The Unfolded Protein Response in Fatty Liver Disease

Anne Henkel; Richard M. Green

doi:10.1055/s-0033-1358522

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2013; 33(04): 321-329
DOI: 10.1055/s-0033-1358522

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Unfolded Protein Response in Fatty Liver Disease

Anne Henkel

¹Division of Gastroenterology and Hepatology, Section of Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois

,

Richard M. Green

²Division of Gastroenterology and Hepatology, Section of Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois

› Author Affiliations

Abstract

The unfolded protein response (UPR) is a protective cellular response activated under conditions of endoplasmic reticulum (ER) stress. The hepatic UPR is activated in several forms of liver disease including nonalcoholic fatty liver disease (NAFLD). Recent data defining the role of the UPR in hepatic lipid metabolism have identified molecular mechanisms that may underlie the association between UPR activation and NAFLD. It has become increasingly evident that the IRE1α/Xbp1 pathway of the UPR is critical for hepatic lipid homeostasis, and dysregulation of this evolutionarily conserved pathway is associated with human nonalcoholic steatohepatitis (NASH). Although increasing evidence has delineated the importance of UPR pathway signaling in fatty liver disorders, the regulation of the hepatic UPR in normal physiology and fatty liver disorders remains incompletely understood. Understanding the role of the UPR in hepatic lipid metabolism may lead to the identification of novel therapeutic targets for the treatment of NAFLD.

Keywords

unfolded protein response - hepatic lipid metabolism - fatty liver - endoplasmic reticulum stress

