Hossain, P., Kawar, B. & El Nahas, M. Obesity and diabetes in the developing world — a growing challenge. N. Engl. J. Med. 356, 213–215 (2007).
Lazo, M. & Clark, J. M. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin. Liver Dis. 28, 339–350 (2008).
Araujo, A. R., Rosso, N., Bedogni, G., Tiribelli, C. & Bellentani, S. Global epidemiology of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: what we need in the future. Liver Int. 38 (Suppl. 1), 47–51 (2018).
Loomba, R. & Sanyal, A. J. The global NAFLD epidemic. Nat. Rev. Gastroenterol. Hepatol. 10, 686–690 (2013).
Younossi, Z. et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 15, 11–20 (2018).
Caligiuri, A., Gentilini, A. & Marra, F. Molecular pathogenesis of NASH. Int. J. Mol. Sci. 17, 1575 (2016).
Younossi, Z. M. et al. Nonalcoholic steatohepatitis is the most rapidly increasing indication for liver transplantation in the United States. Clin. Gastroenterol. Hepatol. https://doi.org/10.1016/j.cgh.2020.05.064 (2020).
Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M. & Sanyal, A. J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 24, 908–922 (2018). This article comprehensively reviews the clinical features, risk factors, known pathogenic mechanisms, preclinical models and treatment possibilities of NAFLD.
Schwabe, R. F., Tabas, I. & Pajvani, U. B. Mechanisms of fibrosis development in nonalcoholic steatohepatitis. Gastroenterology 158, 1913–1928 (2020).
Kim, D., Kim, W. R., Kim, H. J. & Therneau, T. M. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology 57, 1357–1365 (2013).
Dulai, P. S. et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology 65, 1557–1565 (2017).
Angulo, P. et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149, 389–397.e10 (2015).
Ekstedt, M. et al. 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).
Vilar-Gomez, E. et al. Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study. Gastroenterology 155, 443–457.e17 (2018). Together with references 11–13, this study reports that liver fibrosis is the major predictor of clinical outcomes in patients with NAFLD.
Hannah, W. N. Jr. Torres, D. M. & Harrison, S. A. Nonalcoholic steatohepatitis and endpoints in clinical trials. Gastroenterol. Hepatol. 12, 756–763 (2016).
Affo, S., Yu, L. X. & Schwabe, R. F. The role of cancer-associated fibroblasts and fibrosis in liver cancer. Annu. Rev. Pathol. 12, 153–186 (2017).
Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).
Zhu, C. et al. Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aat0344 (2018). This paper demonstrates that aberrant Notch activity specifically in hepatocytes promotes NASH-associated liver fibrosis in a paracrine fashion.
Verdelho Machado, M. & Diehl, A. M. Role of hedgehog signaling pathway in NASH. Int. J. Mol. Sci. 17, 857 (2016).
Yimlamai, D., Fowl, B. H. & Camargo, F. D. Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer. J. Hepatol. 63, 1491–1501 (2015).
Wang, X. et al. Hepatocyte TAZ/WWTR1 promotes inflammation and fibrosis in nonalcoholic steatohepatitis. Cell Metab. 24, 848–862 (2016). This study shows that hepatocyte TAZ is stabilized in NASH and causes liver inflammation and fibrosis by stimulating Hedgehog ligand secretion.
Mooring, M. et al. Hepatocyte stress increases expression of YAP and TAZ in hepatocytes to promote parenchymal inflammation and fibrosis. Hepatology 71, 1813–1830 (2020).
Zong, Y. & Stanger, B. Z. Molecular mechanisms of liver and bile duct development. Wiley Interdiscip. Rev. Dev. Biol. 1, 643–655 (2012).
Chillakuri, C. R., Sheppard, D., Lea, S. M. & Handford, P. A. Notch receptor-ligand binding and activation: insights from molecular studies. Semin. Cell Dev. Biol. 23, 421–428 (2012).
