Metabolic Injury of Hepatocytes Promotes Progression of NAFLD and AALD

Raquel Carvalho-Gontijo; Cuijuan Han; Lei Zhang; Vivian Zhang; Mojgan Hosseini; Kristin Mekeel; Bernd Schnabl; Rohit Loomba; Michael Karin; David A. Brenner; Tatiana Kisseleva

doi:10.1055/s-0042-1755316

Seminars in Liver Disease, Inhaltsverzeichnis

Semin Liver Dis 2022; 42(03): 233-249
DOI: 10.1055/s-0042-1755316

Review Article

Metabolic Injury of Hepatocytes Promotes Progression of NAFLD and AALD

Autor*innen

Raquel Carvalho-Gontijo‡^*

¹Department of Medicine, University of California, San Diego School of Medicine, La Jolla, California

²Department of Surgery, University of California, San Diego School of Medicine, La Jolla, California
Cuijuan Han‡^*

¹Department of Medicine, University of California, San Diego School of Medicine, La Jolla, California

²Department of Surgery, University of California, San Diego School of Medicine, La Jolla, California
Lei Zhang

¹Department of Medicine, University of California, San Diego School of Medicine, La Jolla, California

²Department of Surgery, University of California, San Diego School of Medicine, La Jolla, California
Vivian Zhang

¹Department of Medicine, University of California, San Diego School of Medicine, La Jolla, California

²Department of Surgery, University of California, San Diego School of Medicine, La Jolla, California
Mojgan Hosseini

³Department of Pathology, University of California, San Diego School of Medicine, La Jolla, California
Kristin Mekeel

²Department of Surgery, University of California, San Diego School of Medicine, La Jolla, California
Bernd Schnabl

¹Department of Medicine, University of California, San Diego School of Medicine, La Jolla, California
Rohit Loomba

¹Department of Medicine, University of California, San Diego School of Medicine, La Jolla, California
Michael Karin

⁴Department of Pharmacology, University of California, San Diego School of Medicine, La Jolla, California
David A. Brenner

¹Department of Medicine, University of California, San Diego School of Medicine, La Jolla, California
Tatiana Kisseleva

²Department of Surgery, University of California, San Diego School of Medicine, La Jolla, California

Abstract

Nonalcoholic liver disease is a component of metabolic syndrome associated with obesity, insulin resistance, and hyperlipidemia. Excessive alcohol consumption may accelerate the progression of steatosis, steatohepatitis, and fibrosis. While simple steatosis is considered a benign condition, nonalcoholic steatohepatitis with inflammation and fibrosis may progress to cirrhosis, liver failure, and hepatocellular cancer. Studies in rodent experimental models and primary cell cultures have demonstrated several common cellular and molecular mechanisms in the pathogenesis and regression of liver fibrosis. Chronic injury and death of hepatocytes cause the recruitment of myeloid cells, secretion of inflammatory and fibrogenic cytokines, and activation of myofibroblasts, resulting in liver fibrosis. In this review, we discuss the role of metabolically injured hepatocytes in the pathogenesis of nonalcoholic steatohepatitis and alcohol-associated liver disease. Specifically, the role of chemokine production and de novo lipogenesis in the development of steatotic hepatocytes and the pathways of steatosis regulation are discussed.

Keywords

liver fibrosis - steatotic hepatocytes - de novo lipogenesis - endoplasmic reticulum stress - unfolded protein response