Full Text

References

References
1 Puri P, Mirshahi F, Cheung O , et al. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 2008; 134 (2) 568-576
2 Wang D, Wei Y, Pagliassotti MJ. Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 2006; 147 (2) 943-951
3 Henkel AS, Elias MS, Green RM. Homocysteine supplementation attenuates the unfolded protein response in a murine nutritional model of steatohepatitis. J Biol Chem 2009; 284 (46) 31807-31816
4 Rinella ME, Siddiqui MS, Gardikiotes K, Gottstein J, Elias M, Green RM. Dysregulation of the unfolded protein response in db/db mice with diet-induced steatohepatitis. Hepatology 2011; 54 (5) 1600-1609
5 Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 2005; 115 (10) 2656-2664
6 Zhang K, Kaufman RJ. Signaling the unfolded protein response from the endoplasmic reticulum. J Biol Chem 2004; 279 (25) 25935-25938
7 Wek RC, Cavener DR. Translational control and the unfolded protein response. Antioxid Redox Signal 2007; 9 (12) 2357-2371
8 Marciniak SJ, Ron D. Endoplasmic reticulum stress signaling in disease. Physiol Rev 2006; 86 (4) 1133-1149
9 Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011; 334 (6059) 1081-1086
10 Uemura A, Oku M, Mori K, Yoshida H. Unconventional splicing of XBP1 mRNA occurs in the cytoplasm during the mammalian unfolded protein response. J Cell Sci 2009; 122 (Pt 16) 2877-2886
11 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 (7) 881-891
12 Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999; 397 (6716) 271-274
13 Vattem KM, Wek RC. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc Natl Acad Sci U S A 2004; 101 (31) 11269-11274
14 Harding HP, Novoa I, Zhang Y , et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 2000; 6 (5) 1099-1108
15 Marciniak SJ, Yun CY, Oyadomari S , et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 2004; 18 (24) 3066-3077
16 Ma Y, Brewer JW, Diehl JA, Hendershot LM. Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol 2002; 318 (5) 1351-1365
17 Shen J, Chen X, Hendershot L, Prywes R. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell 2002; 3 (1) 99-111
18 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 (1) 75-89
19 Urano F, Wang X, Bertolotti A , et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 2000; 287 (5453) 664-666
20 Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH. Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol Cell Biol 2006; 26 (8) 3071-3084
21 Hetz C, Bernasconi P, Fisher J , et al. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science 2006; 312 (5773) 572-576
22 Nakagawa T, Zhu H, Morishima N , et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 2000; 403 (6765) 98-103
23 McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 2001; 21 (4) 1249-1259
24 Zinszner H, Kuroda M, Wang X , et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 1998; 12 (7) 982-995
25 Yamaguchi H, Wang HG. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem 2004; 279 (44) 45495-45502
26 Puthalakath H, O'Reilly LA, Gunn P , et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 2007; 129 (7) 1337-1349
27 Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H. TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J 2005; 24 (6) 1243-1255
28 Ji C. Mechanisms of alcohol-induced endoplasmic reticulum stress and organ injuries. Biochem Res Int 2012; 2012: 216450
29 Ji C, Mehrian-Shai R, Chan C, Hsu YH, Kaplowitz N. Role of CHOP in hepatic apoptosis in the murine model of intragastric ethanol feeding. Alcohol Clin Exp Res 2005; 29 (8) 1496-1503
30 Kaplowitz N, Ji C. Unfolding new mechanisms of alcoholic liver disease in the endoplasmic reticulum. J Gastroenterol Hepatol 2006; 21 (Suppl. 03) S7-S9
31 Ji C. Dissection of endoplasmic reticulum stress signaling in alcoholic and non-alcoholic liver injury. J Gastroenterol Hepatol 2008; 23 (Suppl. 01) S16-S24
32 Galligan JJ, Fritz KS, Tipney H , et al. Profiling impaired hepatic endoplasmic reticulum glycosylation as a consequence of ethanol ingestion. J Proteome Res 2011; 10 (4) 1837-1847
33 Galligan JJ, Smathers RL, Shearn CT , et al. Oxidative Stress and the ER Stress Response in a Murine Model for Early-Stage Alcoholic Liver Disease. J Toxicol 2012; 2012: 207594
