A subset of dysregulated metabolic and survival genes is associated with severity of hepatic steatosis in obese Zucker rats[S]

We aimed to characterize the primary abnormalities associated with fat accumulation and vulnerability to hepatocellular injury of obesity-related fatty liver. We performed functional analyses and comparative transcriptomics of isolated primary hepatocytes from livers of obese insulin-resistant Zucker rats (comprising mild to severe hepatic steatosis) and age-matched lean littermates, searching for novel genes linked to chronic hepatic steatosis. Of the tested genome, 1.6% was identified as steatosis linked. Overexpressed genes were mainly dedicated to primary metabolism (100%), signaling, and defense/acute phase (∼70%); detoxification, steroid, and sulfur metabolism (∼65%) as well as cell growth/proliferation and protein synthesis/transformation (∼70%) genes were downregulated. The overexpression of key genes involved in de novo lipogenesis, fatty acid and glycerolipid import and synthesis, as well as acetyl-CoA and cofactor provision was paralleled by enhanced hepatic lipogenesis and production of large triacylglycerol-rich VLDL. Greatest changes in gene expression were seen in those encoding the lipogenic malic enzyme (up to 7-fold increased) and cell-to-cell interacting cadherin 17 (up to 8-fold decreased). Among validated genes, fatty acid synthase, stearoyl-CoA desaturase 1, fatty acid translocase/Cd36, malic enzyme, cholesterol-7α hydroxylase, cadherin 17, and peroxisome proliferator-activated receptor α significantly correlated with severity of hepatic steatosis. In conclusion, dysregulated expression of metabolic and survival genes accompany hepatic steatosis in obese insulin-resistant rats and may render steatotic hepatocytes more vulnerable to cell injury in progressive nonalcoholic fatty liver disease.

• Publication year

  2010

• Venue

  Journal of Lipid Research

• Publication date

  2010-03-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1194/jlr.M001966PMID 19783528PMCID PMC2817580
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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