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

In the paper

“Proteomics analysis of patient serum also identified a protein signature that effectively distinguished different stages of fibrosis (123).”

What the sources say

• Supported

  The Methods and Results describe proteomic analysis of patient serum and plasma and an eight-protein panel that distinguished early fibrosis (F0–1) from more advanced fibrosis groups (F2–3 and F2–4). The claim accurately summarizes that distinction; the paper does not claim to distinguish every individual stage. (LLM, conf=0.91)

  cites [123] Corey KE, Pitts R, Lai M, Loureiro J, Masia R, Osganian SA, Gustafson JL, Hutter MM, Gee DW, Meireles OR, Witkowski ER, Richards SM, Jacob J, Finkel N, Ngo D, Wang TJ, Gerszten RE, Ukomadu C, Jennings LL, ADAMTSL2 protein and a soluble biomarker signature identify at-risk non-alcoholic steatohepatitis and fibrosis in adults with NAFLD. Journal of Hepatology 76, 25– 33 (2022). 34600973 PMC8688231 source

In the paper

“Blocking notch signaling in MASH, both genetically and pharmacologically, can attenuate MASH-associated liver fibrosis (114).”

What the sources say

• Supported

  The Results sections report less collagen deposition after genetic inhibition of hepatocyte Notch and reduced liver fibrosis after pharmacologic inhibition in NASH diet–fed mice. NASH is now termed MASH; the paper’s Discussion clarifies that these intervention findings have not been tested in humans. (LLM, conf=0.93)

  cites [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

“We recently used single nuclear RNA-seq in murine MASH models and patients with MASH to demonstrate enrichment of pathways in myofibroblasts that regulate extracellular matrix production and cell migration, including matrix metalloproteinase (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and lysyl oxidases (LOXLs) (47-49), similar to earlier studies of mouse fibrosis and human cirrhosis”

What the sources say

• Not checked yetcites [47] Wang Z-Y, Keogh A, Waldt A, Cuttat R, Neri M, Zhu S, Schuierer S, Ruchti A, Crochemore C, Knehr J, Bastien J, Ksiazek I, Sánchez-Taltavull D, Ge H, Wu J, Roma G, Helliwell SB, Stroka D, Nigsch F, Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis. Sci Rep-Uk 11, 19396 (2021). PMC8481490 34588551 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

In the paper

“Further informatic subsetting of purified HSCs in the foz/foz mouse model revealed 3 distinct activated cell clusters and 1 inactivated cell cluster, expressing different abundances of classical myofibroblast markers such as alpha smooth muscle actin (Acta2), collagen type 1 alpha 1 (Col1a1), and tissue inhibitors of metalloproteinase 1 (Timp1) at the transcript level.”

In the paper

“Progressive injury leads to changes in the quality and quantity of ECM with accumulation of fibrillar collagen (primarily types I and III) initially within the subendothelial space, which coalesce over years to form fibrils that generate bands of collagen.”

In the paper

“Specifically, accumulation of ECM increases the stiffness of the liver both macro- and microscopically.”

In the paper

“Once fibrosis begins to distort the liver’s architecture, disrupting blood flow and oxygenation of the tissue, the functional and regenerative capacity of liver is impaired to an extent detectable by routine tests including INR, albumin, and platelet count, among others.”

In the paper

“Liver fibrosis develops in response to chronic injury to the parenchyme comprised of hepatocytes.”

In the paper

“Increasing liver stiffness during fibrosis progression is the basis for diagnostic techniques of transient- and magnetic resonance-elastography to stage MASH fibrosis, as an alternative to liver biopsy.”

In the paper

“In fatty liver disease, increased circulating fatty acid uptake and de novo lipogenesis by hepatocytes promotes lipid accumulation with the generation of reactive oxygen species (ROS) and products of lipid peroxidation.”

What the sources say

• 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
• Not checked yetcites [20] Kakisaka K, Cazanave SC, Fingas CD, Guicciardi ME, Bronk SF, Werneburg NW, Mott JL, Gores GJ, Mechanisms of lysophosphatidylcholine-induced hepatocyte lipoapoptosis. Am J Physiol-Gastr L 302, G77– G84 (2011). PMC3345964 21995961 source

In the paper

“Ultimately both fibrosis and the changes it confers throughout the liver contribute to a microenvironment that is permissive for development of hepatocellular carcinoma.”

In the paper

“Dying or damaged hepatocytes secrete damage-associated molecular patterns including high mobility group box 1 protein (HMGB1), osteopontin (SPP1), purinoceptor 14 (P2Y14) ligands, apoptotic bodies, microRNA (miRNA), and DNA that can be packaged into microvesicles and directly taken up by HSCs, leading to their activation into collagen-producing myofibroblasts (see “Cellular plasticity”, below) (23”

What the sources say

• Not checked yetcites [23] Zhan S-S, Jiang JX, Wu J, Halsted C, Friedman SL, Zern MA, Torok NJ, Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo. Hepatology 43, 435– 443 (2006). 16496318 source
• Not checked yetcites [24] Canbay A, Taimr P, Torok N, Higuchi H, Friedman S, Gores GJ, Apoptotic Body Engulfment by a Human Stellate Cell Line Is Profibrogenic. Laboratory Investigation 83, 655– 663 (2003). 12746475 source
• Not checked yetcites [25] Watanabe A, Hashmi A, Gomes DA, Town T, Badou A, Flavell RA, Mehal WZ, Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9. Hepatology 46, 1509– 1518 (2007). 17705260 source
• Not checked yetcites [26] Arriazu E, Ge X, Leung T-M, Magdaleno F, Lopategi A, Lu Y, Kitamura N, Urtasun R, Theise N, Antoine DJ, Nieto N, Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury. Gut 66, 1123 (2017). 26818617 PMC5532463 source
• Not checked yetcites [27] Povero D, Panera N, Eguchi A, Johnson CD, Papouchado BG, de Araujo Horcel L, Pinatel EM, Alisi A, Nobili V, Feldstein AE, Lipid-Induced Hepatocyte-Derived Extracellular Vesicles Regulate Hepatic Stellate Cells via MicroRNA Targeting Peroxisome Proliferator-Activated Receptor-γ. Cellular and Molecular Gastroenterology and Hepatology 1, 646– 663.e644 (2015). 26783552 PMC4714359 source
• Not checked yetcites [28] Lee Y-S, Kim SY, Ko E, Lee J-H, Yi H-S, Yoo YJ, Je J, Suh SJ, Jung YK, Kim JH, Seo YS, Yim HJ, Jeong W-I, Yeon JE, Um SH, Byun KS, Exosomes derived from palmitic acid-treated hepatocytes induce fibrotic activation of hepatic stellate cells. Sci Rep-Uk 7, 3710 (2017). PMC5473841 28623272 source
• Not checked yetcites [29] Hernández A, Reyes D, Geng Y, Arab JP, Cabrera D, Sepulveda R, Solis N, Buist-Homan M, Arrese M, Moshage H, Extracellular vesicles derived from fat-laden hepatocytes undergoing chemical hypoxia promote a pro-fibrotic phenotype in hepatic stellate cells. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1866, 165857 (2020). 32512191 source
• Not checked yetcites [30] An P, Wei L-L, Zhao S, Sverdlov DY, Vaid KA, Miyamoto M, Kuramitsu K, Lai M, Popov YV, Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis. Nature communications 11, 2362 (2020). PMC7217909 32398673 source
• Not checked yetcites [31] Mederacke I, Filliol A, Affo S, Nair A, Hernandez C, Sun Q, Hamberger F, Brundu F, Chen Y, Ravichandra A, Huebener P, Anke H, Shi H, Martínez García de la Torre RA, Smith JR, Henderson NC, Vondran FWR, Rothlin CV, Baehre H, Tabas I, Sancho-Bru P, Schwabe RF, The purinergic P2Y14 receptor links hepatocyte death to hepatic stellate cell activation and fibrogenesis in the liver. Science Translational Medicine 14, eabe5795. 35385339 PMC9436006 source

In the paper

“Hepatocyte death promotes fibrosis indirectly through inflammasome activation and recruitment of inflammatory cells, especially macrophages, that stimulate myofibroblasts and alter extracellular matrix turnover (21, 22).”

What the sources say

• Not checked yetcites [21] Csak T, Ganz M, Pespisa J, Kodys K, Dolganiuc A, Szabo G, Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology 54, 133– 144 (2011). 21488066 PMC4158408 source
• Not checked yetcites [22] Wree A, Eguchi A, McGeough MD, Pena CA, Johnson CD, Canbay A, Hoffman HM, Feldstein AE, NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology 59, 898– 910 (2014). 23813842 PMC4008151 source

In the paper

“This buildup of toxic byproducts eventually exceeds the liver’s detoxification systems, leading to macromolecular damage, cellular stress, and cell death (4, 20).”