Volltext

Referenzen

References
1 Friedman SL. Liver fibrosis – from bench to bedside. J Hepatol 2003; 38 (Suppl 1): S38-S53
2 Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol 2021; 18 (03) 151-166
3 Gao B, Ahmad MF, Nagy LE, Tsukamoto H. Inflammatory pathways in alcoholic steatohepatitis. J Hepatol 2019; 70 (02) 249-259
4 Iwaisako K, Jiang C, Zhang M. et al. Origin of myofibroblasts in the fibrotic liver in mice. Proc Natl Acad Sci U S A 2014; 111 (32) E3297-E3305
5 Desmoulière A. Hepatic stellate cells: the only cells involved in liver fibrogenesis? A dogma challenged. Gastroenterology 2007; 132 (05) 2059-2062
6 Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2021; 18 (04) 223-238
7 Younossi ZM, Otgonsuren M, Henry L. et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology 2015; 62 (06) 1723-1730
8 O'Shea RS, Dasarathy S, McCullough AJ. Practice Guideline Committee of the American Association for the Study of Liver Diseases, Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology 2010; 51 (01) 307-328
9 Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med 2009; 360 (26) 2758-2769
10 Takahashi Y, Fukusato T. Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol 2014; 20 (42) 15539-15548
11 Kim JY, Garcia-Carbonell R, Yamachika S. et al. ER stress drives lipogenesis and steatohepatitis via caspase-2 activation of S1P. Cell 2018; 175 (01) 133-145.e15
12 Tsochatzis EA, Papatheodoridis GV, Archimandritis AJ. Adipokines in nonalcoholic steatohepatitis: from pathogenesis to implications in diagnosis and therapy. Mediators Inflamm 2009; 2009: 831670
13 Moschen AR, Kaser S, Tilg H. Non-alcoholic steatohepatitis: a microbiota-driven disease. Trends Endocrinol Metab 2013; 24 (11) 537-545
14 Avila MA, Dufour JF, Gerbes AL. et al. Recent advances in alcohol-related liver disease (ALD): summary of a Gut round table meeting. Gut 2020; 69 (04) 764-780
15 Cederbaum AI. Alcohol metabolism. Clin Liver Dis 2012; 16 (04) 667-685
16 Lieber CS, Rubin E, DeCarli LM. Hepatic microsomal ethanol oxidizing system (MEOS): differentiation from alcohol dehydrogenase and NADPH oxidase. Biochem Biophys Res Commun 1970; 40 (04) 858-865
17 Teschke R. Alcoholic liver disease: alcohol metabolism, cascade of molecular mechanisms, cellular targets, and clinical aspects. Biomedicines 2018; 6 (04) 106
18 Yan AW, Fouts DE, Brandl J. et al. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology 2011; 53 (01) 96-105
19 Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 2011; 141 (05) 1572-1585
20 Miller AM, Horiguchi N, Jeong WI, Radaeva S, Gao B. Molecular mechanisms of alcoholic liver disease: innate immunity and cytokines. Alcohol Clin Exp Res 2011; 35 (05) 787-793
21 Giles DA, Moreno-Fernandez ME, Divanovic S. IL-17 axis driven inflammation in non-alcoholic fatty liver disease progression. Curr Drug Targets 2015; 16 (12) 1315-1323
22 McGeachy MJ, Cua DJ, Gaffen SL. The IL-17 family of cytokines in health and disease. Immunity 2019; 50 (04) 892-906
23 Oppmann B, Lesley R, Blom B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000; 13 (05) 715-725
24 Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Karow M, Flavell RA. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity 2007; 27 (04) 647-659
25 Radaeva S, Sun R, Pan HN, Hong F, Gao B. Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology 2004; 39 (05) 1332-1342
26 Kong X, Feng D, Mathews S, Gao B. Hepatoprotective and anti-fibrotic functions of interleukin-22: therapeutic potential for the treatment of alcoholic liver disease. J Gastroenterol Hepatol 2013; 28 (Suppl 1): 56-60
27 Zhou D, Pan Q, Shen F. et al. Total fecal microbiota transplantation alleviates high-fat diet-induced steatohepatitis in mice via beneficial regulation of gut microbiota. Sci Rep 2017; 7 (01) 1529
28 Shalapour S, Lin XJ, Bastian IN. et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 2017; 551 (7680): 340-345
29 Llacuna L, Marí M, Lluis JM, García-Ruiz C, Fernández-Checa JC, Morales A. Reactive oxygen species mediate liver injury through parenchymal nuclear factor-kappaB inactivation in prolonged ischemia/reperfusion. Am J Pathol 2009; 174 (05) 1776-1785