Bray, S. J. Notch signalling: a simple pathway becomes complex. Nat. Rev. Mol. Cell Biol. 7, 678–689 (2006).
Kageyama, R., Ohtsuka, T. & Kobayashi, T. The Hes gene family: repressors and oscillators that orchestrate embryogenesis. Development 134, 1243–1251 (2007).
Turnpenny, P. D. & Ellard, S. Alagille syndrome: pathogenesis, diagnosis and management. Eur. J. Hum. Genet. 20, 251–257 (2012).
Loomes, K. M. et al. Characterization of Notch receptor expression in the developing mammalian heart and liver. Am. J. Med. Genet. 112, 181–189 (2002).
Hofmann, J. J. et al. Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome. Development 137, 4061–4072 (2010).
Geisler, F. et al. Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice. Hepatology 48, 607–616 (2008).
Lozier, J., McCright, B. & Gridley, T. Notch signaling regulates bile duct morphogenesis in mice. PLoS ONE 3, e1851 (2008).
Zong, Y. et al. Notch signaling controls liver development by regulating biliary differentiation. Development 136, 1727–1739 (2009). This study shows that Notch controls multiple steps of bile duct development, including the determination of biliary fate and the formation of ductal structures.
Antoniou, A. et al. Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9. Gastroenterology 136, 2325–2333 (2009).
Poncy, A. et al. Transcription factors SOX4 and SOX9 cooperatively control development of bile ducts. Dev. Biol. 404, 136–148 (2015).
Sparks, E. E., Huppert, K. A., Brown, M. A., Washington, M. K. & Huppert, S. S. Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice. Hepatology 51, 1391–1400 (2010).
Tanimizu, N. & Miyajima, A. Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors. J. Cell Sci. 117 (Pt. 15), 3165–3174 (2004).
Dong, J. et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130, 1120–1133 (2007).
Zhao, B., Tumaneng, K. & Guan, K. L. The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat. Cell Biol. 13, 877–883 (2011).
Hansen, C. G., Moroishi, T. & Guan, K. L. YAP and TAZ: a nexus for Hippo signaling and beyond. Trends Cell Biol. 25, 499–513 (2015).
Zhang, N. et al. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev. Cell 19, 27–38 (2010).
Lee, D. H. et al. LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4alpha expression during liver development. Nat. Commun. 7, 11961 (2016).
Alder, O. et al. Hippo signaling influences HNF4A and FOXA2 enhancer switching during hepatocyte differentiation. Cell Rep. 9, 261–271 (2014).
Yimlamai, D. et al. Hippo pathway activity influences liver cell fate. Cell 157, 1324–1338 (2014). This study demonstrates that YAP activation can reprogramme mature hepatocytes to adopt progenitor characteristics.
Fitamant, J. et al. YAP inhibition restores hepatocyte differentiation in advanced HCC, leading to tumor regression. Cell Rep. 10, 1692–1707 (2015).
Niewiadomski, P. et al. Gli proteins: regulation in development and cancer. Cells 8, 147 (2019).
Deutsch, G., Jung, J., Zheng, M., Lora, J. & Zaret, K. S. A bipotential precursor population for pancreas and liver within the embryonic endoderm. Development 128, 871–881 (2001).
Hirose, Y., Itoh, T. & Miyajima, A. Hedgehog signal activation coordinates proliferation and differentiation of fetal liver progenitor cells. Exp. Cell Res. 315, 2648–2657 (2009).
Logan, C. Y. & Nusse, R. The Wnt signaling pathway in development and disease. Annu. Rev. Cell Dev. Biol. 20, 781–810 (2004).
Tan, X. et al. Beta-catenin deletion in hepatoblasts disrupts hepatic morphogenesis and survival during mouse development. Hepatology 47, 1667–1679 (2008).
Tan, X., Behari, J., Cieply, B., Michalopoulos, G. K. & Monga, S. P. Conditional deletion of beta-catenin reveals its role in liver growth and regeneration. Gastroenterology 131, 1561–1572 (2006).
