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Apolipoprotein (apo)AV deficiency aggravates ethanol‐induced liver injury, promoting progression from simple steatosis to alcoholic steatohepatitis and then to liver fibrosis in mice
Author(s) -
Wang David Q,
Gao Bin,
Wang Helen H,
Bari Ornella,
Tso Patrick
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.893.6
Subject(s) - steatohepatitis , steatosis , medicine , endocrinology , fatty liver , liver injury , alcoholic liver disease , hepatic stellate cell , liver disease , sirius red , fibrosis , hepatocyte , biology , chemistry , cirrhosis , biochemistry , disease , in vitro
Background Alcoholic liver disease (ALD) includes a broad spectrum of disorders, ranging from simple steatosis to severe forms of liver injury such as alcoholic steatohepatitis (ASH), fibrosis, and hepatocellular carcinoma. Almost all heavy drinkers suffer from fatty liver, but only 20–40% of them develop more severe forms of ALD, and the underlying mechanisms contributing to disease progression remain elusive. Although there are an increasing number of animal models of ALD, none of them depicts the complex metabolic profile and the histological patterns typical of ALD patients. Because apoAV is synthesized exclusively in the liver, we hypothesize that it plays a critical role in regulating hepatic lipid metabolism, and ethanol interacts with apoAV to severely disrupt hepatic lipid homeostasis, leading to lipotoxic hepatocellular injury. Methods Male apoAV KO, transgenic (Tg) and WT mice were given chronic (5%, v/v) and binge (5g/kg once per wk) ethanol feeding (a modified NIAAA model) for 4 wk. Liver histopathology was examined by H&E and Sirius Red staining. The murine primary hepatocytes and hepatic stellate cells were treated with lysophosphatidylcholine (lysoPC). mRNA and protein levels were studied by qRT‐PCR and Western blots. Lipidomic analysis of liver was performed by ESI‐MS/MS. Results Ethanol caused a dose‐dependent inhibitory effect on mRNA and protein expression of apoAV in WT hepatocytes. This induced the accumulation of excess triglyceride and the formation of numerous lipid droplets in apoAV KO, but not Tg hepatocytes vs. WT controls. After ethanol feeding, apoAV KO mice displayed rapid development of liver steatosis, subsequently evolving from simple steatosis to ASH and then to liver fibrosis. WT mice developed only liver steatosis. Ethanol increased hepatic lysoPC levels, a known lipotoxic fatty acid metabolite, by enhancing its synthesis in KO mice compared to WT mice. Increased lysoPC induced hepatic lipo‐apoptosis through TNFα by stimulating both caspase‐induced apoptosis and reactive oxygen species (ROS)‐mediated mitochondrial dysfunction in KO, but not WT mice. These alterations triggered ASH with a key histological feature of hepatocellular ballooning, and increased collagen secretion by hepatic stellate cells through activating profibrogenic genes and heat shock protein 47, leading to liver fibrosis in KO mice. Conclusions The apoAV KO mouse model closely recapitulates many characteristics of the pathogenic processes and histological patterns of ALD in patients. LysoPC may be a key trigger for ASH, similar to its proposed role in NASH. These innovative studies elucidate a critical role of apoAV in the pathogenesis of ALD. Support or Funding Information This work was supported in part by research grants DK101793 and DK106249, both from the National Institutes of Health (US Public Health Service).