Moderate, chronic ethanol feeding exacerbates carbon tetrachloride–induced hepatic fibrosis via hepatocyte‐specific hypoxia‐inducible factor 1α

Pharmacology Research and Perspectives - Tập 2 Số 5 - 2014
Sagorika Paul1, Dian Chiang2, Megan R. McMullen1, Laura E. Nagy1,2,3
1Center for Liver Disease Research Department of Pathobiology Lerner Research Institute, Cleveland Clinic Cleveland Ohio
2Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio
3Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio

Tóm tắt

AbstractThe hypoxia‐sensing transcriptional factor HIF1α is implicated in a variety of hepato‐pathological conditions; however, the contribution of hepatocyte‐derived HIF1α during progression of alcoholic liver injury is still controversial. HIF1α induces a variety of genes including those involved in apoptosis via p53 activation. Increased hepatocyte apoptosis is critical for progression of liver inflammation, stellate cell activation, and fibrosis. Using hepatocyte‐specific HIF1α‐deficient mice (ΔHepHIF1α−/−), here we investigated the contribution of HIF1α to ethanol‐induced hepatocyte apoptosis and its role in amplification of fibrosis after carbon tetrachloride (CCl4) exposure. Moderate ethanol feeding (11% of kcal) induced accumulation of hypoxia‐sensitive pimonidazole adducts and HIF1α expression in the liver within 4 days of ethanol feeding. Chronic CCl4 treatment increased M30‐positive cells, a marker of hepatocyte apoptosis in pair‐fed control mice. Concomitant ethanol feeding (11% of kcal) amplified CCl4‐induced hepatocyte apoptosis in livers of wild‐type mice, associated with elevated p53K386 acetylation, PUMA expression, and Ly6c+ cell infiltration. Subsequent to increased apoptosis, ethanol‐enhanced induction of profibrotic markers, including stellate cell activation, collagen 1 expression, and extracellular matrix deposition following CCl4 exposure. Ethanol‐induced exacerbation of hepatocyte apoptosis, p53K386 acetylation, and PUMA expression following CCl4 exposure was attenuated in livers of ΔHepHIF1α−/− mice. This protection was also associated with a reduction in Ly6c+ cell infiltration and decreased fibrosis in livers of ΔHepHIF1α−/− mice. In summary, these results indicate that moderate ethanol exposure leads to hypoxia/HIF1α‐mediated signaling in hepatocytes and induction of p53‐dependent apoptosis of hepatocytes, resulting in increased hepatic fibrosis during chronic CCl4 exposure.

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Tài liệu tham khảo

10.1172/JCI24282

10.1016/j.bpg.2011.02.010

10.1002/hep.20051

10.1016/j.jhep.2012.08.008

10.1371/journal.pone.0069114

10.1053/j.gastro.2010.04.041

10.1111/j.1478-3231.2009.02015.x

10.1016/j.transproceed.2008.05.037

10.1002/hep.20310

10.1053/j.gastro.2008.04.038

Elliott PJ, 2008, Sirtuins: novel targets for metabolic disease, Curr Opin Investig Drugs, 9, 371

10.1136/jcp.2003.015032

10.3748/wjg.v19.i24.3781

10.2174/187221309787158434

10.1038/nrc3183

10.4049/jimmunol.1002060

10.1016/j.jhep.2011.09.009

10.1152/ajpgi.00107.2009

10.1152/ajpgi.90368.2008

10.1016/j.cbi.2011.07.001

10.1002/hep.25497

10.1016/j.jhep.2011.07.024

10.1152/ajpgi.00325.2007

10.1002/hep.24516

10.1093/qjmed/hcs069

10.1016/j.jhep.2011.10.026

10.1128/MCB.01218-10

10.1111/j.1530-0277.2011.01720.x

10.1038/cddis.2011.48

10.3748/wjg.15.1219

10.3748/wjg.v16.i11.1358

10.1016/j.bpg.2011.02.004

10.1016/j.cell.2008.03.025

10.3727/000000003108749062

10.1016/j.freeradbiomed.2013.05.009

10.1002/hep.22087

10.1248/bpb.31.1523

Zakhari S, 2006, Overview: how is alcohol metabolized by the body?, Alcohol Res Health, 29, 245

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Pharmacology Research and Perspectives

Tập 2 Số 5

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