonalcoholic fatty liver disease: A narrative review. Metabolism 64, 60– 78 (2015). 25456097 source
• Not checked yetcites [217] Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM, Weight-Reducing Effects of the Plasma Protein Encoded by the obese Gene. Science 269, 543– 546 (1995). 7624777 source
• Not checked yetcites [218] Hummel KP, Dickie MM, Coleman DL, Diabetes, a New Mutation in the Mouse. Science 153, 1127– 1128 (1966). 5918576 source
• Not checked yetcites [219] Sahai A, Malladi P, Pan X, Paul R, Melin-Aldana H, Green RM, Whitington PF, Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin. Am J Physiol-Gastr L 287, G1035– G1043 (2004). 15256362 source

In the paper

“However, liver disease progression is slow on a Western diet alone in common inbred mouse strains such as C57Bl/6 and thus additional injury may accelerate progression, which can be accomplished by administering low weekly doses of the hepatotoxin carbon tetrachloride (CCl4).”

In the paper

“For instance, the diet-induced animal model of non-alcoholic fatty liver disease (DIAMOND) mouse model exposes B6/129 mixed strain mice to a Western diet, leading to the development of hepatocellular carcinoma in most animals between 32-52 weeks (228).”

What the sources say

• Not checked yetcites [228] Asgharpour A, Cazanave SC, Pacana T, Seneshaw M, Vincent R, Banini BA, Kumar DP, Daita K, Min H-K, Mirshahi F, Bedossa P, Sun X, Hoshida Y, Koduru SV, Contaifer D, Warncke UO, Wijesinghe DS, Sanyal AJ, A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer. Journal of Hepatology 65, 579– 588 (2016). 27261415 PMC5012902 source

In the paper

“Earlier stages of MASH fibrosis can regress more easily than advanced stages, a trend observed in other liver diseases (260), which may be explained in part by the marked increase in total collagen and extracellular matrix associated with progressive fibrosis (261).”

What the sources say

• Not checked yetcites [260] Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R, Fibrosis Progression in Nonalcoholic Fatty Liver vs Nonalcoholic Steatohepatitis: A Systematic Review and Meta-analysis of Paired-Biopsy Studies. Clinical Gastroenterology and Hepatology 13, 643– 654.e649 (2015). 24768810 PMC4208976 source

In the paper

“Nevertheless, these interventions suggest that, like HCV and HBV, MASH fibrosis is reversible in non-cirrhotic liver, but unlike in HCV and HBV there is no evidence yet that cirrhosis in MASH is reversible (259).”

What the sources say

• Not checked yetcites [259] Lassailly G, Caiazzo R, Ntandja-Wandji LC, Gnemmi V, Baud G, Verkindt H, Ningarhari M, Louvet A, Leteurtre E, Raverdy V, Dharancy S, Pattou F, Mathurin P, Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis. Gastroenterology 159, 1290– 1301 e1295 (2020). 32553765 source

In the paper

“However, PCLS requires continued access to human liver core biopsies, which can be challenging to acquire.”

In the paper

“As a perhaps simpler alternative to organ-on-chip systems, PCLS cultures are ~200 micron-thick tissue slices cut out of a liver core biopsy that has been shown to maintain cell identity and tissue structure for several days when cultured under specialized conditions (248)(249).”

What the sources say

• Not checked yetcites [248] van de Bovenkamp M, Groothuis GM, Meijer DK, Olinga P, Precision-cut fibrotic rat liver slices as a new model to test the effects of anti-fibrotic drugs in vitro. J Hepatol 45, 696– 703 (2006). 16828918 source
• Not checked yetcites [249] Paish HL, Reed LH, Brown H, Bryan MC, Govaere O, Leslie J, Barksby BS, Garcia Macia M, Watson A, Xu X, Zaki MYW, Greaves L, Whitehall J, French J, White SA, Manas DM, Robinson SM, Spoletini G, Griffiths C, Mann DA, Borthwick LA, Drinnan MJ, Mann J, Oakley F, A Bioreactor Technology for Modeling Fibrosis in Human and Rodent Precision-Cut Liver Slices. Hepatology, (2019). PMC6852483 30963615 source

In the paper

“The microbiome can profoundly influence responsiveness to pharmacotherapies in disease models outside the liver (237, 238), and similar approaches are being explored in MASH.”

What the sources say

• Not checked yetcites [237] Rosshart SP, Vassallo BG, Angeletti D, Hutchinson DS, Morgan AP, Takeda K, Hickman HD, McCulloch JA, Badger JH, Ajami NJ, Trinchieri G, Pardo-Manuel de Villena F, Yewdell JW, Rehermann B, Wild Mouse Gut Microbiota Promotes Host Fitness and Improves Disease Resistance. Cell 171, 1015– 1028.e1013 (2017). 29056339 PMC6887100 source
• Not checked yetcites [238] Rosshart SP, Herz J, Vassallo BG, Hunter A, Wall MK, Badger JH, McCulloch JA, Anastasakis DG, Sarshad AA, Leonardi I, Collins N, Blatter JA, Han S-J, Tamoutounour S, Potapova S, Foster St. Claire MB, Yuan W, Sen SK, Dreier MS, Hild B, Hafner M, Wang D, Iliev ID, Belkaid Y, Trinchieri G, Rehermann B, Laboratory mice born to wild mice have natural microbiota and model human immune responses. Science 365, eaaw4361 (2019). 31371577 PMC7377314 source

In the paper

“Additionally patients may have spontaneous improvement without intervention, a feature that could contribute to the surprisingly high rates of response among placebo patients in clinical trials (250-252).”

What the sources say

• Not checked yetcites [250] Shamseddeen H, Vilar-Gomez E, Chalasani N, Myers RP, Subramanian GM, Shlevin HH, Allgood AE, Orman ES, Spontaneous Fluctuations in Liver Biochemistries in Patients with Compensated NASH Cirrhosis: Implications for Drug Hepatotoxicity Monitoring. Drug Saf 43, 281– 290 (2020). 31907854 PMC7050367 source
• Not checked yetcites [251] Albhaisi S, Sanyal AJ, Applying Non-Invasive Fibrosis Measurements in NAFLD/NASH: Progress to Date. Pharmaceut Med 33, 451– 463 (2019). 31933238 source
• Not checked yetcites [252] Ratziu V, Charlton M, Rational combination therapy for NASH: Insights from clinical trials and error. J Hepatol, (2023). 36603662 source

In the paper

“In theory, organ-on-chip systems have the potential to study inter-organ cross-talk, such as those between the liver and intestine; however, the effectiveness of such systems has yet to be proven.”