34 Longato L, Ripp K, Setshedi M , et al. Insulin resistance, ceramide accumulation, and endoplasmic reticulum stress in human chronic alcohol-related liver disease. Oxid Med Cell Longev 2012; 2012: 479348
35 Tsuchiya M, Ji C, Kosyk O , et al. Interstrain differences in liver injury and one-carbon metabolism in alcohol-fed mice. Hepatology 2012; 56 (1) 130-139
36 Li B, Gao B, Ye L , et al. Hepatitis B virus X protein (HBx) activates ATF6 and IRE1-XBP1 pathways of unfolded protein response. Virus Res 2007; 124 (1-2) 44-49
37 Li J, Liu Y, Wang Z , et al. Subversion of cellular autophagy machinery by hepatitis B virus for viral envelopment. J Virol 2011; 85 (13) 6319-6333
38 Lazar C, Macovei A, Petrescu S, Branza-Nichita N. Activation of ERAD pathway by human hepatitis B virus modulates viral and subviral particle production. PLoS ONE 2012; 7 (3) e34169
39 Tardif KD, Mori K, Siddiqui A. Hepatitis C virus subgenomic replicons induce endoplasmic reticulum stress activating an intracellular signaling pathway. J Virol 2002; 76 (15) 7453-7459
40 Kukihara H, Moriishi K, Taguwa S , et al. Human VAP-C negatively regulates hepatitis C virus propagation. J Virol 2009; 83 (16) 7959-7969
41 Li S, Ye L, Yu X , et al. Hepatitis C virus NS4B induces unfolded protein response and endoplasmic reticulum overload response-dependent NF-kappaB activation. Virology 2009; 391 (2) 257-264
42 Asselah T, Bièche I, Mansouri A , et al. In vivo hepatic endoplasmic reticulum stress in patients with chronic hepatitis C. J Pathol 2010; 221 (3) 264-274
43 Ke PY, Chen SS. Activation of the unfolded protein response and autophagy after hepatitis C virus infection suppresses innate antiviral immunity in vitro. J Clin Invest 2011; 121 (1) 37-56
44 Merquiol E, Uzi D, Mueller T , et al. HCV causes chronic endoplasmic reticulum stress leading to adaptation and interference with the unfolded protein response. PLoS ONE 2011; 6 (9) e24660
45 Bochkis IM, Rubins NE, White P, Furth EE, Friedman JR, Kaestner KH. Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and results in endoplasmic reticulum stress. Nat Med 2008; 14 (8) 828-836
46 Ben Mosbah I, Alfany-Fernández I, Martel C , et al. Endoplasmic reticulum stress inhibition protects steatotic and non-steatotic livers in partial hepatectomy under ischemia-reperfusion. Cell Death Dis 2010; 1: e52
47 Malo A, Krüger B, Seyhun E , et al. Tauroursodeoxycholic acid reduces endoplasmic reticulum stress, trypsin activation, and acinar cell apoptosis while increasing secretion in rat pancreatic acini. Am J Physiol Gastrointest Liver Physiol 2010; 299 (4) G877-G886
48 Seyhun E, Malo A, Schäfer C , et al. Tauroursodeoxycholic acid reduces endoplasmic reticulum stress, acinar cell damage, and systemic inflammation in acute pancreatitis. Am J Physiol Gastrointest Liver Physiol 2011; 301 (5) G773-G782
49 Jiménez-Castro MB, Elias-Miro M, Mendes-Braz M , et al. Tauroursodeoxycholic acid affects PPARγ and TLR4 in Steatotic liver transplantation. Am J Transplant 2012; 12 (12) 3257-3271
50 Dai BH, Geng L, Wang Y , et al. microRNA-199a-5p protects hepatocytes from bile acid-induced sustained endoplasmic reticulum stress. Cell Death Dis 2013; 4: e604
51 Bernstein H, Payne CM, Bernstein C, Schneider J, Beard SE, Crowley CL. Activation of the promoters of genes associated with DNA damage, oxidative stress, ER stress and protein malfolding by the bile salt, deoxycholate. Toxicol Lett 1999; 108 (1) 37-46
52 Lawless MW, Greene CM, Mulgrew A, Taggart CC, O'Neill SJ, McElvaney NG. Activation of endoplasmic reticulum-specific stress responses associated with the conformational disease Z alpha 1-antitrypsin deficiency. J Immunol 2004; 172 (9) 5722-5726
53 Mencin A, Seki E, Osawa Y , et al. Alpha-1 antitrypsin Z protein (PiZ) increases hepatic fibrosis in a murine model of cholestasis. Hepatology 2007; 46 (5) 1443-1452
54 Scott CM, Kruse KB, Schmidt BZ, Perlmutter DH, McCracken AA, Brodsky JL. ADD66, a gene involved in the endoplasmic reticulum-associated degradation of alpha-1-antitrypsin-Z in yeast, facilitates proteasome activity and assembly. Mol Biol Cell 2007; 18 (10) 3776-3787
55 Lawless MW, Mankan AK, Gray SG, Norris S. Endoplasmic reticulum stress—a double edged sword for Z alpha-1 antitrypsin deficiency hepatoxicity. Int J Biochem Cell Biol 2008; 40 (8) 1403-1414