30 Liu RM, Desai LP. Reciprocal regulation of TGF-β and reactive oxygen species: a perverse cycle for fibrosis. Redox Biol 2015; 6: 565-577
31 Hattori S, Dhar DK, Hara N. et al. FR-167653, a selective p38 MAPK inhibitor, exerts salutary effect on liver cirrhosis through downregulation of Runx2. Lab Invest 2007; 87 (06) 591-601
32 Foo NP, Lin SH, Lee YH, Wu MJ, Wang YJ. α-Lipoic acid inhibits liver fibrosis through the attenuation of ROS-triggered signaling in hepatic stellate cells activated by PDGF and TGF-β. Toxicology 2011; 282 (1-2): 39-46
33 Canbay A, Taimr P, Torok N, Higuchi H, Friedman S, Gores GJ. Apoptotic body engulfment by a human stellate cell line is profibrogenic. Lab Invest 2003; 83 (05) 655-663
34 Canbay A, Feldstein AE, Higuchi H. et al. Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology 2003; 38 (05) 1188-1198
35 Garcíade León MdelC, Montfort I, Tello Montes E. et al. Hepatocyte production of modulators of extracellular liver matrix in normal and cirrhotic rat liver. Exp Mol Pathol 2006; 80 (01) 97-108
36 Ibrahim SH, Hirsova P, Tomita K. et al. Mixed lineage kinase 3 mediates release of C-X-C motif ligand 10-bearing chemotactic extracellular vesicles from lipotoxic hepatocytes. Hepatology 2016; 63 (03) 731-744
37 Povero D, Panera N, Eguchi A. et al. Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-γ. Cell Mol Gastroenterol Hepatol 2015; 1 (06) 646-663.e4
38 Eguchi A, Yan R, Pan SQ. et al. Comprehensive characterization of hepatocyte-derived extracellular vesicles identifies direct miRNA-based regulation of hepatic stellate cells and DAMP-based hepatic macrophage IL-1β and IL-17 upregulation in alcoholic hepatitis mice. J Mol Med (Berl) 2020; 98 (07) 1021-1034
39 Lee YS, Kim SY, Ko E. et al. Exosomes derived from palmitic acid-treated hepatocytes induce fibrotic activation of hepatic stellate cells. Sci Rep 2017; 7 (01) 3710
40 Hernández A, Reyes D, Geng Y. et al. Extracellular vesicles derived from fat-laden hepatocytes undergoing chemical hypoxia promote a pro-fibrotic phenotype in hepatic stellate cells. Biochim Biophys Acta Mol Basis Dis 2020; 1866 (10) 165857
41 Niimura F, Okubo S, Fogo A, Ichikawa I. Temporal and spatial expression pattern of the angiotensinogen gene in mice and rats. Am J Physiol 1997; 272 (1, Pt 2): R142-R147
42 Bataller R, Ginès P, Nicolás JM. et al. Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology 2000; 118 (06) 1149-1156
43 Granzow M, Schierwagen R, Klein S. et al. Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis. Hepatology 2014; 60 (01) 334-348
44 Wang X, Cai B, Yang X. et al. Cholesterol stabilizes TAZ in hepatocytes to promote experimental non-alcoholic steatohepatitis. Cell Metab 2020; 31 (05) 969-986.e7
45 Wang X, Zheng Z, Caviglia JM. et al. Hepatocyte TAZ/WWTR1 promotes inflammation and fibrosis in nonalcoholic steatohepatitis. Cell Metab 2016; 24 (06) 848-862
46 Wang X, Sommerfeld MR, Jahn-Hofmann K. et al. A therapeutic silencing RNA targeting hepatocyte TAZ prevents and reverses fibrosis in nonalcoholic steatohepatitis in mice. Hepatol Commun 2019; 3 (09) 1221-1234
47 Canbay A, Bechmann L, Gerken G. Lipid metabolism in the liver. Z Gastroenterol 2007; 45 (01) 35-41
48 Ma HY, Yamamoto G, Xu J. et al. IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease. J Hepatol 2020; 72 (05) 946-959
49 Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005; 115 (05) 1343-1351
50 Hager L, Li L, Pun H. et al. Lecithin:cholesterol acyltransferase deficiency protects against cholesterol-induced hepatic endoplasmic reticulum stress in mice. J Biol Chem 2012; 287 (24) 20755-20768
51 Basseri S, Austin RC. Endoplasmic reticulum stress and lipid metabolism: mechanisms and therapeutic potential. Biochem Res Int 2012; 2012: 841362
52 Davidson NO, Shelness GS. Apolipoprotein B: mRNA editing, lipoprotein assembly, and presecretory degradation. Annu Rev Nutr 2000; 20: 169-193
53 Saran AR, Dave S, Zarrinpar A. Circadian rhythms in the pathogenesis and treatment of fatty liver disease. Gastroenterology 2020; 158 (07) 1948-1966.e1