Gougelet, A. et al. T-cell factor 4 and β-catenin chromatin occupancies pattern zonal liver metabolism in mice. Hepatology 59, 2344–2357 (2014).
Benhamouche, S. et al. Apc tumor suppressor gene is the “zonation-keeper” of mouse liver. Dev. Cell 10, 759–770 (2006).
Yang, J. et al. β-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation! Hepatology 60, 964–976 (2014).
Planas-Paz, L. et al. The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size. Nat. Cell Biol. 18, 467–479 (2016).
Sekine, S., Lan, B. Y., Bedolli, M., Feng, S. & Hebrok, M. Liver-specific loss of beta-catenin blocks glutamine synthesis pathway activity and cytochrome p450 expression in mice. Hepatology 43, 817–825 (2006).
Cordi, S. et al. Role of β-catenin in development of bile ducts. Differentiation 91, 42–49 (2016).
Hayward, P., Kalmar, T. & Martinez Arias, A. Wnt/Notch signalling and information processing during development. Development 135, 411–424 (2008).
So, J. et al. Wnt/β-catenin signaling controls intrahepatic biliary network formation in zebrafish by regulating notch activity. Hepatology 67, 2352–2366 (2018).
Clotman, F. et al. Control of liver cell fate decision by a gradient of TGF beta signaling modulated by Onecut transcription factors. Genes Dev. 19, 1849–1854 (2005).
Wang, W. et al. TGFβ signaling controls intrahepatic bile duct development may through regulating the Jagged1-Notch-Sox9 signaling axis. J. Cell Physiol. 233, 5780–5791 (2018).
Miyaoka, Y. et al. Hypertrophy and unconventional cell division of hepatocytes underlie liver regeneration. Curr. Biol. 22, 1166–1175 (2012).
Yanger, K. et al. Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell 15, 340–349 (2014).
Schaub, J. R., Malato, Y., Gormond, C. & Willenbring, H. Evidence against a stem cell origin of new hepatocytes in a common mouse model of chronic liver injury. Cell Rep. 8, 933–939 (2014). This study, with reference 62, reports that hepatocytes, rather than liver stem cells, are the sources of liver mass regeneration in mouse models.
Chen, F. et al. Broad distribution of hepatocyte proliferation in liver homeostasis and regeneration. Cell Stem Cell 26, 27–33.e4 (2020).
Sun, T. et al. AXIN2+ pericentral hepatocytes have limited contributions to liver homeostasis and regeneration. Cell Stem Cell 26, 97–107.e6 (2020).
Wang, B., Zhao, L., Fish, M., Logan, C. Y. & Nusse, R. Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver. Nature 524, 180–185 (2015).
Font-Burgada, J. et al. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer. Cell 162, 766–779 (2015).
Lin, S. et al. Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury. Nature 556, 244–248 (2018).
Huch, M. et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494, 247–250 (2013).
Tarlow, B. D., Finegold, M. J. & Grompe, M. Clonal tracing of Sox9+ liver progenitors in mouse oval cell injury. Hepatology 60, 278–289 (2014).
Rodrigo-Torres, D. et al. The biliary epithelium gives rise to liver progenitor cells. Hepatology 60, 1367–1377 (2014).
Jors, S. et al. Lineage fate of ductular reactions in liver injury and carcinogenesis. J. Clin. Invest. 125, 2445–2457 (2015). Together with references 70 and 71, this study shows that ductular reaction or the ‘oval cell response’ predominantly derives from cholangiocytes.
Russell, J. O. et al. Hepatocyte-specific beta-catenin deletion during severe liver injury provokes cholangiocytes to differentiate into hepatocytes. Hepatology 69, 742–759 (2019).
Lu, W. Y. et al. Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat. Cell Biol. 17, 971–983 (2015).