56 Carroll TP, Greene CM, O'Connor CA, Nolan AM, O'Neill SJ, McElvaney NG. Evidence for unfolded protein response activation in monocytes from individuals with alpha-1 antitrypsin deficiency. J Immunol 2010; 184 (8) 4538-4546
57 Greene CM, McElvaney NG. Z α-1 antitrypsin deficiency and the endoplasmic reticulum stress response. World J Gastrointest Pharmacol Ther 2010; 1 (5) 94-101
58 Smith SE, Granell S, Salcedo-Sicilia L , et al. Activating transcription factor 6 limits intracellular accumulation of mutant α(1)-antitrypsin Z and mitochondrial damage in hepatoma cells. J Biol Chem 2011; 286 (48) 41563-41577
59 Lawless MW, Mankan AK, White M, O'Dwyer MJ, Norris S. Expression of hereditary hemochromatosis C282Y HFE protein in HEK293 cells activates specific endoplasmic reticulum stress responses. BMC Cell Biol 2007; 8: 30
60 Pinto JP, Ramos P, de Almeida SF , et al. Protective role of calreticulin in HFE hemochromatosis. Free Radic Biol Med 2008; 44 (1) 99-108
61 Isom HC, McDevitt EI, Moon MS. Elevated hepatic iron: a confounding factor in chronic hepatitis C. Biochim Biophys Acta 2009; 1790 (7) 650-662
62 Lou LX, Geng B, Chen Y, Yu F, Zhao J, Tang CS. Endoplasmic reticulum stress involved in heart and liver injury in iron-loaded rats. Clin Exp Pharmacol Physiol 2009; 36 (7) 612-618
63 Oliveira SJ, Pinto JP, Picarote G , et al. ER stress-inducible factor CHOP affects the expression of hepcidin by modulating C/EBPalpha activity. PLoS ONE 2009; 4 (8) e6618
64 Vecchi C, Montosi G, Zhang K , et al. ER stress controls iron metabolism through induction of hepcidin. Science 2009; 325 (5942) 877-880
65 Emadali A, Nguyên DT, Rochon C, Tzimas GN, Metrakos PP, Chevet E. Distinct endoplasmic reticulum stress responses are triggered during human liver transplantation. J Pathol 2005; 207 (1) 111-118
66 Dara L, Ji C, Kaplowitz N. The contribution of endoplasmic reticulum stress to liver diseases. Hepatology 2011; 53 (5) 1752-1763
67 Dai R, Chen R, Li H. Cross-talk between PI3K/Akt and MEK/ERK pathways mediates endoplasmic reticulum stress-induced cell cycle progression and cell death in human hepatocellular carcinoma cells. Int J Oncol 2009; 34 (6) 1749-1757
68 Tang J, Guo YS, Zhang Y , et al. CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma. Cell Death Differ 2012; 19 (11) 1779-1790
69 Xu M, Lu N, Sun Z , et al. Activation of the unfolded protein response contributed to the selective cytotoxicity of oroxylin A in human hepatocellular carcinoma HepG2 cells. Toxicol Lett 2012; 212 (2) 113-125
70 Honma Y, Harada M. Sorafenib enhances proteasome inhibitor-mediated cytotoxicity via inhibition of unfolded protein response and keratin phosphorylation. Exp Cell Res 2013; 319 (14) 2166-2178
71 Yi P, Higa A, Taouji S , et al. Sorafenib-mediated targeting of the AAA⁺ ATPase p97/VCP leads to disruption of the secretory pathway, endoplasmic reticulum stress, and hepatocellular cancer cell death. Mol Cancer Ther 2012; 11 (12) 2610-2620
72 Xu M, Lu N, Zhang H , et al. Wogonin induced cytotoxicity in human hepatocellular carcinoma cells by activation of unfolded protein response and inactivation of AKT. Hepatol Res 2013; 43 (8) 890-905
73 Duan Q, Wang X, Gong W , et al. ER stress negatively modulates the expression of the miR-199a/214 cluster to regulates tumor survival and progression in human hepatocellular cancer. PLoS ONE 2012; 7 (2) e31518
74 Yang F, Zhang L, Wang F , et al. Modulation of the unfolded protein response is the core of microRNA-122-involved sensitivity to chemotherapy in hepatocellular carcinoma. Neoplasia 2011; 13 (7) 590-600
75 Chen R, Dai RY, Duan CY , et al. Unfolded protein response suppresses cisplatin-induced apoptosis via autophagy regulation in human hepatocellular carcinoma cells. Folia Biol (Praha) 2011; 57 (3) 87-95
76 Fu S, Yang L, Li P , et al. Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 2011; 473 (7348) 528-531
77 Lee AH, Scapa EF, Cohen DE, Glimcher LH. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 2008; 320 (5882) 1492-1496
78 Ota T, Gayet C, Ginsberg HN. Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodents. J Clin Invest 2008; 118 (1) 316-332
79 Rutkowski DT, Wu J, Back SH , et al. UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. Dev Cell 2008; 15 (6) 829-840