54 Pouwels S, Sakran N, Graham Y. et al. Non-alcoholic fatty liver disease (NAFLD): a review of pathophysiology, clinical management and effects of weight loss. BMC Endocr Disord 2022; 22 (01) 63
55 Lebeaupin C, Vallée D, Hazari Y, Hetz C, Chevet E, Bailly-Maitre B. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J Hepatol 2018; 69 (04) 927-947
56 Kleiner DE, Brunt EM, Van Natta M. et al; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41 (06) 1313-1321
57 Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 2013; 10 (11) 686-690
58 Caballero F, Fernández A, De Lacy AM, Fernández-Checa JC, Caballería J, García-Ruiz C. Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH. J Hepatol 2009; 50 (04) 789-796
59 Farrell GC, van Rooyen D. Liver cholesterol: is it playing possum in NASH?. Am J Physiol Gastrointest Liver Physiol 2012; 303 (01) G9-G11
60 Shimano H, Sato R. SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology. Nat Rev Endocrinol 2017; 13 (12) 710-730
61 Bertolio R, Napoletano F, Mano M. et al. Sterol regulatory element binding protein 1 couples mechanical cues and lipid metabolism. Nat Commun 2019; 10 (01) 1326
62 Adams CJ, Kopp MC, Larburu N, Nowak PR, Ali MMU. Structure and molecular mechanism of ER stress signaling by the unfolded protein response signal activator IRE1. Front Mol Biosci 2019; 6: 11
63 Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997; 89 (03) 331-340
64 Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002; 109 (09) 1125-1131
65 Toth JI, Datta S, Athanikar JN, Freedman LP, Osborne TF. Selective coactivator interactions in gene activation by SREBP-1a and -1c. Mol Cell Biol 2004; 24 (18) 8288-8300
66 Im SS, Yousef L, Blaschitz C. et al. Linking lipid metabolism to the innate immune response in macrophages through sterol regulatory element binding protein-1a. Cell Metab 2011; 13 (05) 540-549
67 Shimano H, Horton JD, Hammer RE, Shimomura I, Brown MS, Goldstein JL. Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. J Clin Invest 1996; 98 (07) 1575-1584
68 Brown MS, Radhakrishnan A, Goldstein JL. Retrospective on cholesterol homeostasis: the central role of SCAP. Annu Rev Biochem 2018; 87: 783-807
69 Azzu V, Vacca M, Kamzolas I. et al. Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression. Mol Metab 2021; 48: 101210
70 Lee SH, Lee JH, Im SS. The cellular function of SCAP in metabolic signaling. Exp Mol Med 2020; 52 (05) 724-729
71 Yabe D, Komuro R, Liang G, Goldstein JL, Brown MS. Liver-specific mRNA for INSIG-2 down-regulated by insulin: implications for fatty acid synthesis. Proc Natl Acad Sci U S A 2003; 100 (06) 3155-3160
72 Yellaturu CR, Deng X, Cagen LM. et al. Insulin enhances post-translational processing of nascent SREBP-1c by promoting its phosphorylation and association with COPII vesicles. J Biol Chem 2009; 284 (12) 7518-7532
73 Hannah VC, Ou J, Luong A, Goldstein JL, Brown MS. Unsaturated fatty acids down-regulate SREBP isoforms 1a and 1c by two mechanisms in HEK-293 cells. J Biol Chem 2001; 276 (06) 4365-4372
74 Owen JL, Zhang Y, Bae SH. et al. Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. Proc Natl Acad Sci U S A 2012; 109 (40) 16184-16189
75 Brown AJ, Sun L, Feramisco JD, Brown MS, Goldstein JL. Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism. Mol Cell 2002; 10 (02) 237-245
76 Goldstein JL, Rawson RB, Brown MS. Mutant mammalian cells as tools to delineate the sterol regulatory element-binding protein pathway for feedback regulation of lipid synthesis. Arch Biochem Biophys 2002; 397 (02) 139-148
77 Espenshade PJ, Hughes AL. Regulation of sterol synthesis in eukaryotes. Annu Rev Genet 2007; 41: 401-427
78 Sakai J, Duncan EA, Rawson RB, Hua X, Brown MS, Goldstein JL. Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment. Cell 1996; 85 (07) 1037-1046
79 Sakai J, Rawson RB, Espenshade PJ. et al. Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells. Mol Cell 1998; 2 (04) 505-514
80 Ye J, Davé UP, Grishin NV, Goldstein JL, Brown MS. Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane cleavage by site-2 protease. Proc Natl Acad Sci U S A 2000; 97 (10) 5123-5128