Raven, A. et al. Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature 547, 350–354 (2017).
Monga, S. P., Pediaditakis, P., Mule, K., Stolz, D. B. & Michalopoulos, G. K. Changes in WNT/beta-catenin pathway during regulated growth in rat liver regeneration. Hepatology 33, 1098–1109 (2001).
Nelsen, C. J., Rickheim, D. G., Timchenko, N. A., Stanley, M. W. & Albrecht, J. H. Transient expression of cyclin D1 is sufficient to promote hepatocyte replication and liver growth in vivo. Cancer Res. 61, 8564–8568 (2001).
Ochoa, B. et al. Hedgehog signaling is critical for normal liver regeneration after partial hepatectomy in mice. Hepatology 51, 1712–1723 (2010).
Grijalva, J. L. et al. Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration. Am. J. Physiol. Gastrointest. Liver Physiol. 307, G196–G204 (2014).
Lu, L., Finegold, M. J. & Johnson, R. L. Hippo pathway coactivators Yap and Taz are required to coordinate mammalian liver regeneration. Exp. Mol. Med. 50, e423 (2018).
Kim, A. R. et al. TAZ stimulates liver regeneration through interleukin-6-induced hepatocyte proliferation and inhibition of cell death after liver injury. FASEB J. 33, 5914–5923 (2019).
Swiderska-Syn, M. et al. Hedgehog regulates yes-associated protein 1 in regenerating mouse liver. Hepatology 64, 232–244 (2016).
Langiewicz, M. et al. Hedgehog pathway mediates early acceleration of liver regeneration induced by a novel two-staged hepatectomy in mice. J. Hepatol. 66, 560–570 (2017).
Kohler, C. et al. Expression of Notch-1 and its ligand Jagged-1 in rat liver during liver regeneration. Hepatology 39, 1056–1065 (2004).
Wang, L. et al. Disruption of the transcription factor recombination signal-binding protein-Jkappa (RBP-J) leads to veno-occlusive disease and interfered liver regeneration in mice. Hepatology 49, 268–277 (2009).
Cuervo, H. et al. Endothelial notch signaling is essential to prevent hepatic vascular malformations in mice. Hepatology 64, 1302–1316 (2016).
Duan, J. L. et al. Endothelial Notch activation reshapes the angiocrine of sinusoidal endothelia to aggravate liver fibrosis and blunt regeneration in mice. Hepatology 68, 677–690 (2018).
Yanger, K. et al. Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes. Dev. 27, 719–724 (2013). This study shows that Notch promotes transdifferentiation of mature hepatocytes into cholangiocytes in several mouse models of liver injury.
Boulter, L. et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat. Med. 18, 572–579 (2012).
Morell, C. M. et al. Notch signaling and progenitor/ductular reaction in steatohepatitis. PLoS ONE 12, e0187384 (2017).
Walter, T. J., Vanderpool, C., Cast, A. E. & Huppert, S. S. Intrahepatic bile duct regeneration in mice does not require Hnf6 or Notch signaling through Rbpj. Am. J. Pathol. 184, 1479–1488 (2014).
Schaub, J. R. et al. De novo formation of the biliary system by TGFbeta-mediated hepatocyte transdifferentiation. Nature 557, 247–251 (2018).
Pepe-Mooney, B. J. et al. Single-cell analysis of the liver epithelium reveals dynamic heterogeneity and an essential role for YAP in homeostasis and regeneration. Cell Stem Cell https://doi.org/10.1016/j.stem.2019.04.004 (2019).
Planas-Paz, L. et al. YAP, but not RSPO-LGR4/5, signaling in biliary epithelial cells promotes a ductular reaction in response to liver injury. Cell Stem Cell 25, 39–53.e10 (2019).
Sato, K. et al. Ductular reaction in liver diseases: pathological mechanisms and translational significances. Hepatology 69, 420–430 (2019).
