Semin Liver Dis 2020; 40(04): 346-357
DOI: 10.1055/s-0040-1713115
Review Article

Nonalcoholic Steatohepatitis Promoting Kinases

Samar H. Ibrahim
1   Division of Gastroenterology & Hepatology in the Department of Pediatrics, Medicine Mayo Clinic, Rochester, Minnesota
2   Division of Gastroenterology & Hepatology in the Department of Medicine Mayo Clinic, Rochester, Minnesota
,
Petra Hirsova
2   Division of Gastroenterology & Hepatology in the Department of Medicine Mayo Clinic, Rochester, Minnesota
,
Harmeet Malhi
2   Division of Gastroenterology & Hepatology in the Department of Medicine Mayo Clinic, Rochester, Minnesota
,
Gregory J. Gores
2   Division of Gastroenterology & Hepatology in the Department of Medicine Mayo Clinic, Rochester, Minnesota
› Author Affiliations
Funding Funding support from the AASLD Foundation Bridge Award (to SHI), the NIH grant DK111397 (to SHI), Gilead Science career development award (to SHI), and the Mayo Clinic K2R pipeline (to SHI); NIH grant DK41876 (to GJG); Mayo Clinic Center for Cell Signaling in Gastroenterology (NIDDK P30DK084567) Pilot and Feasibility Award (to PH); NIH grant DK11378 (to HM); and the Mayo Foundation.

Abstract

Nonalcoholic hepatitis (NASH) is the progressive inflammatory form of nonalcoholic fatty liver disease. Although the mechanisms of hepatic inflammation in NASH remain incompletely understood, emerging literature implicates the proinflammatory environment created by toxic lipid-induced hepatocyte injury, termed lipotoxicity. Interestingly, numerous NASH-promoting kinases in hepatocytes, immune cells, and adipocytes are activated by the lipotoxic insult associated with obesity. In the current review, we discuss recent advances in NASH-promoting kinases as disease mediators and therapeutic targets. The focus of the review is mainly on the mitogen-activated protein kinases including mixed lineage kinase 3, apoptosis signal-regulating kinase 1, c-Jun N-terminal kinase, and p38 MAPK; the endoplasmic reticulum (ER) stress kinases protein kinase RNA-like ER kinase and inositol-requiring protein-1α; as well as the Rho-associated protein kinase 1. We also discuss various pharmacological agents targeting these stress kinases in NASH that are under different phases of development.



Publication History

Article published online:
11 June 2020

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 
  • References

  • 1 Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64 (01) 73-84
  • 2 Machado MV, Diehl AM. Pathogenesis of nonalcoholic steatohepatitis. Gastroenterology 2016; 150 (08) 1769-1777
  • 3 Hirsova P, Ibrahim SH, Gores GJ, Malhi H. Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis. J Lipid Res 2016; 57 (10) 1758-1770
  • 4 Jaeschke A, Davis RJ. Metabolic stress signaling mediated by mixed-lineage kinases. Mol Cell 2007; 27 (03) 498-508
  • 5 Hirsova P, Gores GJ. Death receptor-mediated cell death and proinflammatory signaling in nonalcoholic steatohepatitis. Cell Mol Gastroenterol Hepatol 2015; 1 (01) 17-27
  • 6 Ibrahim SH, Hirsova P, Gores GJ. Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation. Gut 2018; 67 (05) 963-972
  • 7 Win S, Than TA, Zhang J, Oo C, Min RWM, Kaplowitz N. New insights into the role and mechanism of c-Jun-N-terminal kinase signaling in the pathobiology of liver diseases. Hepatology 2018; 67 (05) 2013-2024
  • 8 Lawan A, Bennett AM. Mitogen-activated protein kinase regulation in hepatic metabolism. Trends Endocrinol Metab 2017; 28 (12) 868-878
  • 9 Ibrahim SH, Gores GJ, Hirsova P. et al. Mixed lineage kinase 3 deficient mice are protected against the high fat high carbohydrate diet-induced steatohepatitis. Liver Int 2014; 34 (03) 427-437