81 Nagoshi E, Yoneda Y. Dimerization of sterol regulatory element-binding protein 2 via the helix-loop-helix-leucine zipper domain is a prerequisite for its nuclear localization mediated by importin beta. Mol Cell Biol 2001; 21 (08) 2779-2789
82 Lee SJ, Sekimoto T, Yamashita E. et al. The structure of importin-beta bound to SREBP-2: nuclear import of a transcription factor. Science 2003; 302 (5650): 1571-1575
83 Shimomura I, Bashmakov Y, Ikemoto S, Horton JD, Brown MS, Goldstein JL. Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Natl Acad Sci U S A 1999; 96 (24) 13656-13661
84 Liu Y, Major AS, Zienkiewicz J. et al. Nuclear transport modulation reduces hypercholesterolemia, atherosclerosis, and fatty liver. J Am Heart Assoc 2013; 2 (02) e000093
85 Peterson TR, Sengupta SS, Harris TE. et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 2011; 146 (03) 408-420
86 Hirano Y, Yoshida M, Shimizu M, Sato R. Direct demonstration of rapid degradation of nuclear sterol regulatory element-binding proteins by the ubiquitin-proteasome pathway. J Biol Chem 2001; 276 (39) 36431-36437
87 Kuan YC, Hashidume T, Shibata T. et al. Heat shock protein 90 modulates lipid homeostasis by regulating the stability and function of sterol regulatory element-binding protein (SREBP) and SREBP cleavage-activating protein. J Biol Chem 2017; 292 (07) 3016-3028
88 Gong Y, Lee JN, Lee PC, Goldstein JL, Brown MS, Ye J. Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feedback control of cholesterol synthesis and uptake. Cell Metab 2006; 3 (01) 15-24
89 Asano L, Watanabe M, Ryoden Y. et al. Vitamin D metabolite, 25-hydroxyvitamin D, regulates lipid metabolism by inducing degradation of SREBP/SCAP. Cell Chem Biol 2017; 24 (02) 207-217
90 Goldstein JL, DeBose-Boyd RA, Brown MS. Protein sensors for membrane sterols. Cell 2006; 124 (01) 35-46
91 Yabe D, Brown MS, Goldstein JL. Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins. Proc Natl Acad Sci U S A 2002; 99 (20) 12753-12758
92 Yang T, Espenshade PJ, Wright ME. et al. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 2002; 110 (04) 489-500
93 Brown MS, Goldstein JL. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab 2008; 7 (02) 95-96
94 Kohjima M, Higuchi N, Kato M. et al. SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease. Int J Mol Med 2008; 21 (04) 507-511
95 Li S, Brown MS, Goldstein JL. Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc Natl Acad Sci U S A 2010; 107 (08) 3441-3446
96 Ai D, Baez JM, Jiang H. et al. Activation of ER stress and mTORC1 suppresses hepatic sortilin-1 levels in obese mice. J Clin Invest 2012; 122 (05) 1677-1687
97 Schadinger SE, Bucher NL, Schreiber BM, Farmer SR. PPARgamma2 regulates lipogenesis and lipid accumulation in steatotic hepatocytes. Am J Physiol Endocrinol Metab 2005; 288 (06) E1195-E1205
98 Repa JJ, Liang G, Ou J. et al. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev 2000; 14 (22) 2819-2830
99 Nguyen P, Leray V, Diez M. et al. Liver lipid metabolism. J Anim Physiol Anim Nutr (Berl) 2008; 92 (03) 272-283
100 Oliner JD, Andresen JM, Hansen SK, Zhou S, Tjian R. SREBP transcriptional activity is mediated through an interaction with the CREB-binding protein. Genes Dev 1996; 10 (22) 2903-2911
101 Yang F, Vought BW, Satterlee JS. et al. An ARC/mediator subunit required for SREBP control of cholesterol and lipid homeostasis. Nature 2006; 442 (7103): 700-704
102 Nakagawa H, Umemura A, Taniguchi K. et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell 2014; 26 (03) 331-343
103 Farrell GC, van Rooyen D, Gan L, Chitturi S. NASH is an inflammatory disorder: pathogenic, prognostic and therapeutic implications. Gut Liver 2012; 6 (02) 149-171
104 Marí M, Caballero F, Colell A. et al. Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metab 2006; 4 (03) 185-198
105 Bánhegyi G, Baumeister P, Benedetti A. et al. Endoplasmic reticulum stress. Ann N Y Acad Sci 2007; 1113: 58-71
106 Bobrovnikova-Marjon E, Hatzivassiliou G, Grigoriadou C. et al. PERK-dependent regulation of lipogenesis during mouse mammary gland development and adipocyte differentiation. Proc Natl Acad Sci U S A 2008; 105 (42) 16314-16319