Tarlow, B. D. et al. Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. Cell Stem Cell 15, 605–618 (2014).
Deng, X. et al. Chronic liver injury induces conversion of biliary epithelial cells into hepatocytes. Cell Stem Cell 23, 114–122.e3 (2018).
Limaye, P. B. et al. Expression of specific hepatocyte and cholangiocyte transcription factors in human liver disease and embryonic development. Lab. Invest. 88, 865–872 (2008).
Grompe, M. et al. Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I. Nat. Genet. 10, 453–460 (1995).
Miyamura, N. et al. YAP determines the cell fate of injured mouse hepatocytes in vivo. Nat. Commun. 8, 16017 (2017).
Wree, A., Broderick, L., Canbay, A., Hoffman, H. M. & Feldstein, A. E. From NAFLD to NASH to cirrhosis – new insights into disease mechanisms. Nat. Rev. Gastroenterol. Hepatol. 10, 627–636 (2013).
Buzzetti, E., Pinzani, M. & Tsochatzis, E. A. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 65, 1038–1048 (2016).
Cusi, K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 142, 711–725.e6 (2012).
Neuschwander-Tetri, B. A. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 52, 774–788 (2010).
Hardy, T., Oakley, F., Anstee, Q. M. & Day, C. P. Nonalcoholic fatty liver disease: pathogenesis and disease spectrum. Annu. Rev. Pathol. 11, 451–496 (2016).
Friedman, S. L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol. Rev. 88, 125–172 (2008).
Cordero-Espinoza, L. & Huch, M. The balancing act of the liver: tissue regeneration versus fibrosis. J. Clin. Invest. 128, 85–96 (2018).
Mederacke, I. et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat. Commun. 4, 2823 (2013). This study revealed HSCs as the predominant contributors of liver fibrosis in mouse models.
Asgharpour, A. et al. A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer. J. Hepatol. 65, 579–588 (2016).
Clapper, J. R. et al. 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–G495 (2013).
Wolf, M. J. et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 26, 549–564 (2014).
Nakagawa, H. et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell 26, 331–343 (2014).
Tsuchida, T. et al. A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. J. Hepatol. 69, 385–395 (2018).
Machado, M. V. & Diehl, A. M. Hedgehog signalling in liver pathophysiology. J. Hepatol. 68, 550–562 (2018).
Sicklick, J. K. et al. Hedgehog signaling maintains resident hepatic progenitors throughout life. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G859–G870 (2006).
Michelotti, G. A. et al. Smoothened is a master regulator of adult liver repair. J. Clin. Invest. 123, 2380–2394 (2013).
Kwon, H. et al. Inhibition of hedgehog signaling ameliorates hepatic inflammation in mice with nonalcoholic fatty liver disease. Hepatology 63, 1155–1169 (2016).
Chung, S. I. et al. Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model. J. Hepatol. 64, 618–627 (2016).
Matz-Soja, M. et al. Hedgehog signaling is a potent regulator of liver lipid metabolism and reveals a GLI-code associated with steatosis. eLife 5, e13308 (2016).
Marbach-Breitruck, E. et al. Tick-Tock Hedgehog-Mutual crosstalk with liver circadian clock promotes liver steatosis. J. Hepatol. 70, 1192–1202 (2019).
Guy, C. D. et al. Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology 55, 1711–1721 (2012).
Jung, Y. et al. Signals from dying hepatocytes trigger growth of liver progenitors. Gut 59, 655–665 (2010).
Guy, C. D., Suzuki, A., Abdelmalek, M. F., Burchette, J. L. & Diehl, A. M. Treatment response in the PIVENS trial is associated with decreased Hedgehog pathway activity. Hepatology 61, 98–107 (2015). This study, with reference 121, shows that Hedgehog pathway activation is associated with disease severity and treatment response in patients with NASH.
Lee, Y. A. et al. Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap. Nat. Commun. 9, 4962 (2018).