What the sources say

• 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
• Not checked yetcites [20] Kakisaka K, Cazanave SC, Fingas CD, Guicciardi ME, Bronk SF, Werneburg NW, Mott JL, Gores GJ, Mechanisms of lysophosphatidylcholine-induced hepatocyte lipoapoptosis. Am J Physiol-Gastr L 302, G77– G84 (2011). PMC3345964 21995961 source

In the paper

“Like hepatocytes, cholangiocytes can undergo lipoapoptosis and senescence in the presence of increased saturated fatty acids, which may provoke release of damage-associated molecular patterns, senescence-associated secretory patterns (such as chemokine ligand 2 (CCL2)), and SPP1, which activate HSCs to generate fibrosis (37-40).”

What the sources say

• Not checked yetcites [37] Tabibian JH, O'Hara SP, Splinter PL, Trussoni CE, LaRusso NF, Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis. Hepatology 59, 2263– 2275 (2014). 24390753 PMC4167827 source
• 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 [39] Natarajan SK, Ingham SA, Mohr AM, Wehrkamp CJ, Ray A, Roy S, Cazanave SC, Phillippi MA, Mott JL, Saturated free fatty acids induce cholangiocyte lipoapoptosis. Hepatology 60, 1942– 1956 (2014). 24753158 PMC4553418 source
• Not checked yetcites [40] Chiba M, Sasaki M, Kitamura S, Ikeda H, Sato Y, Nakanuma Y, Participation of bile ductular cells in the pathological progression of non-alcoholic fatty liver disease. Journal of Clinical Pathology 64, 564 (2011). 21486894 source

In the paper

“The detection of both quiescent and activated HSCs in mouse liver injury models using single cell RNA-seq reinforces HSC activation as a driver of fibrosis common across etiologies that includes MASH (46-50).”

What the sources say

• 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
• Not checked yetcites [47] Wang Z-Y, Keogh A, Waldt A, Cuttat R, Neri M, Zhu S, Schuierer S, Ruchti A, Crochemore C, Knehr J, Bastien J, Ksiazek I, Sánchez-Taltavull D, Ge H, Wu J, Roma G, Helliwell SB, Stroka D, Nigsch F, Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis. Sci Rep-Uk 11, 19396 (2021). PMC8481490 34588551 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 [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

In the paper

“Other macrophage-secreted cytokines that may promote HSC activation include PDGF, tumor necrosis factor alpha (TNFα), and interleukin 1 beta ( IL-1β) (65-69).”

What the sources say

• Not checked yetcites [65] Pradere J-P, Kluwe J, De Minicis S, Jiao J-J, Gwak G-Y, Dapito DH, Jang M-K, Guenther ND, Mederacke I, Friedman R, Dragomir A-C, Aloman C, Schwabe RF, Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 58, 1461– 1473 (2013). 23553591 PMC3848418 source
• Not checked yetcites [66] Petrasek J, Bala S, Csak T, Lippai D, Kodys K, Menashy V, Barrieau M, Min S-Y, Kurt-Jones EA, Szabo G, IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. The Journal of Clinical Investigation 122, 3476– 3489 (2012). 22945633 PMC3461900 source
• Not checked yetcites [67] Wong L, Yamasaki G, Johnson RJ, Friedman SL, Induction of beta-platelet-derived growth factor receptor in rat hepatic lipocytes during cellular activation in vivo and in culture. The Journal of Clinical Investigation 94, 1563– 1569 (1994). 7929832 PMC295310 source
• Not checked yetcites [68] Hellerbrand C, Stefanovic B, Giordano F, Burchardt ER, Brenner DA, The role of TGFβ1 in initiating hepatic stellate cell activation in vivo. Journal of Hepatology 30, 77– 87 (1999). 9927153 source
• Not checked yetcites [69] Cai B, Dongiovanni P, Corey KE, Wang X, Shmarakov IO, Zheng Z, Kasikara C, Davra V, Meroni M, Chung RT, Rothlin CV, Schwabe RF, Blaner WS, Birge RB, Valenti L, Tabas I, Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis. Cell Metabolism 31, 406– 421.e407 (2020). 31839486 PMC7004886 source

In the paper

“First, a subset of monocytes recruited into the chronically injured liver differentiate into profibrogenic, triggering receptor expressed on myeloid cells 2 (TREM2)-expressing macrophages (73).”

What the sources say

• Not checked yetcites [73] Wen Y, Lambrecht J, Ju C, Tacke F, Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities. Cellular & Molecular Immunology 18, 45– 56 (2021). 33041338 PMC7852525 source

In the paper

“Fibrogenic cells in the liver exhibit extraordinary plasticity in chronic injury from MASH, especially the activation of HSCs into myofibroblasts.”

In the paper

“Macrophages regulate extracellular matrix composition and turnover through the expression of small amounts of collagens (for example COL1A1, collagen type 3 alpha 1 (COL3A1)) and matrix metalloproteases (for example matrix metalloprotease 2 (MMP2), matrix metalloprotease 13 (MMP13) (59, 60).”

What the sources say

• Not checked yetcites [59] Ramachandran P, Matchett KP, Dobie R, Wilson-Kanamori JR, Henderson NC, Single-cell technologies in hepatology: new insights into liver biology and disease pathogenesis. Nature Reviews Gastroenterology & Hepatology 17, 457– 472 (2020). 32483353 source
• Not checked yetcites [60] Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, Wu S, Lang R, Iredale JP, Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. The Journal of Clinical Investigation 115, 56– 65 (2005). 15630444 PMC539199 source

In the paper

“Natural killer (NK) cells have an intriguing capacity to clear activated HSCs (91-94).”

What the sources say

• Not checked yetcites [91] Muhanna N, Abu Tair L, Doron S, Amer J, Azzeh M, Mahamid M, Friedman S, Safadi R, Amelioration of hepatic fibrosis by NK cell activation. Gut 60, 90– 98 (2011). 20660699 source
• Not checked yetcites [92] Abu-Tair L, Axelrod JH, Doron S, Ovadya Y, Krizhanovsky V, Galun E, Amer J, Safadi R, Natural Killer Cell-Dependent Anti-Fibrotic Pathway in Liver Injury via Toll-Like Receptor-9. PLoS One 8, e82571 (2013). 24340043 PMC3858328 source
• Not checked yetcites [93] Zhang Y, Wu Y, Shen W, Wang B, Yuan X, Crosstalk between NK cells and hepatic stellate cells in liver fibrosis (Review). Mol Med Rep 25, (2022). PMC9133963 35506449 source
• 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

“Monocyte-derived macrophages also stimulate HSC migration and recruitment through the secretion of CCL2, chemokine ligand 5 (CCL5), and SPP1 (70-72).”

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 [71] Miura K, Yang L, van Rooijen N, Ohnishi H, Seki E, Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am J Physiol-Gastr L 302, G1310– G1321 (2012). PMC3378163 22442158 source
• Not checked yetcites [72] Seki E, De Minicis S, Gwak G-Y, Kluwe J, Inokuchi S, Bursill CA, Llovet JM, Brenner DA, Schwabe RF, CCR1 and CCR5 promote hepatic fibrosis in mice. The Journal of Clinical Investigation 119, 1858– 1870 (2009). 19603542 PMC2701864 source

In the paper

“Macrophages’ primary fibrosis-promoting activity is to stimulate myofibroblasts (59, 64).”

What the sources say

• Not checked yetcites [59] Ramachandran P, Matchett KP, Dobie R, Wilson-Kanamori JR, Henderson NC, Single-cell technologies in hepatology: new insights into liver biology and disease pathogenesis. Nature Reviews Gastroenterology & Hepatology 17, 457– 472 (2020). 32483353 source
• Not checked yetcites [64] Fallowfield JA, Mizuno M, Kendall TJ, Constandinou CM, Benyon RC, Duffield JS, Iredale JP, Scar-Associated Macrophages Are a Major Source of Hepatic Matrix Metalloproteinase-13 and Facilitate the Resolution of Murine Hepatic Fibrosis. The Journal of Immunology 178, 5288 (2007). 17404313 source

In the paper

“A nuanced appreciation of macrophage function is emerging, with evidence of both pro- and anti-fibrogenic functions based on studies using cell transplantation, chemical manipulation, or depletion (60-63).”