107 Lee JN, Ye J. Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1. J Biol Chem 2004; 279 (43) 45257-45265
108 Colgan SM, Hashimi AA, Austin RC. Endoplasmic reticulum stress and lipid dysregulation. Expert Rev Mol Med 2011; 13: e4
109 Wang X, Zelenski NG, Yang J, Sakai J, Brown MS, Goldstein JL. Cleavage of sterol regulatory element binding proteins (SREBPs) by CPP32 during apoptosis. EMBO J 1996; 15 (05) 1012-1020
110 Pastorino JG, Shulga N. Tumor necrosis factor-alpha can provoke cleavage and activation of sterol regulatory element-binding protein in ethanol-exposed cells via a caspase-dependent pathway that is cholesterol insensitive. J Biol Chem 2008; 283 (37) 25638-25649
111 Schwarz DS, Blower MD. The endoplasmic reticulum: structure, function and response to cellular signaling. Cell Mol Life Sci 2016; 73 (01) 79-94
112 Liu X, Green RM. Endoplasmic reticulum stress and liver diseases. Liver Res 2019; 3 (01) 55-64
113 Boelens J, Lust S, Offner F, Bracke ME, Vanhoecke BW. Review. The endoplasmic reticulum: a target for new anticancer drugs. In Vivo 2007; 21 (02) 215-226
114 Gething MJ, Sambrook J. Protein folding in the cell. Nature 1992; 355 (6355): 33-45
115 Ruddon RW, Bedows E. Assisted protein folding. J Biol Chem 1997; 272 (06) 3125-3128
116 Hammond C, Braakman I, Helenius A. Role of N-linked oligosaccharide recognition, glucose trimming, and calnexin in glycoprotein folding and quality control. Proc Natl Acad Sci U S A 1994; 91 (03) 913-917
117 Knittler MR, Dirks S, Haas IG. Molecular chaperones involved in protein degradation in the endoplasmic reticulum: quantitative interaction of the heat shock cognate protein BiP with partially folded immunoglobulin light chains that are degraded in the endoplasmic reticulum. Proc Natl Acad Sci U S A 1995; 92 (05) 1764-1768
118 Blond-Elguindi S, Cwirla SE, Dower WJ. et al. Affinity panning of a library of peptides displayed on bacteriophages reveals the binding specificity of BiP. Cell 1993; 75 (04) 717-728
119 Brodsky JL, Werner ED, Dubas ME, Goeckeler JL, Kruse KB, McCracken AA. The requirement for molecular chaperones during endoplasmic reticulum-associated protein degradation demonstrates that protein export and import are mechanistically distinct. J Biol Chem 1999; 274 (06) 3453-3460
120 Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011; 334 (6059): 1081-1086
121 Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999; 397 (6716): 271-274
122 Hosoi T, Ozawa K. Endoplasmic reticulum stress in disease: mechanisms and therapeutic opportunities. Clin Sci (Lond) 2009; 118 (01) 19-29
123 Meusser B, Hirsch C, Jarosch E, Sommer T. ERAD: the long road to destruction. Nat Cell Biol 2005; 7 (08) 766-772
124 Kammoun HL, Chabanon H, Hainault I. et al. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J Clin Invest 2009; 119 (05) 1201-1215
125 Zhang K, Wang S, Malhotra J. et al. The unfolded protein response transducer IRE1α prevents ER stress-induced hepatic steatosis. EMBO J 2011; 30 (07) 1357-1375
126 Zhang K, Kaufman RJ. Signaling the unfolded protein response from the endoplasmic reticulum. J Biol Chem 2004; 279 (25) 25935-25938
127 Groenendyk J, Peng Z, Dudek E. et al. Interplay between the oxidoreductase PDIA6 and microRNA-322 controls the response to disrupted endoplasmic reticulum calcium homeostasis. Sci Signal 2014; 7 (329): ra54
128 Eletto D, Eletto D, Dersh D, Gidalevitz T, Argon Y. Protein disulfide isomerase A6 controls the decay of IRE1α signaling via disulfide-dependent association. Mol Cell 2014; 53 (04) 562-576
129 Hur KY, So JS, Ruda V. et al. IRE1α activation protects mice against acetaminophen-induced hepatotoxicity. J Exp Med 2012; 209 (02) 307-318
130 Higa A, Taouji S, Lhomond S. et al. Endoplasmic reticulum stress-activated transcription factor ATF6α requires the disulfide isomerase PDIA5 to modulate chemoresistance. Mol Cell Biol 2014; 34 (10) 1839-1849
131 Lake AD, Novak P, Hardwick RN. et al. The adaptive endoplasmic reticulum stress response to lipotoxicity in progressive human nonalcoholic fatty liver disease. Toxicol Sci 2014; 137 (01) 26-35