  • 10 Tomita K, Kabashima A, Freeman BL, Bronk SF, Hirsova P, Ibrahim SH. Mixed lineage kinase 3 mediates the induction of CXCL10 by a STAT1-dependent mechanism during hepatocyte lipotoxicity. J Cell Biochem 2017; 118 (10) 3249-3259
  • 11 Tomita K, Kohli R, MacLaurin BL. et al. Mixed-lineage kinase 3 pharmacological inhibition attenuates murine nonalcoholic steatohepatitis. JCI Insight 2017; 2 (15) 94488
  • 12 Caunt CJ, Keyse SM. Dual-specificity MAP kinase phosphatases (MKPs): shaping the outcome of MAP kinase signalling. FEBS J 2013; 280 (02) 489-504
  • 13 Schuster S, Feldstein AE. NASH: Novel therapeutic strategies targeting ASK1 in NASH. Nat Rev Gastroenterol Hepatol 2017; 14 (06) 329-330
  • 14 Wang PX, Ji YX, Zhang XJ. et al. Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates. Nat Med 2017; 23 (04) 439-449
  • 15 Xiang M, Wang PX, Wang AB. et al. Targeting hepatic TRAF1-ASK1 signaling to improve inflammation, insulin resistance, and hepatic steatosis. J Hepatol 2016; 64 (06) 1365-1377
  • 16 Nishitoh H, Saitoh M, Mochida Y. et al. ASK1 is essential for JNK/SAPK activation by TRAF2. Mol Cell 1998; 2 (03) 389-395
  • 17 Wang Y, Wen H, Fu J. et al. Hepatocyte TNF receptor-associated factor 6 aggravates hepatic inflammation and fibrosis by promoting lysine 6-linked polyubiquitination of apoptosis signal-regulating kinase 1. Hepatology 2020; 71 (01) 93-111
  • 18 Harrison SA, Wong VWS, Okanoue T. et al. Safety and efficacy of selonsertib for the treatment of bridging fibrosis or compensated cirrhosis due to nonalcoholic steatohepatitis (NASH): results of the phase 3 stellar studies. Hepatology 2019; 70: 45a-46a
  • 19 Loomba R, Lawitz E, Mantry PS. et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology 2017
  • 20 Huang Z, Wu LM, Zhang JL. et al. Dual specificity phosphatase 12 regulates hepatic lipid metabolism through inhibition of the lipogenesis and apoptosis signal-regulating kinase 1 pathways. Hepatology 2019; 70 (04) 1099-1118
  • 21 Zhang QY, Zhao LP, Tian XX. et al. The novel intracellular protein CREG inhibits hepatic steatosis, obesity, and insulin resistance. Hepatology 2017; 66 (03) 834-854
  • 22 Zhang P, Wang PX, Zhao LP. et al. The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis. Nat Med 2018; 24 (01) 84-94
  • 23 Challa TD, Wueest S, Lucchini FC. et al. Liver ASK1 protects from non-alcoholic fatty liver disease and fibrosis. EMBO Mol Med 2019; 11 (10) e10124
  • 24 Brancho D, Ventura JJ, Jaeschke A, Doran B, Flavell RA, Davis RJ. Role of MLK3 in the regulation of mitogen-activated protein kinase signaling cascades. Mol Cell Biol 2005; 25 (09) 3670-3681
  • 25 Sharma M, Urano F, Jaeschke A. Cdc42 and Rac1 are major contributors to the saturated fatty acid-stimulated JNK pathway in hepatocytes. J Hepatol 2012; 56 (01) 192-198
  • 26 Kant S, Barrett T, Vertii A. et al. Role of the mixed-lineage protein kinase pathway in the metabolic stress response to obesity. Cell Rep 2013; 4 (04) 681-688
  • 27 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
  • 28 Tomita K, Freeman BL, Bronk SF. et al. CXCL10-mediates macrophage, but not other innate immune cells-associated inflammation in murine nonalcoholic steatohepatitis. Sci Rep 2016; 6: 28786
  • 29 Zhang X, Shen J, Man K. et al. CXCL10 plays a key role as an inflammatory mediator and a non-invasive biomarker of non-alcoholic steatohepatitis. J Hepatol 2014; 61 (06) 1365-1375
  • 30 Finch A, Davis W, Carter WG, Saklatvala J. Analysis of mitogen-activated protein kinase pathways used by interleukin 1 in tissues in vivo: activation of hepatic c-Jun N-terminal kinases 1 and 2, and mitogen-activated protein kinase kinases 4 and 7. Biochem J 2001; 353 (Pt 2): 275-281