What the sources say

• Not checked yetcites [60] Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, Wu S, Lang R, Iredale JP, Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. The Journal of Clinical Investigation 115, 56– 65 (2005). 15630444 PMC539199 source
• Not checked yetcites [61] Rivera CA, Bradford BU, Hunt KJ, Adachi Y, Schrum LW, Koop DR, Burchardt ER, Rippe RA, Thurman RG, Attenuation of CCl4-induced hepatic fibrosis by GdCl3 treatment or dietary glycine. Am J Physiol-Gastr L 281, G200– G207 (2001). 11408273 source
• Not checked yetcites [62] Karlmark KR, Weiskirchen R, Zimmermann HW, Gassler N, Ginhoux F, Weber C, Merad M, Luedde T, Trautwein C, Tacke F, Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50, 261– 274 (2009). 19554540 source
• Not checked yetcites [63] Thomas JA, Pope C, Wojtacha D, Robson AJ, Gordon-Walker TT, Hartland S, Ramachandran P, Van Deemter M, Hume DA, Iredale JP, Forbes SJ, Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology 53, 2003– 2015 (2011). 21433043 source

In the paper

“In recent years, advancements in genomics and single-cell analyses, largely facilitated by technological breakthroughs in massive parallel sequencing coupled with the development of corresponding informatic pipelines, have provided significant insights into transcriptomic drivers/gene signatures, tissue heterogeneity, and cell-cell communication networks that underlie MASH fibrosis.”

In the paper

“These monocyte-derived macrophages are generally more fibrogenic than Kupffer cells based on their expression of genes related to ECM turnover.”

In the paper

“Similar evidence is emerging from human cirrhotic patients where multiple HSC subsets can be detected with either quiescent or activated gene expression profiles (47) (99).”

What the sources say

• Not checked yetcites [47] Wang Z-Y, Keogh A, Waldt A, Cuttat R, Neri M, Zhu S, Schuierer S, Ruchti A, Crochemore C, Knehr J, Bastien J, Ksiazek I, Sánchez-Taltavull D, Ge H, Wu J, Roma G, Helliwell SB, Stroka D, Nigsch F, Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis. Sci Rep-Uk 11, 19396 (2021). PMC8481490 34588551 source
• Not checked yetcites [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 source

In the paper

“A maresin 1/ RAR-related orphan receptor alpha (RORα)/12-lipoxygenase autoregulatory circuit prevents inflammation and progression of MASH (102).”

What the sources say

• Not checked yetcites [102] Han Y-H, Shin K-O, Kim J-Y, Khadka DB, Kim H-J, Lee Y-M, Cho W-J, Cha J-Y, Lee B-J, Lee M-O, A maresin 1/RORα/12-lipoxygenase autoregulatory circuit prevents inflammation and progression of nonalcoholic steatohepatitis. The Journal of Clinical Investigation 129, 1684– 1698 (2019). 30855276 PMC6436872 source

In the paper

“These “Fab 5” cells (CD9+TREM2+ macrophages that express SPP1, transmembrane glycoprotein NMB (GPNMB), fatty acid binding protein 5 (FABP5), and CD63 molecule (CD63)) could represent a candidate macrophage target to reduce fibrogenesis by their inactivation or depletion.”

In the paper

“A five-marker signature has recently been described that identified pro-fibrotic macrophages across different tissues, including liver (103).”

What the sources say

• Not checked yetcites [103] Fabre T, Barron AMS, Christensen SM, Asano S, Bound K, Lech MP, Wadsworth MH 2nd, Chen X, Wang C, Wang J, McMahon J, Schlerman F, White A, Kravarik KM, Fisher AJ, Borthwick LA, Hart KM, Henderson NC, Wynn TA, Dower K, Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation. Sci Immunol 8, eadd8945 (2023). 37027478 source

In the paper

“Further correlation of circulating proteomics with liver transcriptomics has generated a proteo-transcriptomic signature that outperforms current non-invasive methods in predicting patients with progressive MASLD (124).”

What the sources say

• Not checked yetcites [124] Govaere O, Hasoon M, Alexander L, Cockell S, Tiniakos D, Ekstedt M, Schattenberg JM, Boursier J, Bugianesi E, Ratziu V, Investigators L, Daly AK, Anstee QM, A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures. Nat Metab 5, 572– 578 (2023). 37037945 PMC10132975 source

In the paper

“Hepatocytes also exhibit plasticity in response to chronic injury in MASH, reactivating several developmental pathways that promote epithelial renewal but also contribute to fibrosis.”

In the paper

“Liver macrophages also exhibit considerable plasticity derived from the infiltration of monocytes into the injured liver in response to damage cues and their subsequent differentiation into liver macrophages (100).”

What the sources say

• Not checked yetcites [100] Guilliams M, Scott CL, Liver macrophages in health and disease. Immunity 55, 1515– 1529 (2022). 36103850 source

In the paper

“Increased TAZ abundance in hepatocytes, partly due to cholesterol stabilization, induces Hedgehog expression and secretion that stimulates HSC activation in MASH.”

In the paper

“Although the molecular mechanisms through which LSECs contribute to MASH fibrosis are not fully understood, studies in chemically-induced and bile duct ligation (BDL) mouse models of fibrosis suggest that an imbalance between C-X-C motif chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (CXCR7) activation in LSECs promotes HSC activation and fibrosis over liver regeneration (110).”

What the sources say

• Not checked yetcites [110] Ding B-S, Cao Z, Lis R, Nolan DJ, Guo P, Simons M, Penfold ME, Shido K, Rabbany SY, Rafii S, Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 505, 97– 102 (2014). 24256728 PMC4142699 source

In the paper

“These important observations help reconcile the many reports that were often at odds in defining the role of CAFs in liver cancer, a serious complication of advanced MASH.”

In the paper

“Applying recent developments in informatic tools and databases (130, 131) has uncovered an altered cell-cell communication network in MASH based on the differential expression of ligands and receptors in different cell types (48, 49).”

What the sources say

• Not checked yetcites [130] Efremova M, Vento-Tormo M, Teichmann SA, Vento-Tormo R, CellPhoneDB: inferring cell–cell communication from combined expression of multi-subunit ligand–receptor complexes. Nature Protocols 15, 1484– 1506 (2020). 32103204 source
• Not checked yetcites [131] Jin S, Guerrero-Juarez CF, Zhang L, Chang I, Ramos R, Kuan C-H, Myung P, Plikus MV, Nie Q, Inference and analysis of cell-cell communication using CellChat. Nature communications 12, 1088 (2021). PMC7889871 33597522 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

In the paper

“Large-scale genome-wide association studies (GWAS) have identified several genetic polymorphisms that increase the risk of MASH by affecting the amount of fat in the liver and causing lipotoxicity in hepatocytes.”

In the paper

“TGFβ is the major signaling pathway promoting fibrogenesis by myofibroblasts in MASH and other chronic diseases in which there is hepatocyte injury (96).”

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

In the paper

“Additionally, after the initial discovery of Membrane Bound O-Acyltransferase Domain Containing 7 (MBOAT7) as a risk gene for alcohol-related cirrhosis, MBOAT7 allele rs641738 was subsequently verified as a risk factor for MASH (137-139).”

What the sources say

• Not checked yetcites [137] Buch S, Stickel F, Trépo E, Way M, Herrmann A, Nischalke HD, Brosch M, Rosendahl J, Berg T, Ridinger M, Rietschel M, McQuillin A, Frank J, Kiefer F, Schreiber S, Lieb W, Soyka M, Semmo N, Aigner E, Datz C, Schmelz R, Brückner S, Zeissig S, Stephan A-M, Wodarz N, Devière J, Clumeck N, Sarrazin C, Lammert F, Gustot T, Deltenre P, Völzke H, Lerch MM, Mayerle J, Eyer F, Schafmayer C, Cichon S, Nöthen MM, Nothnagel M, Ellinghaus D, Huse K, Franke A, Zopf S, Hellerbrand C, Moreno C, Franchimont D, Morgan MY, Hampe J, A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as source
• Not checked yetcites [138] Thangapandi VR, Knittelfelder O, Brosch M, Patsenker E, Vvedenskaya O, Buch S, Hinz S, Hendricks A, Nati M, Herrmann A, Rekhade DR, Berg T, Matz-Soja M, Huse K, Klipp E, Pauling JK, Wodke JA, Miranda Ackerman J, Bonin M. v., Aigner E, Datz C, von Schönfels W, Nehring S, Zeissig S, Röcken C, Dahl A, Chavakis T, Stickel F, Shevchenko A, Schafmayer C, Hampe J, Subramanian P, Loss of hepatic Mboat7 leads to liver fibrosis. Gut 70, 940– 950 (2021). 32591434 PMC8040158 source
• Not checked yetcites [139] Mancina RM, Dongiovanni P, Petta S, Pingitore P, Meroni M, Rametta R, Boren J, Montalcini T, Pujia A, Wiklund O, Hindy G, Spagnuolo R, Motta BM, Pipitone RM, Craxi A, Fargion S, Nobili V, Kakela P, Karja V, Mannisto V, Pihlajamaki J, Reilly DF, Castro-Perez J, Kozlitina J, Valenti L, Romeo S, The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent. Gastroenterology 150, 1219– 1230 e1216 (2016). 26850495 PMC4844071 source

In the paper

“Nonetheless, as the genetic databases such as the UK Biobank continue to scale up, further variants are likely to emerge with the hope that they may yield informative aggregate disease risk scores when combined with clinical and diagnostic features; such polygenic scores has been shown to improve predictions of disease severity by fibrosis score alone (146).”

