Open AccessModerate, chronic ethanol feeding exacerbates carbon tetrachloride–induced hepatic fibrosis via hepatocyte‐specific hypoxia‐inducible factor 1 α
Author(s) -
Roychowdhury Sanjoy,
Chiang Dian J.,
McMullen Megan R.,
Nagy Laura E.
Publication year - 2014
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.61
Subject(s) - hepatocyte , apoptosis , hepatic stellate cell , fibrosis , chemistry , cancer research , alcoholic liver disease , puma , endocrinology , biology , medicine , cirrhosis , biochemistry , in vitro
The hypoxia‐sensing transcriptional factor HIF 1 α is implicated in a variety of hepato‐pathological conditions; however, the contribution of hepatocyte‐derived HIF 1 α during progression of alcoholic liver injury is still controversial. HIF 1 α 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 HIF 1 α ‐deficient mice (ΔHepHIF1 α −/− ), here we investigated the contribution of HIF 1 α to ethanol‐induced hepatocyte apoptosis and its role in amplification of fibrosis after carbon tetrachloride (CCl 4 ) exposure. Moderate ethanol feeding (11% of kcal) induced accumulation of hypoxia‐sensitive pimonidazole adducts and HIF 1 α expression in the liver within 4 days of ethanol feeding. Chronic CCl 4 treatment increased M30‐positive cells, a marker of hepatocyte apoptosis in pair‐fed control mice. Concomitant ethanol feeding (11% of kcal) amplified CCl 4 ‐induced hepatocyte apoptosis in livers of wild‐type mice, associated with elevated p53 K386 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 CCl 4 exposure. Ethanol‐induced exacerbation of hepatocyte apoptosis, p53 K386 acetylation, and PUMA expression following CCl 4 exposure was attenuated in livers of ΔHep HIF 1 α −/− mice. This protection was also associated with a reduction in Ly6c + cell infiltration and decreased fibrosis in livers of ΔHep HIF 1 α −/− mice. In summary, these results indicate that moderate ethanol exposure leads to hypoxia/ HIF 1 α ‐mediated signaling in hepatocytes and induction of p53‐dependent apoptosis of hepatocytes, resulting in increased hepatic fibrosis during chronic CCl 4 exposure.