Manmadhan, S. & Ehmer, U. Hippo signaling in the liver — a long and ever-expanding story. Front. Cell Dev. Biol. 7, 33 (2019).
Mannaerts, I. et al. The Hippo pathway effector YAP controls mouse hepatic stellate cell activation. J. Hepatol. 63, 679–688 (2015).
Martin, K. et al. PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis. Nat. Commun. 7, 12502 (2016).
Du, K. et al. Hedgehog-YAP signaling pathway regulates glutaminolysis to control activation of hepatic stellate cells. Gastroenterology 154, 1465–1479.e13 (2018).
Machado, M. V. et al. Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease. J. Hepatol. 63, 962–970 (2015).
Russell, J. O. & Monga, S. P. Wnt/β-catenin signaling in liver development, homeostasis, and pathobiology. Annu. Rev. Pathol. 13, 351–378 (2018).
Go, G. W. et al. The combined hyperlipidemia caused by impaired Wnt-LRP6 signaling is reversed by Wnt3a rescue. Cell Metab. 19, 209–220 (2014).
Lehwald, N. et al. β-catenin regulates hepatic mitochondrial function and energy balance in mice. Gastroenterology 143, 754–764 (2012).
Liu, H. et al. Wnt signaling regulates hepatic metabolism. Sci. Signal. 4, ra6 (2011).
Kordes, C., Sawitza, I. & Haussinger, D. Canonical Wnt signaling maintains the quiescent stage of hepatic stellate cells. Biochem. Biophys. Res. Commun. 367, 116–123 (2008).
Ge, W. S. et al. β-catenin is overexpressed in hepatic fibrosis and blockage of Wnt/β-catenin signaling inhibits hepatic stellate cell activation. Mol. Med. Rep. 9, 2145–2151 (2014).
Ni, M. M. et al. Novel Insights on Notch signaling pathways in liver fibrosis. Eur. J. Pharmacol. 826, 66–74 (2018).
Pajvani, U. B. et al. Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner. Nat. Med. 17, 961–967 (2011).
Pajvani, U. B. et al. Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability. Nat. Med. 19, 1055–1060 (2013). References 137 and 138 show that, in mature hepatocytes, Notch sits at the bifurcation of insulin signalling to regulate glucose and lipid metabolism.
Kitamura, T. et al. A Foxo/Notch pathway controls myogenic differentiation and fiber type specification. J. Clin. Invest. 117, 2477–2485 (2007).
Valenti, L. et al. Hepatic notch signaling correlates with insulin resistance and nonalcoholic fatty liver disease. Diabetes 62, 4052–4062 (2013).
He, F. et al. Myeloid-specific disruption of recombination signal binding protein Jkappa ameliorates hepatic fibrosis by attenuating inflammation through cylindromatosis in mice. Hepatology 61, 303–314 (2015).
Xu, J. et al. NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation. J. Clin. Invest. 125, 1579–1590 (2015).
Chen, Y. et al. Inhibition of Notch signaling by a gamma-secretase inhibitor attenuates hepatic fibrosis in rats. PLoS ONE 7, e46512 (2012).
Chen, Y. X., Weng, Z. H. & Zhang, S. L. Notch3 regulates the activation of hepatic stellate cells. World J. Gastroenterol. 18, 1397–1403 (2012).
Xie, G. et al. Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice. Hepatology 58, 1801–1813 (2013).
Yang, Y. M. et al. Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis. Sci. Transl Med. 11, eaat9284 (2019).
Ouchi, R. et al. Modeling steatohepatitis in humans with pluripotent stem cell-derived organoids. Cell Metab. 30, 374–384.e6 (2019).
Wang, S. et al. RNA binding proteins control transdifferentiation of hepatic stellate cells into myofibroblasts. Cell Physiol. Biochem. 48, 1215–1229 (2018).
Hyun, J. et al. Dysregulated activation of fetal liver programme in acute liver failure. Gut 68, 1076–1087 (2019).