132 Lee S, Kim S, Hwang S, Cherrington NJ, Ryu DY. Dysregulated expression of proteins associated with ER stress, autophagy and apoptosis in tissues from nonalcoholic fatty liver disease. Oncotarget 2017; 8 (38) 63370-63381
133 Puri P, Mirshahi F, Cheung O. et al. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 2008; 134 (02) 568-576
134 Tirasophon W, Welihinda AA, Kaufman RJ. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (IRE1p) in mammalian cells. Genes Dev 1998; 12 (12) 1812-1824
135 Sepulveda D, Rojas-Rivera D, Rodríguez DA. et al. Interactome screening identifies the ER luminal chaperone Hsp47 as a regulator of the unfolded protein response transducer IRE1α. Mol Cell 2018; 69 (02) 238-252.e7
136 Karagöz GE, Acosta-Alvear D, Nguyen HT, Lee CP, Chu F, Walter P. An unfolded protein-induced conformational switch activates mammalian IRE1. eLife 2017; 6: e30700
137 Lee KP, Dey M, Neculai D, Cao C, Dever TE, Sicheri F. Structure of the dual enzyme IRE1 reveals the basis for catalysis and regulation in nonconventional RNA splicing. Cell 2008; 132 (01) 89-100
138 Hollien J, Lin JH, Li H, Stevens N, Walter P, Weissman JS. Regulated IRE1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol 2009; 186 (03) 323-331
139 Hollien J, Weissman JS. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 2006; 313 (5783): 104-107
140 Siwecka N, Rozpędek-Kamińska W, Wawrzynkiewicz A, Pytel D, Diehl JA, Majsterek I. The structure, activation and signaling of IRE1 and its role in determining cell fate. Biomedicines 2021; 9 (02) 156
141 Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 2003; 23 (21) 7448-7459
142 Jiang S, Yan C, Fang QC. et al. Fibroblast growth factor 21 is regulated by the IRE1α-XBP1 branch of the unfolded protein response and counteracts endoplasmic reticulum stress-induced hepatic steatosis. J Biol Chem 2014; 289 (43) 29751-29765
143 Reimold AM, Etkin A, Clauss I. et al. An essential role in liver development for transcription factor XBP-1. Genes Dev 2000; 14 (02) 152-157
144 Zhang K, Wong HN, Song B, Miller CN, Scheuner D, Kaufman RJ. The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis. J Clin Invest 2005; 115 (02) 268-281
145 Wang S, Chen Z, Lam V. et al. IRE1α-XBP1s induces PDI expression to increase MTP activity for hepatic VLDL assembly and lipid homeostasis. Cell Metab 2012; 16 (04) 473-486
146 Shi Y, Vattem KM, Sood R. et al. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol 1998; 18 (12) 7499-7509
147 Harding HP, Novoa I, Zhang Y. et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 2000; 6 (05) 1099-1108
148 Jiang HY, Wek SA, McGrath BC. et al. Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response. Mol Cell Biol 2004; 24 (03) 1365-1377
149 Novoa I, Zeng H, Harding HP, Ron D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol 2001; 153 (05) 1011-1022
150 Harding HP, Zhang Y, Scheuner D, Chen JJ, Kaufman RJ, Ron D. Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2alpha) dephosphorylation in mammalian development. Proc Natl Acad Sci U S A 2009; 106 (06) 1832-1837
151 Adachi Y, Yamamoto K, Okada T, Yoshida H, Harada A, Mori K. ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum. Cell Struct Funct 2008; 33 (01) 75-89
152 Wu J, Rutkowski DT, Dubois M. et al. ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell 2007; 13 (03) 351-364
153 Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 2001; 107 (07) 881-891
154 Yamamoto K, Sato T, Matsui T. et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. Dev Cell 2007; 13 (03) 365-376
155 Moncan M, Mnich K, Blomme A, Almanza A, Samali A, Gorman AM. Regulation of lipid metabolism by the unfolded protein response. J Cell Mol Med 2021; 25 (03) 1359-1370
156 Raychaudhuri S, Prinz WA. The diverse functions of oxysterol-binding proteins. Annu Rev Cell Dev Biol 2010; 26: 157-177
157 Das AK, Uhler MD, Hajra AK. Molecular cloning and expression of mammalian peroxisomal trans-2-enoyl-coenzyme A reductase cDNAs. J Biol Chem 2000; 275 (32) 24333-24340
158 Baker CH, Matsuda SP, Liu DR, Corey EJ. Molecular cloning of the human gene encoding lanosterol synthase from a liver cDNA library. Biochem Biophys Res Commun 1995; 213 (01) 154-160