What the sources say

• Not checked yetcites [146] De Vincentis A, Tavaglione F, Jamialahmadi O, Picardi A, Antonelli Incalzi R, Valenti L, Romeo S, Vespasiani-Gentilucci U, A Polygenic Risk Score to Refine Risk Stratification and Prediction for Severe Liver Disease by Clinical Fibrosis Scores. Clin Gastroenterol Hepatol 20, 658– 673 (2022). 34091049 source

In the paper

“Conversely, carriers of the PNPLA3 allele rs6006460[T] (encoding S453I), enriched in African Americans, are associated with decreased MASLD (132-134).”

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

“In models of liver cancer (both cholangiocarcinoma and hepatocellular carcinoma) different subsets of HSC-derived cancer-associated fibroblasts (CAFs) have divergent functions that can either promote or attenuate cancer (97, 98).”

What the sources say

• 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

“These findings support the idea that DNA methylation changes play a key role in driving MASLD.”

In the paper

“The convergence of different fibrogenic pathways in MASH upon SPP1 makes it a potential therapeutic target.”

In the paper

“Among them, histone deacetylase 2 (HDAC2) and DNA methyltransferase 1 (DNMT1) are believed to induce the endothelial production of insulin like growth factor binding protein 7 (IGFBP7)/ADAM metallopeptidase with thrombospondin type 1 motif 1 (ADAMTS1), which in turn recruits profibrogenic Th17 cells and affects the vascular niche (173).”

What the sources say

• Not checked yetcites [173] Zhang H, Ma Y, Cheng X, Wu D, Huang X, Chen B, Ren Y, Jiang W, Tang X, Bai T, Chen Y, Zhao Y, Zhang C, Xiao X, Liu J, Deng Y, Ye T, Chen L, Liu H-M, Friedman SL, Chen L, Ding B-S, Cao Z, Targeting epigenetically maladapted vascular niche alleviates liver fibrosis in nonalcoholic steatohepatitis. Science Translational Medicine 13, eabd1206 (2021). 34613814 source

In the paper

“However, it may play an even more prominent role in MASH fibrosis, where it is reportedly activated not only in HSCs but also in hepatocytes and endothelial cells.”

In the paper

“Additional signaling pathways also directly promote or block HSC activation in MASH fibrosis, including fibroblast growth factor 21 (FGF21) (164), glucagon-like peptide 2/ glucagon-like peptide 2 receptor (165), interleukin 11 (IL11) (46, 166), and chemokine ligand 2 (CCL25)/C-C chemokine receptor type 9 (CCR9) (167).”

What the sources say

• Not checked yetcites [164] Xu P, Zhang Y, Liu Y, Yuan Q, Song L, Liu M, Liu Z, Yang Y, Li J, Li D, Ren G, Fibroblast growth factor 21 attenuates hepatic fibrogenesis through TGF-β/smad2/3 and NF-κB signaling pathways. Toxicol Appl Pharm 290, 43– 53 (2016). 26592322 source
• Not checked yetcites [165] Fuchs S, Yusta B, Baggio LL, Varin EM, Matthews D, Drucker DJ, Loss of Glp2r signaling activates hepatic stellate cells and exacerbates diet-induced steatohepatitis in mice. JCI Insight 5, (2020). PMC7205439 32191643 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
• Not checked yetcites [166] Widjaja AA, Viswanathan S, Wei Ting JG, Tan J, Shekeran SG, Carling D, Lim W-W, Cook SA, IL11 stimulates ERK/P90RSK to inhibit LKB1/AMPK and activate mTOR initiating a mesenchymal program in stromal, epithelial, and cancer cells. iScience 25, (2022). PMC9386112 35992082 source

In the paper

“These signals include sonic hedgehog, which activates hedgehog signaling in the surrounding stromal cells (157).”

What the sources say

• Not checked yetcites [157] Rangwala F, Guy CD, Lu J, Suzuki A, Burchette JL, Abdelmalek MF, Chen W, Diehl AM, Increased production of sonic hedgehog by ballooned hepatocytes. The Journal of Pathology 224, 401– 410 (2011). 21547909 PMC3628812 source

In the paper

“For instance, miR-331-3p and miR-30c can distinguish between twins, with one developing MASLD and the other not (168).”

What the sources say

• Not checked yetcites [168] Zarrinpar A, Gupta S, Maurya MR, Subramaniam S, Loomba R, Serum microRNAs explain discordance of non-alcoholic fatty liver disease in monozygotic and dizygotic twins: a prospective study. Gut 65, 1546 (2016). 26002934 PMC5089367 source

In the paper

“In addition, TGFβ signaling in hepatocytes drive MASH fibrosis by regulating lipid metabolism and hepatocyte apoptosis (151, 152).”

What the sources say

• Not checked yetcites [151] Yang L, Roh YS, Song J, Zhang B, Liu C, Loomba R, Seki E, Transforming growth factor beta signaling in hepatocytes participates in steatohepatitis through regulation of cell death and lipid metabolism in mice. Hepatology 59, 483– 495 (2014). 23996730 PMC3946696 source
• Not checked yetcites [152] Liu D, Wang K, Li K, Xu R, Chang X, Zhu Y, Sun P, Han X, Ets-1 deficiency alleviates nonalcoholic steatohepatitis via weakening TGF-β1 signaling-mediated hepatocyte apoptosis. Cell Death Dis 10, 458 (2019). 31189885 PMC6561928 source

In the paper

“A nanoparticle-based approach to target γ-secretase inhibitor and block NOTCH activity reduced MASH fibrosis in mice (156).”

What the sources say

• Not checked yetcites [156] Richter LR, Wan Q, Wen D, Zhang Y, Yu J, Kang J. k., Zhu C, McKinnon EL, Gu Z, Qiang L, Pajvani UB, Targeted Delivery of Notch Inhibitor Attenuates Obesity-Induced Glucose Intolerance and Liver Fibrosis. ACS Nano 14, 6878– 6886 (2020). 32441510 PMC7444843 source

In the paper

“Recent studies have shed light on the specific epigenetic changes, including DNA and histone modification, and microRNAs, associated with MASLD.”

In the paper

“Notch signaling has been identified as an important driver of HSC activation in fibrosis in general (114, 153).”

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
• Not checked yetcites [153] Bansal R, van Baarlen J, Storm G, Prakash J, The interplay of the Notch signaling in hepatic stellate cells and macrophages determines the fate of liver fibrogenesis. Sci Rep 5, 18272 (2015). 26658360 PMC4677309 source

In the paper

“Indeed SPP1-deficient mice are protected from MASH fibrosis in the MCD model (162).”

What the sources say

• Not checked yetcites [162] Schulien I, Hockenjos B, Schmitt-Graeff A, Perdekamp MG, Follo M, Thimme R, Hasselblatt P, The transcription factor c-Jun/AP-1 promotes liver fibrosis during non-alcoholic steatohepatitis by regulating Osteopontin expression. Cell Death & Differentiation 26, 1688– 1699 (2019). 30778201 PMC6748141 source

In the paper

“Other epigenetic regulators, such as methyl CpG binding protein 2 (MECP2), enhancer of zeste homolog 1/2 (EZH1/2), bromodomain-containing protein 4 (BRD4), Sirtuin 1 (SIRT1), lysine-specific demethylase 4D (KDM4D), and tet methylcytosine dioxygenase 3 (TET3), can contribute to chemically-induced liver fibrosis (174-178) (179, 180) (181).”