Younossi, Z. et al. Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates. Clin. Gastroenterol. Hepatol. 17, 748–755.e3 (2019).
Younossi, Z. M. et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology 62, 1723–1730 (2015).
Anstee, Q. M., Reeves, H. L., Kotsiliti, E., Govaere, O. & Heikenwalder, M. From NASH to HCC: current concepts and future challenges. Nat. Rev. Gastroenterol. Hepatol. 16, 411–428 (2019). This review systemically discusses the epidemiology, pathogenesis and clinical management and diagnosis of NASH-induced HCC.
Zender, S. et al. A critical role for notch signaling in the formation of cholangiocellular carcinomas. Cancer Cell 23, 784–795 (2013).
Villanueva, A. et al. Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology 143, 1660–1669.e7 (2012).
Cox, A. G. et al. Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth. Nat. Cell Biol. 18, 886–896 (2016).
Yuan, W. C. et al. NUAK2 is a critical YAP target in liver cancer. Nat. Commun. 9, 4834 (2018).
Kim, W. et al. Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma. Gut 67, 1692–1703 (2018).
Hagenbeek, T. J. et al. The Hippo pathway effector TAZ induces TEAD-dependent liver inflammation and tumors. Sci. Signal. 11, eaaj1757 (2018).
Senni, N. et al. β-catenin-activated hepatocellular carcinomas are addicted to fatty acids. Gut 68, 322–334 (2019).
Adebayo Michael, A. O. et al. Inhibiting glutamine-dependent mTORC1 activation ameliorates liver cancers driven by β-catenin mutations. Cell Metab. 29, 1135–1150.e6 (2019).
Ruiz de Galarreta, M. et al. β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov. 9, 1124–1141 (2019).
Sia, D. et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology 153, 812–826 (2017).
Harding, J. J. et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin. Cancer Res. 25, 2116–2126 (2019).
Kim, W. et al. Hippo signaling interactions with Wnt/beta-catenin and Notch signaling repress liver tumorigenesis. J. Clin. Invest. 127, 137–152 (2017).
Febbraio, M. A. et al. Preclinical models for studying NASH-driven HCC: how useful are they? Cell Metab. 29, 18–26 (2019). This review comprehensively summarizes the current knowledge of NASH-driven HCC and existing mouse models to study this disease.
Sparling, D. P. et al. Adipocyte-specific blockade of gamma-secretase, but not inhibition of Notch activity, reduces adipose insulin sensitivity. Mol. Metab. 5, 113–121 (2016).
van Es, J. H. et al. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435, 959–963 (2005).
Kim, K. et al. γ-secretase inhibition lowers plasma triglyceride-rich lipoproteins by stabilizing the LDL receptor. Cell Metab. 27, 816–827.e4 (2018).
Richter, L. R. et al. Targeted delivery of notch inhibitor attenuates obesity-induced glucose intolerance and liver fibrosis. ACS Nano 14, 6878–6886 (2020).
Wittrup, A. & Lieberman, J. Knocking down disease: a progress report on siRNA therapeutics. Nat. Rev. Genet. 16, 543–552 (2015).
Wang, X. et al. A therapeutic silencing RNA targeting hepatocyte TAZ prevents and reverses fibrosis in nonalcoholic steatohepatitis in mice. Hepatol. Commun. 3, 1221–1234 (2019).
Ganesh, S. et al. Direct pharmacological inhibition of beta-catenin by RNA interference in tumors of diverse origin. Mol. Cancer Ther. 15, 2143–2154 (2016).
Saggi, H. et al. Loss of hepatocyte β-catenin protects mice from experimental porphyria-associated liver injury. J. Hepatol. 70, 108–117 (2019).
Tao, J. et al. Targeting β-catenin in hepatocellular cancers induced by coexpression of mutant β-catenin and K-Ras in mice. Hepatology 65, 1581–1599 (2017).