Journal
JOURNAL OF LIPID RESEARCH
Volume 51, Issue 3, Pages 500-513Publisher
ELSEVIER
DOI: 10.1194/jlr.M001966
Keywords
gene expression; lipid synthesis; triglyceride secretion
Categories
Funding
- Ministerio de Educacion y Ciencia [SAF2007/60211]
- Instituto de Salud Carlos III [RETIC G03/015, PI06/0221]
- Gobierno Vasco [IT-325-07]
- Instituto de Salud Carlos III, Spain
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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 (similar to 70%); detoxification, steroid, and sulfur metabolism (similar to 65%) as well as cell growth/proliferation and protein synthesis/transformation (similar to 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-7 alpha hydroxylase, cadherin 17, and peroxisome proliferator-activated receptor alpha 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.-Buque, X., M. J. Martinez, A. Cano, M. E. Miquilena-Colina, C. Garcia-Monzon, P. Aspichueta, and B. Ochoa. A subset of dysregulated metabolic and survival genes is associated with severity of hepatic steatosis in obese Zucker rats. J. Lipid Res. 2010. 51: 500-513.
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