What the sources say

• Not checked yetcites [174] Ding N, Hah N, Yu RT, Sherman MH, Benner C, Leblanc M, He M, Liddle C, Downes M, Evans RM, BRD4 is a novel therapeutic target for liver fibrosis. Proc Natl Acad Sci U S A 112, 15713– 15718 (2015). 26644586 PMC4697417 source
• Not checked yetcites [175] Barcena-Varela M, Caruso S, Llerena S, Alvarez-Sola G, Uriarte I, Latasa MU, Urtasun R, Rebouissou S, Alvarez L, Jimenez M, Santamaria E, Rodriguez-Ortigosa C, Mazza G, Rombouts K, Jose-Eneriz E. San, Rabal O, Agirre X, Iraburu M, Santos-Laso A, Banales JM, Zucman-Rossi J, Prosper F, Oyarzabal J, Berasain C, Avila MA, Fernandez-Barrena MG, Dual Targeting of Histone Methyltransferase G9a and DNA-Methyltransferase 1 for the Treatment of Experimental Hepatocellular Carcinoma. Hepatology 69, 587– 603 (2019). 30014490 source
• Not checked yetcites [176] Martin-Mateos R, De Assuncao TM, Arab JP, Jalan-Sakrikar N, Yaqoob U, Greuter T, Verma VK, Mathison AJ, Cao S, Lomberk G, Mathurin P, Urrutia R, Huebert RC, Shah VH, Enhancer of Zeste Homologue 2 Inhibition Attenuates TGF-beta Dependent Hepatic Stellate Cell Activation and Liver Fibrosis. Cell Mol Gastroenterol Hepatol 7, 197– 209 (2019). 30539787 PMC6282644 source
• Not checked yetcites [177] Grindheim JM, Nicetto D, Donahue G, Zaret KS, Polycomb Repressive Complex 2 Proteins EZH1 and EZH2 Regulate Timing of Postnatal Hepatocyte Maturation and Fibrosis by Repressing Genes With Euchromatic Promoters in Mice. Gastroenterology 156, 1834– 1848 (2019). 30689973 PMC6599454 source
• Not checked yetcites [178] Dong F, Jiang S, Li J, Wang Y, Zhu L, Huang Y, Jiang X, Hu X, Zhou Q, Zhang Z, Bao Z, The histone demethylase KDM4D promotes hepatic fibrogenesis by modulating Toll-like receptor 4 signaling pathway. EBioMedicine 39, 472– 483 (2019). 30527625 PMC6354657 source
• Not checked yetcites [179] Mann J, Chu DC, Maxwell A, Oakley F, Zhu NL, Tsukamoto H, Mann DA, MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology 138, 705– 714, 714 e701-704 (2010). 19843474 PMC2819585 source
• Not checked yetcites [180] 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– 1328 (2017). 27002005 PMC5031527 source
• Not checked yetcites [181] Xu Y, Sun X, Zhang R, Cao T, Cai S-Y, Boyer JL, Zhang X, Li D, Huang Y, A Positive Feedback Loop of TET3 and TGF-β1 Promotes Liver Fibrosis. Cell reports 30, 1310– 1318.e1315 (2020). 32023451 PMC7063678 source

In the paper

“Recent studies using single nucleus ATAC-seq to profile the epigenome of hepatocytes from MASH mice have revealed increased NOTCH binding in the Ephrin Type-B Receptor 2 (EPHB2) locus, resulting in the upregulation of EPHB2 as a driver of MASH fibrosis (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

“To establish causality, transplantation of fecal microbiota from patients with MASLD or MASH induced steatosis and fibrosis in antibiotic-treated and germ-free mice (87, 202, 203).”

What the sources say

• Not checked yetcites [87] Barrow F, Khan S, Fredrickson G, Wang H, Dietsche K, Parthiban P, Robert S, Kaiser T, Winer S, Herman A, Adeyi O, Mouzaki M, Khoruts A, Hogquist KA, Staley C, Winer DA, Revelo XS, Microbiota-Driven Activation of Intrahepatic B Cells Aggravates NASH Through Innate and Adaptive Signaling. Hepatology 74, 704– 722 (2021). 33609303 PMC8377092 source
• Not checked yetcites [202] Yuan J, Chen C, Cui J, Lu J, Yan C, Wei X, Zhao X, Li N, Li S, Xue G, Cheng W, Li B, Li H, Lin W, Tian C, Zhao J, Han J, An D, Zhang Q, Wei H, Zheng M, Ma X, Li W, Chen X, Zhang Z, Zeng H, Ying S, Wu J, Yang R, Liu D, Fatty Liver Disease Caused by High-Alcohol-Producing Klebsiella pneumoniae. Cell Metabolism 30, 675– 688.e677 (2019). 31543403 source
• Not checked yetcites [203] Chiu C-C, Ching Y-H, Li Y-P, Liu J-Y, Huang Y-T, Huang Y-W, Yang S-S, Huang W-C, Chuang H-L, Nonalcoholic Fatty Liver Disease Is Exacerbated in High-Fat Diet-Fed Gnotobiotic Mice by Colonization with the Gut Microbiota from Patients with Nonalcoholic Steatohepatitis. Nutrients 9, 1220 (2017). 29113135 PMC5707692 source

In the paper

“There are some data linking specific bacterial strains to fibrosis in MASH including the alcohol-producing Klebsiella pneumoniae and Porphyromonas gingivalis; the latter directly promotes HSC activation in culture (202, 205, 206).”

What the sources say

• Not checked yetcites [202] Yuan J, Chen C, Cui J, Lu J, Yan C, Wei X, Zhao X, Li N, Li S, Xue G, Cheng W, Li B, Li H, Lin W, Tian C, Zhao J, Han J, An D, Zhang Q, Wei H, Zheng M, Ma X, Li W, Chen X, Zhang Z, Zeng H, Ying S, Wu J, Yang R, Liu D, Fatty Liver Disease Caused by High-Alcohol-Producing Klebsiella pneumoniae. Cell Metabolism 30, 675– 688.e677 (2019). 31543403 source
• Not checked yetcites [205] Nagasaki A, Sakamoto S, Chea C, Ishida E, Furusho H, Fujii M, Takata T, Miyauchi M, Odontogenic infection by Porphyromonas gingivalis exacerbates fibrosis in NASH via hepatic stellate cell activation. Sci Rep-Uk 10, 4134 (2020). PMC7058079 32139740 source
• Not checked yetcites [206] Furusho H, Miyauchi M, Hyogo H, Inubushi T, Ao M, Ouhara K, Hisatune J, Kurihara H, Sugai M, Hayes CN, Nakahara T, Aikata H, Takahashi S, Chayama K, Takata T, Dental infection of Porphyromonas gingivalis exacerbates high fat diet-induced steatohepatitis in mice. Journal of Gastroenterology 48, 1259– 1270 (2013). 23307045 source

In the paper

“There are some data linking specific bacterial strains to fibrosis in MASH including the alcohol-producing Klebsiella pneumoniae and Porphyromonas gingivalis; the latter directly promotes HSC activation in culture (202, 205, 206).”

What the sources say

• Not checked yetcites [202] Yuan J, Chen C, Cui J, Lu J, Yan C, Wei X, Zhao X, Li N, Li S, Xue G, Cheng W, Li B, Li H, Lin W, Tian C, Zhao J, Han J, An D, Zhang Q, Wei H, Zheng M, Ma X, Li W, Chen X, Zhang Z, Zeng H, Ying S, Wu J, Yang R, Liu D, Fatty Liver Disease Caused by High-Alcohol-Producing Klebsiella pneumoniae. Cell Metabolism 30, 675– 688.e677 (2019). 31543403 source
• Not checked yetcites [205] Nagasaki A, Sakamoto S, Chea C, Ishida E, Furusho H, Fujii M, Takata T, Miyauchi M, Odontogenic infection by Porphyromonas gingivalis exacerbates fibrosis in NASH via hepatic stellate cell activation. Sci Rep-Uk 10, 4134 (2020). PMC7058079 32139740 source
• Not checked yetcites [206] Furusho H, Miyauchi M, Hyogo H, Inubushi T, Ao M, Ouhara K, Hisatune J, Kurihara H, Sugai M, Hayes CN, Nakahara T, Aikata H, Takahashi S, Chayama K, Takata T, Dental infection of Porphyromonas gingivalis exacerbates high fat diet-induced steatohepatitis in mice. Journal of Gastroenterology 48, 1259– 1270 (2013). 23307045 source

In the paper

“In vivo studies have confirmed that TLR4 knockout MCD mice are protected against the profibrotic effect of cholesterol supplementation (187).”

What the sources say

• Not checked yetcites [187] 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

“Similarly, pharmacological or genetic inhibition of ATP citrate lyase, which acts upstream of ACC1/2, reduces steatosis and fibrosis, possibly through direct inhibition of HSC activation (192).”