  • 31 Hirosumi J, Tuncman G, Chang L. et al. A central role for JNK in obesity and insulin resistance. Nature 2002; 420 (6913): 333-336
  • 32 Schattenberg JM, Singh R, Wang Y. et al. JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology 2006; 43 (01) 163-172
  • 33 Singh R, Wang Y, Xiang Y, Tanaka KE, Gaarde WA, Czaja MJ. Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance. Hepatology 2009; 49 (01) 87-96
  • 34 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
  • 35 Cazanave SC, Mott JL, Elmi NA. et al. JNK1-dependent PUMA expression contributes to hepatocyte lipoapoptosis. J Biol Chem 2009; 284 (39) 26591-26602
  • 36 Kodama Y, Kisseleva T, Iwaisako K. et al. c-Jun N-terminal kinase-1 from hematopoietic cells mediates progression from hepatic steatosis to steatohepatitis and fibrosis in mice. Gastroenterology 2009; 137 (04) 1467-1477.e5
  • 37 Malhi H, Bronk SF, Werneburg NW, Gores GJ. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem 2006; 281 (17) 12093-12101
  • 38 Han MS, Jung DY, Morel C. et al. JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science 2013; 339 (6116): 218-222
  • 39 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
  • 40 Sabio G, Das M, Mora A. et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 2008; 322 (5907): 1539-1543
  • 41 Sabio G, Cavanagh-Kyros J, Ko HJ. et al. Prevention of steatosis by hepatic JNK1. Cell Metab 2009; 10 (06) 491-498
  • 42 Vernia S, Cavanagh-Kyros J, Garcia-Haro L. et al. The PPARα-FGF21 hormone axis contributes to metabolic regulation by the hepatic JNK signaling pathway. Cell Metab 2014; 20 (03) 512-525
  • 43 Win S, Than TA, Le BH, García-Ruiz C, Fernandez-Checa JC, Kaplowitz N. Sab (Sh3bp5) dependence of JNK mediated inhibition of mitochondrial respiration in palmitic acid induced hepatocyte lipotoxicity. J Hepatol 2015; 62 (06) 1367-1374
  • 44 BonDurant LD, Ameka M, Naber MC. et al. FGF21 regulates metabolism through adipose-dependent and -independent mechanisms. Cell Metab 2017; 25 (04) 935-944.e4
  • 45 Vernia S, Cavanagh-Kyros J, Barrett T, Tournier C, Davis RJ. Fibroblast growth factor 21 mediates glycemic regulation by hepatic JNK. Cell Rep 2016; 14 (10) 2273-2280
  • 46 Sanyal A, Charles ED, Neuschwander-Tetri BA. et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet 2019; 392 (10165): 2705-2717
  • 47 Win S, Than TA, Min RWM, Aghajan M, Kaplowitz N. c-Jun N-terminal kinase mediates mouse liver injury through a novel Sab (SH3BP5)-dependent pathway leading to inactivation of intramitochondrial Src. Hepatology 2016; 63 (06) 1987-2003
  • 48 Jing Y, Liu W, Cao H. et al. Hepatic p38α regulates gluconeogenesis by suppressing AMPK. J Hepatol 2015; 62 (06) 1319-1327
  • 49 Lawan A, Zhang L, Gatzke F. et al. Hepatic mitogen-activated protein kinase phosphatase 1 selectively regulates glucose metabolism and energy homeostasis. Mol Cell Biol 2015; 35 (01) 26-40
  • 50 González-Terán B, Matesanz N, Nikolic I. et al. p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration. EMBO J 2016; 35 (05) 536-552
  • 51 Zhang X, Fan L, Wu J. et al. Macrophage p38α promotes nutritional steatohepatitis through M1 polarization. J Hepatol 2019; 71 (01) 163-174
  • 52 Min L, He B, Hui L. Mitogen-activated protein kinases in hepatocellular carcinoma development. Semin Cancer Biol 2011; 21 (01) 10-20
  • 53 Sakurai T, Kudo M, Umemura A. et al. p38α inhibits liver fibrogenesis and consequent hepatocarcinogenesis by curtailing accumulation of reactive oxygen species. Cancer Res 2013; 73 (01) 215-224
  • 54 Hui L, Bakiri L, Mairhorfer A. et al. p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway. Nat Genet 2007; 39 (06) 741-749
  • 55 Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007; 8 (07) 519-529