159 Chen YQ, Kuo MS, Li S. et al. AGPAT6 is a novel microsomal glycerol-3-phosphate acyltransferase. J Biol Chem 2008; 283 (15) 10048-10057
160 So JS, Hur KY, Tarrio M. et al. Silencing of lipid metabolism genes through IRE1α-mediated mRNA decay lowers plasma lipids in mice. Cell Metab 2012; 16 (04) 487-499
161 Lee AH, Glimcher LH. Intersection of the unfolded protein response and hepatic lipid metabolism. Cell Mol Life Sci 2009; 66 (17) 2835-2850
162 Upton JP, Wang L, Han D. et al. IRE1α cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2. Science 2012; 338 (6108): 818-822
163 Moserova I, Truxova I, Garg AD. et al. Caspase-2 and oxidative stress underlie the immunogenic potential of high hydrostatic pressure-induced cancer cell death. OncoImmunology 2016; 6 (01) e1258505
164 Li H, Meng Q, Xiao F. et al. ATF4 deficiency protects mice from high-carbohydrate-diet-induced liver steatosis. Biochem J 2011; 438 (02) 283-289
165 Xiao G, Zhang T, Yu S. et al. ATF4 protein deficiency protects against high fructose-induced hypertriglyceridemia in mice. J Biol Chem 2013; 288 (35) 25350-25361
166 Bommiasamy H, Back SH, Fagone P. et al. ATF6alpha induces XBP1-independent expansion of the endoplasmic reticulum. J Cell Sci 2009; 122 (Pt 10): 1626-1636
167 Chen X, Zhang F, Gong Q. et al. Hepatic ATF6 increases fatty acid oxidation to attenuate hepatic steatosis in mice through peroxisome proliferator-activated receptor α. Diabetes 2016; 65 (07) 1904-1915
168 Zeng L, Lu M, Mori K. et al. ATF6 modulates SREBP2-mediated lipogenesis. EMBO J 2004; 23 (04) 950-958
169 Okada T, Yoshida H, Akazawa R, Negishi M, Mori K. Distinct roles of activating transcription factor 6 (ATF6) and double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) in transcription during the mammalian unfolded protein response. Biochem J 2002; 366 (Pt 2): 585-594
170 Shoulders MD, Ryno LM, Genereux JC. et al. Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell Rep 2013; 3 (04) 1279-1292
171 Glembotski CC, Rosarda JD, Wiseman RL. Proteostasis and beyond: ATF6 in ischemic disease. Trends Mol Med 2019; 25 (06) 538-550
172 Batista-Gonzalez A, Vidal R, Criollo A, Carreño LJ. New insights on the role of lipid metabolism in the metabolic reprogramming of macrophages. Front Immunol 2020; 10: 2993
173 Artyomov MN, Sergushichev A, Schilling JD. Integrating immunometabolism and macrophage diversity. Semin Immunol 2016; 28 (05) 417-424
174 Sukhorukov VN, Khotina VA, Chegodaev YS, Ivanova E, Sobenin IA, Orekhov AN. Lipid metabolism in macrophages: focus on atherosclerosis. Biomedicines 2020; 8 (08) 262
175 Rong S, Cortés VA, Rashid S. et al. Expression of SREBP-1c requires SREBP-2-mediated generation of a sterol ligand for LXR in livers of mice. eLife 2017; 6: e25015
176 Hazra S, Xiong S, Wang J. et al. Peroxisome proliferator-activated receptor gamma induces a phenotypic switch from activated to quiescent hepatic stellate cells. J Biol Chem 2004; 279 (12) 11392-11401
177 Mann J, Chu DC, Maxwell A. et al. MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology 2010; 138 (02) 705-714 , 714.e1–714.e4
178 Liu X, Xu J, Rosenthal S. et al. Identification of lineage-specific transcription factors that prevent activation of hepatic stellate cells and promote fibrosis resolution. Gastroenterology 2020; 158 (06) 1728-1744.e14
179 Tomita K, Teratani T, Suzuki T. et al. Free cholesterol accumulation in hepatic stellate cells: mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. Hepatology 2014; 59 (01) 154-169
180 Kang Q, Chen A. Curcumin suppresses expression of low-density lipoprotein (LDL) receptor, leading to the inhibition of LDL-induced activation of hepatic stellate cells. Br J Pharmacol 2009; 157 (08) 1354-1367
181 Kang Q, Chen A. Curcumin inhibits SREBP-2 expression in activated hepatic stellate cells in vitro by reducing the activity of specificity protein-1. Endocrinology 2009; 150 (12) 5384-5394
182 Bruschi FV, Claudel T, Tardelli M, Starlinger P, Marra F, Trauner M. PNPLA3 I148M variant impairs liver X receptor signaling and cholesterol homeostasis in human hepatic stellate cells. Hepatol Commun 2019; 3 (09) 1191-1204