What the sources say

• Not checked yetcites [192] Morrow MR, Batchuluun B, Wu J, Ahmadi E, Leroux JM, Mohammadi-Shemirani P, Desjardins EM, Wang Z, Tsakiridis EE, Lavoie DCT, Reihani A, Smith BK, Kwiecien JM, Lally JSV, Nero TL, Parker MW, Ask K, Scott JW, Jiang L, Paré G, Pinkosky SL, Steinberg GR, Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia. Cell Metabolism 34, 919– 936.e918 (2022). 35675800 source

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 [201] Scorletti E, Afolabi PR, Miles EA, Smith DE, Almehmadi A, Alshathry A, Childs CE, Del Fabbro S, Bilson J, Moyses HE, Clough GF, Sethi JK, Patel J, Wright M, Breen DJ, Peebles C, Darekar A, Aspinall R, Fowell AJ, Dowman JK, Nobili V, Targher G, Delzenne NM, Bindels LB, Calder PC, Byrne CD, Synbiotics Alter Fecal Microbiomes, But Not Liver Fat or Fibrosis, in a Randomized Trial of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 158, 1597– 1610.e1597 (2020). 31987796 PMC7613160 source

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

“This reinforces the potential therapeutic value of targeting NOTCH activity in MASH.”

In the paper

“Inhibition of ACC1/2 using small-molecule inhibitors can reduce steatosis in hepatocytes, but it also directly blocks primary HSC activation in culture and reduces liver fibrosis in a choline-deficient, high-fat diet rat model of MASH (190, 191).”

What the sources say

• Not checked yetcites [190] Bates J, Vijayakumar A, Ghoshal S, Marchand B, Yi S, Kornyeyev D, Zagorska A, Hollenback D, Walker K, Liu K, Pendem S, Newstrom D, Brockett R, Mikaelian I, Kusam S, Ramirez R, Lopez D, Li L, Fuchs BC, Breckenridge DG, Acetyl-CoA carboxylase inhibition disrupts metabolic reprogramming during hepatic stellate cell activation. Journal of Hepatology 73, 896– 905 (2020). 32376414 source
• Not checked yetcites [191] Ross TT, Crowley C, Kelly KL, Rinaldi A, Beebe DA, Lech MP, Martinez RV, Carvajal-Gonzalez S, Boucher M, Hirenallur-Shanthappa D, Morin J, Opsahl AC, Vargas SR, Bence KK, Pfefferkorn JA, Esler WP, Acetyl-CoA Carboxylase Inhibition Improves Multiple Dimensions of NASH Pathogenesis in Model Systems. Cellular and Molecular Gastroenterology and Hepatology 10, 829– 851 (2020). 32526482 PMC7509217 source

In the paper

“Inhibition of ACC1/2 using small-molecule inhibitors can reduce steatosis in hepatocytes, but it also directly blocks primary HSC activation in culture and reduces liver fibrosis in a choline-deficient, high-fat diet rat model of MASH (190, 191).”

What the sources say

• Not checked yetcites [190] Bates J, Vijayakumar A, Ghoshal S, Marchand B, Yi S, Kornyeyev D, Zagorska A, Hollenback D, Walker K, Liu K, Pendem S, Newstrom D, Brockett R, Mikaelian I, Kusam S, Ramirez R, Lopez D, Li L, Fuchs BC, Breckenridge DG, Acetyl-CoA carboxylase inhibition disrupts metabolic reprogramming during hepatic stellate cell activation. Journal of Hepatology 73, 896– 905 (2020). 32376414 source
• Not checked yetcites [191] Ross TT, Crowley C, Kelly KL, Rinaldi A, Beebe DA, Lech MP, Martinez RV, Carvajal-Gonzalez S, Boucher M, Hirenallur-Shanthappa D, Morin J, Opsahl AC, Vargas SR, Bence KK, Pfefferkorn JA, Esler WP, Acetyl-CoA Carboxylase Inhibition Improves Multiple Dimensions of NASH Pathogenesis in Model Systems. Cellular and Molecular Gastroenterology and Hepatology 10, 829– 851 (2020). 32526482 PMC7509217 source

In the paper

“MASH fibrosis is linked to a unique gut microbiome (193-197), and specific microbiome signatures can distinguish human MASH from MASLD (4, 198, 199).”

What the sources say

• Not checked yetcites [193] Leung H, Long X, Ni Y, Qian L, Nychas E, Siliceo SL, Pohl D, Hanhineva K, Liu Y, Xu A, Nielsen HB, Belda E, Clément K, Loomba R, Li H, Jia W, Panagiotou G, Risk assessment with gut microbiome and metabolite markers in NAFLD development. Science Translational Medicine 14, eabk0855 (2022). 35675435 PMC9746350 source
• Not checked yetcites [194] Lelouvier B, Servant F, Paisse S, Brunet AC, Benyahya S, Serino M, Valle C, Ortiz MR, Puig J, Courtney M, Federici M, Fernandez-Real JM, Burcelin R, Amar J, Changes in blood microbiota profiles associated with liver fibrosis in obese patients: A pilot analysis. Hepatology 64, 2015– 2027 (2016). 27639192 source
• Not checked yetcites [195] Schwimmer JB, Johnson JS, Angeles JE, Behling C, Belt PH, Borecki I, Bross C, Durelle J, Goyal NP, Hamilton G, Holtz ML, Lavine JE, Mitreva M, Newton KP, Pan A, Simpson PM, Sirlin CB, Sodergren E, Tyagi R, Yates KP, Weinstock GM, Salzman NH, Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease. Gastroenterology 157, 1109– 1122 (2019). 31255652 PMC6756995 source
• Not checked yetcites [196] Loomba R, Seguritan V, Li W, Long T, Klitgord N, Bhatt A, Dulai PS, Caussy C, Bettencourt R, Highlander SK, Jones MB, Sirlin CB, Schnabl B, Brinkac L, Schork N, Chen CH, Brenner DA, Biggs W, Yooseph S, Venter JC, Nelson KE, Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metab 25, 1054– 1062 e1055 (2017). 28467925 PMC5502730 source
• Not checked yetcites [197] Carter JK, Bhattacharya D, Borgerding JN, Fiel MI, Faith JJ, Friedman SL, Modeling dysbiosis of human NASH in mice: Loss of gut microbiome diversity and overgrowth of Erysipelotrichales. PLoS One 16, e0244763 (2021). 33395434 PMC7781477 source

In the paper

“Mechanistically, cholesterol accumulation in cultured HSCs has been found to increase TLR4 abundance by suppressing its endosomal degradation, which sensitizes these 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

“Similarly, pharmacological or genetic inhibition of ATP citrate lyase, which acts upstream of ACC1/2, reduces steatosis and fibrosis, possibly through direct inhibition of HSC activation (192).”

What the sources say

• Not checked yetcites [192] Morrow MR, Batchuluun B, Wu J, Ahmadi E, Leroux JM, Mohammadi-Shemirani P, Desjardins EM, Wang Z, Tsakiridis EE, Lavoie DCT, Reihani A, Smith BK, Kwiecien JM, Lally JSV, Nero TL, Parker MW, Ask K, Scott JW, Jiang L, Paré G, Pinkosky SL, Steinberg GR, Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia. Cell Metabolism 34, 919– 936.e918 (2022). 35675800 source

In the paper

“In particular, the activation of HSCs in culture is associated with increased glycolysis, lipolysis, and glutaminolysis, which provide the energy needed for this energy-intensive process (as detailed in (182)).”

What the sources say

• Not checked yetcites [182] Trivedi P, Wang S, Friedman SL, The Power of Plasticity—Metabolic Regulation of Hepatic Stellate Cells. Cell Metabolism 33, 242– 257 (2021). 33232666 PMC7858232 source

In the paper

“Inhibition of ACC1/2 using small-molecule inhibitors can reduce steatosis in hepatocytes, but it also directly blocks primary HSC activation in culture and reduces liver fibrosis in a choline-deficient, high-fat diet rat model of MASH (190, 191).”

What the sources say

• Not checked yetcites [190] Bates J, Vijayakumar A, Ghoshal S, Marchand B, Yi S, Kornyeyev D, Zagorska A, Hollenback D, Walker K, Liu K, Pendem S, Newstrom D, Brockett R, Mikaelian I, Kusam S, Ramirez R, Lopez D, Li L, Fuchs BC, Breckenridge DG, Acetyl-CoA carboxylase inhibition disrupts metabolic reprogramming during hepatic stellate cell activation. Journal of Hepatology 73, 896– 905 (2020). 32376414 source
• Not checked yetcites [191] Ross TT, Crowley C, Kelly KL, Rinaldi A, Beebe DA, Lech MP, Martinez RV, Carvajal-Gonzalez S, Boucher M, Hirenallur-Shanthappa D, Morin J, Opsahl AC, Vargas SR, Bence KK, Pfefferkorn JA, Esler WP, Acetyl-CoA Carboxylase Inhibition Improves Multiple Dimensions of NASH Pathogenesis in Model Systems. Cellular and Molecular Gastroenterology and Hepatology 10, 829– 851 (2020). 32526482 PMC7509217 source

In the paper

“MASH fibrosis is linked to a unique gut microbiome (193-197), and specific microbiome signatures can distinguish human MASH from MASLD (4, 198, 199).”