80 Lee JS, Mendez R, Heng HH, Yang ZQ, Zhang K. Pharmacological ER stress promotes hepatic lipogenesis and lipid droplet formation. Am J Transl Res 2012; 4 (1) 102-113
81 Liao W, Chan L. Tunicamycin induces ubiquitination and degradation of apolipoprotein B in HepG2 cells. Biochem J 2001; 353 (Pt 3) 493-501
82 Jo H, Choe SS, Shin KC , et al. Endoplasmic reticulum stress induces hepatic steatosis via increased expression of the hepatic very low-density lipoprotein receptor. Hepatology 2013; 57 (4) 1366-1377
83 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
84 Ozcan U, Yilmaz E, Ozcan L , et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 2006; 313 (5790) 1137-1140
85 Xie Q, Khaoustov VI, Chung CC , et al. Effect of tauroursodeoxycholic acid on endoplasmic reticulum stress-induced caspase-12 activation. Hepatology 2002; 36 (3) 592-601
86 Vilatoba M, Eckstein C, Bilbao G , et al. Sodium 4-phenylbutyrate protects against liver ischemia reperfusion injury by inhibition of endoplasmic reticulum-stress mediated apoptosis. Surgery 2005; 138 (2) 342-351
87 Ozcan U, Cao Q, Yilmaz E , et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004; 306 (5695) 457-461
88 Nakatani Y, Kaneto H, Kawamori D , et al. Involvement of endoplasmic reticulum stress in insulin resistance and diabetes. J Biol Chem 2005; 280 (1) 847-851
89 Boden G, Duan X, Homko C , et al. Increase in endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant individuals. Diabetes 2008; 57 (9) 2438-2444
90 Sharma NK, Das SK, Mondal AK , et al. Endoplasmic reticulum stress markers are associated with obesity in nondiabetic subjects. J Clin Endocrinol Metab 2008; 93 (11) 4532-4541
91 Feng B, Yao PM, Li Y , et al. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol 2003; 5 (9) 781-792
92 Boden G, Song W, Duan X , et al. Infusion of glucose and lipids at physiological rates causes acute endoplasmic reticulum stress in rat liver. Obesity (Silver Spring) 2011; 19 (7) 1366-1373
93 Wei Y, Wang D, Topczewski F, Pagliassotti MJ. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am J Physiol Endocrinol Metab 2006; 291 (2) E275-E281
94 Cao J, Dai DL, Yao L , et al. Saturated fatty acid induction of endoplasmic reticulum stress and apoptosis in human liver cells via the PERK/ATF4/CHOP signaling pathway. Mol Cell Biochem 2012; 364 (1-2) 115-129
95 Pineau L, Colas J, Dupont S , et al. Lipid-induced ER stress: synergistic effects of sterols and saturated fatty acids. Traffic 2009; 10 (6) 673-690
96 Listenberger LL, Han X, Lewis SE , et al. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci U S A 2003; 100 (6) 3077-3082
97 Peng G, Li L, Liu Y , et al. Oleate blocks palmitate-induced abnormal lipid distribution, endoplasmic reticulum expansion and stress, and insulin resistance in skeletal muscle. Endocrinology 2011; 152 (6) 2206-2218
98 Fu S, Watkins SM, Hotamisligil GS. The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab 2012; 15 (5) 623-634
99 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 (5) 1201-1215
100 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 (4) 487-499
101 Zhang K, Wang S, Malhotra J , et al. The unfolded protein response transducer IRE1α prevents ER stress-induced hepatic steatosis. EMBO J 2011; 30 (7) 1357-1375
102 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 (4) 473-486
103 Deng Y, Wang ZV, Tao C , et al. The Xbp1s/GalE axis links ER stress to postprandial hepatic metabolism. J Clin Invest 2013; 123 (1) 455-468
104 Oyadomari S, Harding HP, Zhang Y, Oyadomari M, Ron D. Dephosphorylation of translation initiation factor 2alpha enhances glucose tolerance and attenuates hepatosteatosis in mice. Cell Metab 2008; 7 (6) 520-532
105 Schroeder-Gloeckler JM, Rahman SM, Janssen RC , et al. CCAAT/enhancer-binding protein beta deletion reduces adiposity, hepatic steatosis, and diabetes in Lepr(db/db) mice. J Biol Chem 2007; 282 (21) 15717-15729
106 Millward CA, Heaney JD, Sinasac DS , et al. Mice with a deletion in the gene for CCAAT/enhancer-binding protein beta are protected against diet-induced obesity. Diabetes 2007; 56 (1) 161-167
107 Seo J, Fortuno III ES, Suh JM , et al. Atf4 regulates obesity, glucose homeostasis, and energy expenditure. Diabetes 2009; 58 (11) 2565-2573