  • 56 Maiers JL, Malhi H. Endoplasmic reticulum stress in metabolic liver diseases and hepatic fibrosis. Semin Liver Dis 2019; 39 (02) 235-248
  • 57 Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2000; 2 (06) 326-332
  • 58 Han J, Kaufman RJ. The role of ER stress in lipid metabolism and lipotoxicity. J Lipid Res 2016; 57 (08) 1329-1338
  • 59 Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 2000; 5 (05) 897-904
  • 60 Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 2003; 23 (20) 7198-7209
  • 61 Fusakio ME, Willy JA, Wang Y. et al. Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver. Mol Biol Cell 2016; 27 (09) 1536-1551
  • 62 Lu M, Lawrence DA, Marsters S. et al. Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis. Science 2014; 345 (6192): 98-101
  • 63 Wali JA, Rondas D, McKenzie MD. et al. The proapoptotic BH3-only proteins Bim and Puma are downstream of endoplasmic reticulum and mitochondrial oxidative stress in pancreatic islets in response to glucotoxicity. Cell Death Dis 2014; 5: e1124
  • 64 Glab JA, Doerflinger M, Nedeva C. et al. DR5 and caspase-8 are dispensable in ER stress-induced apoptosis. Cell Death Differ 2017; 24 (05) 944-950
  • 65 Han D, Lerner AG, Vande Walle L. et al. IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 2009; 138 (03) 562-575
  • 66 Tirasophon W, Lee K, Callaghan B, Welihinda A, Kaufman RJ. The endoribonuclease activity of mammalian IRE1 autoregulates its mRNA and is required for the unfolded protein response. Genes Dev 2000; 14 (21) 2725-2736
  • 67 Hollien J, Weissman JS. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 2006; 313 (5783): 104-107
  • 68 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
  • 69 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 (06) 520-532
  • 70 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
  • 71 Yang L, Calay ES, Fan J. et al. METABOLISM. S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction. Science 2015; 349 (6247): 500-506
  • 72 Wang JM, Qiu Y, Yang Z. et al. IRE1α prevents hepatic steatosis by processing and promoting the degradation of select microRNAs. Sci Signal 2018; 11 (530) eaao4617
  • 73 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
  • 74 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
  • 75 Harnoss JM, Le Thomas A, Shemorry A. et al. Disruption of IRE1α through its kinase domain attenuates multiple myeloma. Proc Natl Acad Sci U S A 2019; 116 (33) 16420-16429
  • 76 Liu X, Henkel AS, LeCuyer BE, Schipma MJ, Anderson KA, Green RM. Hepatocyte X-box binding protein 1 deficiency increases liver injury in mice fed a high-fat/sugar diet. Am J Physiol Gastrointest Liver Physiol 2015; 309 (12) G965-G974
  • 77 Bailly-Maitre B, Belgardt BF, Jordan SD. et al. Hepatic Bax inhibitor-1 inhibits IRE1alpha and protects from obesity-associated insulin resistance and glucose intolerance. J Biol Chem 2010; 285 (09) 6198-6207
  • 78 Lebeaupin C, Proics E, de Bieville CH. et al. ER stress induces NLRP3 inflammasome activation and hepatocyte death. Cell Death Dis 2015; 6: e1879
  • 79 Kakazu E, Mauer AS, Yin M, Malhi H. Hepatocytes release ceramide-enriched pro-inflammatory extracellular vesicles in an IRE1α-dependent manner. J Lipid Res 2016; 57 (02) 233-245
  • 80 Toriguchi K, Hatano E, Tanabe K. et al. Attenuation of steatohepatitis, fibrosis, and carcinogenesis in mice fed a methionine-choline deficient diet by CCAAT/enhancer-binding protein homologous protein deficiency. J Gastroenterol Hepatol 2014; 29 (05) 1109-1118
  • 81 Lam M, Marsters SA, Ashkenazi A, Walter P. Misfolded proteins bind and activate death receptor 5 to trigger apoptosis during unresolved endoplasmic reticulum stress. eLife 2020; 9: 9