What the sources say

• 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
• Not checked yetcites [198] Lee G, You HJ, Bajaj JS, Joo SK, Yu J, Park S, Kang H, Park JH, Kim JH, Lee DH, Lee S, Kim W, Ko G, Distinct signatures of gut microbiome and metabolites associated with significant fibrosis in non-obese NAFLD. Nature communications 11, 4982 (2020). PMC7536225 33020474 source
• Not checked yetcites [199] Caussy C, Hsu C, Lo MT, Liu A, Bettencourt R, Ajmera VH, Bassirian S, Hooker J, Sy E, Richards L, Schork N, Schnabl B, Brenner DA, Sirlin CB, Chen CH, Loomba R, N. i. T. C. Genetics of, Link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD. Hepatology 68, (2018). PMC6151296 29572891 source

In the paper

“Just as not all obese individuals develop MASLD and MASH, different strains of mice exhibit varying susceptibility to these conditions.”

In the paper

“On the other hand, the replacement of Ruminococcus faecis, found to be deficient in patients with MASH fibrosis improved fibrosis in the MCD rodent MASH model (198).”

What the sources say

• Not checked yetcites [198] Lee G, You HJ, Bajaj JS, Joo SK, Yu J, Park S, Kang H, Park JH, Kim JH, Lee DH, Lee S, Kim W, Ko G, Distinct signatures of gut microbiome and metabolites associated with significant fibrosis in non-obese NAFLD. Nature communications 11, 4982 (2020). PMC7536225 33020474 source

In the paper

“To recapitulate this co-morbidity, a mouse model of diabetes due to beta cell depletion by a low dose of streptozotocin was subjected to subsequently high-fat diet feeding to induce MASH and hepatocellular carcinoma at 20 weeks (235, 236).”

What the sources say

• Not checked yetcites [235] Fujii M, Shibazaki Y, Wakamatsu K, Honda Y, Kawauchi Y, Suzuki K, Arumugam S, Watanabe K, Ichida T, Asakura H, Yoneyama H, A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma. Medical Molecular Morphology 46, 141– 152 (2013). 23430399 source
• Not checked yetcites [236] Sadi G, Baloğlu MC, Pektaş MB, Differential Gene Expression in Liver Tissues of Streptozotocin-Induced Diabetic Rats in Response to Resveratrol Treatment. PLOS ONE 10, e0124968 (2015). 25905778 PMC4408020 source

In the paper

“Similarly, another MASH model combines the Agouti yellow mutation driving hyperphagia with a Western diet and fructose water, where mice start to develop fibrosis after 16 weeks (231).”

What the sources say

• Not checked yetcites [231] St. Rose K, Yan J, Xu F, Williams J, Dweck V, Saxena D, Schwabe RF, Caviglia JM, Mouse model of NASH that replicates key features of the human disease and progresses to fibrosis stage 3. Hepatology Communications 6, 2676– 2688 (2022). 35923109 PMC9512466 source

In the paper

“Our laboratory uses a simple rodent model of MASH, the “FAT-MASH” mouse, which robustly develops Fibrosis and Tumors, features of advanced disease, after 24 weeks of a Western diet combined with a small weekly dose of the liver toxin CCl4 (45).”

What the sources say

• 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

In the paper

“Increased cholesterol in turn promotes MASH fibrosis through the TAZ/Indian hedgehog pathway described above (232-234).”

What the sources say

• Not checked yetcites [232] Teratani T, Tomita K, Suzuki T, Oshikawa T, Yokoyama H, Shimamura K, Tominaga S, Hiroi S, Irie R, Okada Y, Kurihara C, Ebinuma H, Saito H, Hokari R, Sugiyama K, Kanai T, Miura S, Hibi T, A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells. Gastroenterology 142, 152– 164 e110 (2012). 21995947 source
• Not checked yetcites [233] Ioannou GN, The Role of Cholesterol in the Pathogenesis of NASH. Trends Endocrinol Metab 27, 84– 95 (2016). 26703097 source
• Not checked yetcites [234] 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 KL, Buck J, Levin LR, Tontonoz P, Schwabe RF, Tabas I, Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis. Cell Metab 31, 969– 986 e967 (2020). 32259482 PMC7313619 source

In the paper

“Previous MASLD models that relied only on a single perturbation, for example a Western diet or genetic mutations, typically lack the features or gene expression patterns of human MASH (227).”

What the sources say

• Not checked yetcites [227] Teufel A, Itzel T, Erhart W, Brosch M, Wang XY, Kim YO, von Schönfels W, Herrmann A, Brückner S, Stickel F, Dufour J-F, Chavakis T, Hellerbrand C, Spang R, Maass T, Becker T, Schreiber S, Schafmayer C, Schuppan D, Hampe J, Comparison of Gene Expression Patterns Between Mouse Models of Nonalcoholic Fatty Liver Disease and Liver Tissues From Patients. Gastroenterology 151, 513– 525.e510 (2016). 27318147 source

In the paper

“Bacterial lipopolysaccharides can exacerbate fibrosis in mice fed a high-fat diet, provoking an inflammatory cascade through TLR4 that indirectly activates fibrogenic cells (207).”

What the sources say

• Not checked yetcites [207] Imajo K, Fujita K, Yoneda M, Nozaki Y, Ogawa Y, Shinohara Y, Kato S, Mawatari H, Shibata W, Kitani H, Ikejima K, Kirikoshi H, Nakajima N, Saito S, Maeyama S, Watanabe S, Wada K, Nakajima A, Hyperresponsivity to Low-Dose Endotoxin during Progression to Nonalcoholic Steatohepatitis Is Regulated by Leptin-Mediated Signaling. Cell Metabolism 16, 44– 54 (2012). 22768838 source

In the paper

“It is worth noting that the FAT-MASH mice exhibit transcriptomic similarities to human MASH patients (48), and their microbiome changes also resemble human MASH pathology (197).”

What the sources say

• Not checked yetcites [197] Carter JK, Bhattacharya D, Borgerding JN, Fiel MI, Faith JJ, Friedman SL, Modeling dysbiosis of human NASH in mice: Loss of gut microbiome diversity and overgrowth of Erysipelotrichales. PLoS One 16, e0244763 (2021). 33395434 PMC7781477 source

In the paper

“However, it is worth noting that the etiology of MASH in these models may not precisely parallel human MASH, as these mutations are not observed in patients.”

In the paper

“Dietary cholesterol supplementation in the FAT-MASH mice is necessary to approximate liver cholesterol levels seen in human MASH, since mice are poor cholesterol absorbers compared to humans.”

In the paper

“It is worth noting that the FAT-MASH mice exhibit transcriptomic similarities to human MASH patients (48), and their microbiome changes also resemble human MASH pathology (197).”

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

“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

“Several transgenic animals have been developed to study MASH pathogenesis, including those that overexpress urokinase-type plasminogen activator (MUP-uPA) (221) or sterol regulatory element-binding protein 1 (SREBP1) (222, 223).”

What the sources say

• Not checked yetcites [221] Nakagawa H, Umemura A, Taniguchi K, Font-Burgada J, Dhar D, Ogata H, Zhong Z, Valasek Mark A., Seki E, Hidalgo J, Koike K, Kaufman Randal J., Karin M, ER Stress Cooperates with Hypernutrition to Trigger TNF-Dependent Spontaneous HCC Development. Cancer Cell 26, 331– 343 (2014). 25132496 PMC4165611 source
• Not checked yetcites [222] Shimomura I, Hammer RE, Richardson JA, Ikemoto S, Bashmakov Y, Goldstein JL, Brown MS, Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes & Development 12, 3182– 3194 (1998). 9784493 PMC317215 source
• Not checked yetcites [223] Nakayama H, Otabe S, Ueno T, Hirota N, Yuan X, Fukutani T, Hashinaga T, Wada N, Yamada K, Transgenic mice expressing nuclear sterol regulatory element–binding protein 1c in adipose tissue exhibit liver histology similar to nonalcoholic steatohepatitis. Metabolism 56, 470– 475 (2007). 17379003 source

In the paper

“Additionally, mice deficient in methionine adenosyltransferase 1A (MAT1A) (224), phosphatase and tensin homolog (PTEN) (225), or alternative oxidase (AOX) (226) spontaneously exhibit pathological features of MASH.”