108 Chikka MR, McCabe DD, Tyra HM, Rutkowski DT. C/EBP homologous protein (CHOP) contributes to suppression of metabolic genes during endoplasmic reticulum stress in the liver. J Biol Chem 2013; 288 (6) 4405-4415
109 Yamamoto K, Takahara K, Oyadomari S , et al. Induction of liver steatosis and lipid droplet formation in ATF6alpha-knockout mice burdened with pharmacological endoplasmic reticulum stress. Mol Biol Cell 2010; 21 (17) 2975-2986
110 Zeng L, Lu M, Mori K , et al. ATF6 modulates SREBP2-mediated lipogenesis. EMBO J 2004; 23 (4) 950-958
111 Lindor KD, Kowdley KV, Heathcote EJ , et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 2004; 39 (3) 770-778
112 Wu SD, Li L, Wang JY. Ursodeoxycholic acid for nonalcoholic steatohepatitis. Eur J Gastroenterol Hepatol 2012; 24 (11) 1247-1253
113 Chalasani N, Younossi Z, Lavine JE , et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012; 55 (6) 2005-2023
114 Werstuck GH, Lentz SR, Dayal S , et al. Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest 2001; 107 (10) 1263-1273
115 Chen X, Sebastian BM, Tang H , et al. Taurine supplementation prevents ethanol-induced decrease in serum adiponectin and reduces hepatic steatosis in rats. Hepatology 2009; 49 (5) 1554-1562
116 Gentile CL, Nivala AM, Gonzales JC , et al. Experimental evidence for therapeutic potential of taurine in the treatment of nonalcoholic fatty liver disease. Am J Physiol Regul Integr Comp Physiol 2011; 301 (6) R1710-R1722
117 Ji C, Kaplowitz N. Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury. World J Gastroenterol 2004; 10 (12) 1699-1708
118 Kaplowitz N, Than TA, Shinohara M, Ji C. Endoplasmic reticulum stress and liver injury. Semin Liver Dis 2007; 27 (4) 367-377
119 Zhang XM, Wang XT, Cai H, Leung SW, Guggino SE. Characterization of endogenous betaine gamma-amino-n-butyric acid cotransporter glycoform and its hyperosmotic regulation in MDCK cells. Pflugers Arch 2007; 454 (1) 143-153
120 Esfandiari F, You M, Villanueva JA, Wong DH, French SW, Halsted CH. S-adenosylmethionine attenuates hepatic lipid synthesis in micropigs fed ethanol with a folate-deficient diet. Alcohol Clin Exp Res 2007; 31 (7) 1231-1239
121 Ou X, Yang H, Ramani K , et al. Inhibition of human betaine-homocysteine methyltransferase expression by S-adenosylmethionine and methylthioadenosine. Biochem J 2007; 401 (1) 87-96
122 Akoglu B, Schrott M, Bolouri H , et al. The folic acid metabolite L-5-methyltetrahydrofolate effectively reduces total serum homocysteine level in orthotopic liver transplant recipients: a double-blind placebo-controlled study. Eur J Clin Nutr 2008; 62 (6) 796-801
123 Hirsch S, Poniachick J, Avendaño M , et al. Serum folate and homocysteine levels in obese females with non-alcoholic fatty liver. Nutrition 2005; 21 (2) 137-141
124 Papandreou D, Rousso I, Malindretos P, Makedou A, Arvanitidou M. Effects of oral folate supplementation on serum total homocysteine and cholesterol levels in hyperhomocysteinemic children. Nutr Clin Pract 2010; 25 (4) 390-393
125 Symons JD, Zaid UB, Athanassious CN, Mullick AE, Lentz SR, Rutledge JC. Influence of folate on arterial permeability and stiffness in the absence or presence of hyperhomocysteinemia. Arterioscler Thromb Vasc Biol 2006; 26 (4) 814-818
126 Woo CW, Prathapasinghe GA, Siow YL , O K. Hyperhomocysteinemia induces liver injury in rat: protective effect of folic acid supplementation. Biochim Biophys Acta 2006; 1762 (7) 656-665
127 Sharma S, Mells JE, Fu PP, Saxena NK, Anania FA. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS ONE 2011; 6 (9) e25269
128 Kudo T. [Therapeutic strategies for Alzheimer disease based on endoplasmic reticulum stress]. Nihon Shinkei Seishin Yakurigaku Zasshi 2010; 30 (4) 163-168
129 Inokuchi Y, Nakajima Y, Shimazawa M , et al. Effect of an inducer of BiP, a molecular chaperone, on endoplasmic reticulum (ER) stress-induced retinal cell death. Invest Ophthalmol Vis Sci 2009; 50 (1) 334-344
130 Takano K, Tabata Y, Kitao Y , et al. Methoxyflavones protect cells against endoplasmic reticulum stress and neurotoxin. Am J Physiol Cell Physiol 2007; 292 (1) C353-C361
131 Gorbatyuk MS, Gorbatyuk OS. The molecular chaperone GRP78/BiP as a therapeutic target for neurodegenerative disorders: a mini review. J Genet Syndr Gene Ther 2013; 4 (2) 128