  • 82 Idrissova L, Malhi H, Werneburg NW. et al. TRAIL receptor deletion in mice suppresses the inflammation of nutrient excess. J Hepatol 2015; 62 (05) 1156-1163
  • 83 Pearce LR, Komander D, Alessi DR. The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol 2010; 11 (01) 9-22
  • 84 Julian L, Olson MF. Rho-associated coiled-coil containing kinases (ROCK): structure, regulation, and functions. Small GTPases 2014; 5: e29846
  • 85 Lee DH, Shi J, Jeoung NH. et al. Targeted disruption of ROCK1 causes insulin resistance in vivo. J Biol Chem 2009; 284 (18) 11776-11780
  • 86 Lee SH, Huang H, Choi K. et al. ROCK1 isoform-specific deletion reveals a role for diet-induced insulin resistance. Am J Physiol Endocrinol Metab 2014; 306 (03) E332-E343
  • 87 Huang H, Lee SH, Sousa-Lima I. et al. Rho-kinase/AMPK axis regulates hepatic lipogenesis during overnutrition. J Clin Invest 2018; 128 (12) 5335-5350
  • 88 Hirsova P, Ibrahim SH, Krishnan A. et al. Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes. Gastroenterology 2016; 150 (04) 956-967
  • 89 Hirsova P, Ibrahim SH, Verma VK. et al. Extracellular vesicles in liver pathobiology: small particles with big impact. Hepatology 2016; 64 (06) 2219-2233
  • 90 Guo Q, Furuta K, Lucien F. et al. Integrin β1-enriched extracellular vesicles mediate monocyte adhesion and promote liver inflammation in murine NASH. J Hepatol 2019; 71 (06) 1193-1205
  • 91 Olson MF. Applications for ROCK kinase inhibition. Curr Opin Cell Biol 2008; 20 (02) 242-248
  • 92 Jahani V, Kavousi A, Mehri S, Karimi G. Rho kinase, a potential target in the treatment of metabolic syndrome. Biomed Pharmacother 2018; 106: 1024-1030
  • 93 Musso G, De Michieli F, Bongiovanni D. et al. New pharmacologic agents that target inflammation and fibrosis in nonalcoholic steatohepatitis-related kidney disease. Clin Gastroenterol Hepatol 2017; 15 (07) 972-985
  • 94 Kitamura K, Tada S, Nakamoto N. et al. Rho/Rho kinase is a key enzyme system involved in the angiotensin II signaling pathway of liver fibrosis and steatosis. J Gastroenterol Hepatol 2007; 22 (11) 2022-2033
  • 95 Zhou H, Fang C, Zhang L, Deng Y, Wang M, Meng F. Fasudil hydrochloride hydrate, a Rho-kinase inhibitor, ameliorates hepatic fibrosis in rats with type 2 diabetes. Chin Med J (Engl) 2014; 127 (02) 225-231
  • 96 Wang HW, Liu PY, Oyama N. et al. Deficiency of ROCK1 in bone marrow-derived cells protects against atherosclerosis in LDLR-/- mice. FASEB J 2008; 22 (10) 3561-3570
  • 97 Thorlacius K, Slotta JE, Laschke MW. et al. Protective effect of fasudil, a Rho-kinase inhibitor, on chemokine expression, leukocyte recruitment, and hepatocellular apoptosis in septic liver injury. J Leukoc Biol 2006; 79 (05) 923-931
  • 98 Shimada H, Rajagopalan LE. Rho-kinase mediates lysophosphatidic acid-induced IL-8 and MCP-1 production via p38 and JNK pathways in human endothelial cells. FEBS Lett 2010; 584 (13) 2827-2832
  • 99 Rao J, Ye Z, Tang H. et al. The RhoA/ROCK pathway ameliorates adhesion and inflammatory infiltration induced by AGEs in glomerular endothelial cells. Sci Rep 2017; 7: 39727
  • 100 Kuroda S, Tashiro H, Igarashi Y. et al. Rho inhibitor prevents ischemia-reperfusion injury in rat steatotic liver. J Hepatol 2012; 56 (01) 146-152
  • 101 Kawada N, Seki S, Kuroki T, Kaneda K. ROCK inhibitor Y-27632 attenuates stellate cell contraction and portal pressure increase induced by endothelin-1. Biochem Biophys Res Commun 1999; 266 (02) 296-300
  • 102 Tangkijvanich P, Tam SP, Yee Jr HF. Wound-induced migration of rat hepatic stellate cells is modulated by endothelin-1 through rho-kinase-mediated alterations in the acto-myosin cytoskeleton. Hepatology 2001; 33 (01) 74-80