What the sources say

• Not checked yetcites [224] Lu SC, Alvarez L, Huang Z-Z, Chen L, An W, Corrales FJ, Avila MA, Kanel G, Mato JM, Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation. Proceedings of the National Academy of Sciences 98, 5560– 5565 (2001). PMC33252 11320206 source
• Not checked yetcites [225] Stiles B, Wang Y, Stahl A, Bassilian S, Lee WP, Kim Y-J, Sherwin R, Devaskar S, Lesche R, Magnuson MA, Wu H, Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity. Proceedings of the National Academy of Sciences 101, 2082– 2087 (2004). PMC357055 14769918 source
• Not checked yetcites [226] Fan C-Y, Pan J, Usuda N, Yeldandi AV, Rao MS, Reddy JK, Steatohepatitis, spontaneous peroxisome proliferation and liver tumors in mice lacking peroxisomal fatty Acyl-CoA oxidase: implications for peroxisome proliferator-activated receptor α natural ligand metabolism. Journal of Biological Chemistry 273, 15639– 15645 (1998). 9624157 source

In the paper

“One widely used popular mouse model is MCD diet, in which mice rapidly develop severe inflammation and fibrosis in the liver characteristic of human disease pathology, within a period of several weeks.”

In the paper

“On the other hand, diet-induced MASH models such as the amylin liver NASH (AMLN) and Gubra-amylin NASH (GAN) models follow the natural course of human MASH development in which mice become overweight prior to developing fatty liver, followed by inflammation and fibrosis (214, 215).”

What the sources say

• Not checked yetcites [214] Boland ML, Oro D, Tolbol KS, Thrane ST, Nielsen JC, Cohen TS, Tabor DE, Fernandes F, Tovchigrechko A, Veidal SS, Warrener P, Sellman BR, Jelsing J, Feigh M, Vrang N, Trevaskis JL, Hansen HH, Towards a standard diet-induced and biopsy-confirmed mouse model of non-alcoholic steatohepatitis: Impact of dietary fat source. World J Gastroenterol 25, 4904– 4920 (2019). 31543682 PMC6737317 source
• Not checked yetcites [215] Clapper JR, Hendricks MD, Gu G, Wittmer C, Dolman CS, Herich J, Athanacio J, Villescaz C, Ghosh SS, Heilig JS, Lowe C, Roth JD, Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment. Am J Physiol Gastrointest Liver Physiol 305, G483– 495 (2013). 23886860 source

In the paper

“Microbial acetate on the other hand, is protective against MASH fibrosis through activation of the free fatty acid receptor 2 (FFAR2) receptor on hepatocytes and modulation of lipid metabolism (208).”

What the sources say

• Not checked yetcites [208] Aoki R, Onuki M, Hattori K, Ito M, Yamada T, Kamikado K, Kim Y-G, Nakamoto N, Kimura I, Clarke JM, Kanai T, Hase K, Commensal microbe-derived acetate suppresses NAFLD/NASH development via hepatic FFAR2 signalling in mice. Microbiome 9, 188 (2021). 34530928 PMC8447789 source

In the paper

“Spontaneous fibrosis regression was also observed in patients with hepatitis B virus (HBV) treated with antivirals to suppress HBV activity (255).”

What the sources say

• Not checked yetcites [255] Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, Washington MK, Germanidis G, Flaherty JF, Aguilar Schall R, Bornstein JD, Kitrinos KM, Subramanian GM, McHutchison JG, Heathcote EJ, Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 381, 468– 475 (2013). 23234725 source

In the paper

“Furthermore, the transcriptomes of these bipotent cell-derived MASH organoid cultures resemble those of human MASH.”

What the sources say

• Not checked yetcites [243] McCarron S, Bathon B, Conlon DM, Abbey D, Rader DJ, Gawronski K, Brown CD, Olthoff KM, Shaked A, Raabe TD, Functional Characterization of Organoids Derived From Irreversibly Damaged Liver of Patients With NASH. Hepatology 74, 1825– 1844 (2021). 33901295 PMC12928191 source

In the paper

“Although this model recapitulates diabetes and fatty liver, it is unclear if it is generalizable to human MASH because the animals have glucose intolerance due to insulin depletion and not insulin resistance, which is more typical of human MASH.”

In the paper

“Recent studies of patients cured of hepatitis C virus (HCV) have highlighted the liver's impressive ability to resorb advanced fibrosis or cirrhosis once the underlying injury is removed (254).”

What the sources say

• Not checked yetcites [254] D'Ambrosio R, Aghemo A, Rumi MG, Ronchi G, Donato MF, Paradis V, Colombo M, Bedossa P, A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis. Hepatology 56, 532– 543 (2012). 22271347 source

In the paper

“MASH organoids can be generated from induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs) via stepwise differentiation that parallels liver development, followed by exposure to free fatty acids (240, 241).”

What the sources say

• Not checked yetcites [240] Ramli MNB, Lim YS, Koe CT, Demircioglu D, Tng W, Gonzales KAU, Tan CP, Szczerbinska I, Liang H, Soe EL, Lu Z, Ariyachet C, Yu KM, Koh SH, Yaw LP, Jumat NHB, Lim JSY, Wright G, Shabbir A, Dan YY, Ng H-H, Chan Y-S, Human Pluripotent Stem Cell-Derived Organoids as Models of Liver Disease. Gastroenterology 159, 1471– 1486.e1412 (2020). 32553762 source
• Not checked yetcites [241] Ouchi R, Togo S, Kimura M, Shinozawa T, Koido M, Koike H, Thompson W, Karns RA, Mayhew CN, McGrath PS, McCauley HA, Zhang R-R, Lewis K, Hakozaki S, Ferguson A, Saiki N, Yoneyama Y, Takeuchi I, Mabuchi Y, Akazawa C, Yoshikawa HY, Wells JM, Takebe T, Modeling Steatohepatitis in Humans with Pluripotent Stem Cell-Derived Organoids. Cell Metabolism 30, 374– 384.e376 (2019). 31155493 PMC6687537 source

In the paper

“Such clinical observations, coupled with the knowledge that fibrosis is the most significant predictor of patient mortality in MASH, focus renewed attention on mechanisms of both spontaneous and pharmacologic-induced fibrosis regression (13-16), as more research is needed to develop clinical interventions that halt progression or reverse the disease.”

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

“Some of these placebo responses could represent inadvertent changes in lifestyle by patients as they participate in clinical trials (253).”

What the sources say

• Not checked yetcites [253] Ng CH, Xiao J, Lim WH, Chin YH, Yong JN, Tan DJH, Tay P, Syn N, Foo R, Chan M, Chew N, Tan EXX, Huang DQ, Dan YY, Tamaki N, Siddiqui MS, Sanyal AJ, Loomba R, Noureddin M, Muthiah MD, Placebo effect on progression and regression in NASH: Evidence from a meta-analysis. Hepatology 75, 1647– 1661 (2022). 34990037 source

In the paper

“Clinical interventions such as weight loss resulting from dietary changes, bariatric surgery, pharmacological agents, or the use of farnesoid X receptor (FXR) agonists have been associated with fibrosis regression in patients with MASH (256-258).”

What the sources say

• Not checked yetcites [256] Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, Friedman SL, Diago M, Romero-Gomez M, Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology 149, 367– 378.e365 (2015). 25865049 source
• Not checked yetcites [257] Dixon JB, Bhathal PS, Hughes NR, O'Brien PE, Nonalcoholic fatty liver disease: Improvement in liver histological analysis with weight loss. Hepatology 39, 1647– 1654 (2004). 15185306 source
• Not checked yetcites [258] Naoumov NV, Brees D, Loeffler J, Chng E, Ren Y, Lopez P, Tai D, Lamle S, Sanyal AJ, Digital pathology with artificial intelligence analyses provides greater insights into treatment-induced fibrosis regression in NASH. Journal of Hepatology 77, 1399– 1409 (2022). 35779659 source

In the paper

“Furthermore, iPSC-derived MASH organoids from different donors have been used to screen for MASH susceptibility loci, leading to the identification of the glucokinase regulator (GCKR) allele rs1260326[T] which increases lipid loading in hepatocytes (242).”

What the sources say

• Not checked yetcites [242] Kimura M, Iguchi T, Iwasawa K, Dunn A, Thompson WL, Yoneyama Y, Chaturvedi P, Zorn AM, Wintzinger M, Quattrocelli M, Watanabe-Chailland M, Zhu G, Fujimoto M, Kumbaji M, Kodaka A, Gindin Y, Chung C, Myers RP, Subramanian GM, Hwa V, Takebe T, En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH. Cell 185, 4216– 4232.e4216 (2022). 36240780 PMC9617783 source

In the paper

“Other shortcomings of current mouse MASH models include the difficulty recapitulating late-stage disease, including cirrhosis and hepatic decompensation, where treatment is most urgently needed.”