Increased liver oxidative stress and altered PUFA metabolism precede development of non-alcoholic steatohepatitis in SREBP-1a transgenic spontaneously hypertensive rats with genetic predisposition to hepatic steatosis
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
HL35018
NHLBI NIH HHS - United States
HL56028
NHLBI NIH HHS - United States
HL63709
NHLBI NIH HHS - United States
- MeSH
- Genetic Predisposition to Disease MeSH
- Liver metabolism pathology MeSH
- Rats MeSH
- Humans MeSH
- Fatty Acids, Unsaturated metabolism MeSH
- Oxidative Stress * MeSH
- Rats, Inbred SHR MeSH
- Rats, Transgenic MeSH
- Sterol Regulatory Element Binding Protein 1 genetics metabolism MeSH
- Fatty Liver genetics metabolism pathology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Names of Substances
- Fatty Acids, Unsaturated MeSH
- Sterol Regulatory Element Binding Protein 1 MeSH
- SREBF1 protein, human MeSH Browser
The temporal relationship of hepatic steatosis and changes in liver oxidative stress and fatty acid (FA) composition to the development of non-alcoholic steatohepatitis (NASH) remain to be clearly defined. Recently, we developed an experimental model of hepatic steatosis and NASH, the transgenic spontaneously hypertensive rat (SHR) that overexpresses a dominant positive form of the human SREBP-1a isoform in the liver. These rats are genetically predisposed to hepatic steatosis at a young age that ultimately progresses to NASH in older animals. Young transgenic SHR versus SHR controls exhibited simple hepatic steatosis which was associated with significantly increased hepatic levels of oxidative stress markers, conjugated dienes, and TBARS, with decreased levels of antioxidative enzymes and glutathione and lower concentrations of plasma alpha- and gamma-tocopherol. Transgenic rats exhibited increased plasma levels of saturated FA, decreased levels of n-3 and n-6 polyunsaturated FA (PUFA), and increased n-6/n-3 PUFA ratios. These results are consistent with the hypothesis that excess fat accumulation in the liver in association with increased oxidative stress and disturbances in the metabolism of saturated and unsaturated fatty acids may precede and contribute to the primary pathogenesis of NASH.
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