Altered expression of transcription factors and genes regulating lipogenesis in liver and adipose tissue of mice with high fat diet-induced obesity and nonalcoholic fatty liver disease

Sep 17, 2008European journal of gastroenterology & hepatology

Changes in gene activity controlling fat production in the liver and fat tissue of mice with obesity and fatty liver disease caused by a high-fat diet

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Abstract

Mice fed a high-fat diet for 9 months developed obesity, insulin resistance, and liver disease.

Mice on a high-fat diet (HF) weighed more than those on a standard fat diet (SF).
Fasting resulted in decreased hepatic expression of several transcription factors and lipogenic enzymes in both HF and SF mice.
Fasting increased the expression and protein content of fatty acid synthase (FAS) in the liver of HF mice compared to SF mice.
In adipose tissue, fasting led to decreased expression of certain lipogenic factors in SF mice but not in HF mice.
In HF mice, the expression and protein levels of lipogenic enzymes remained elevated during fasting, suggesting ongoing fat production.

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OBJECTIVE: To determine whether expression of transcription factors and lipogenic enzymes is altered in liver and adipose tissue of mice with obesity, insulin resistance, and nonalcoholic fatty liver disease.

METHODS: Mice were fed chow containing 9% of calories from standard fat (SF) or 20% of calories from high fat (HF) and killed after 9 months in the fasted or fed state.

MEASUREMENTS: Liver injury was evaluated by histology and serum aminotransferase levels. Transcription factor expression was measured by real-time PCR. Lipogenic enzymes were measured by real-time PCR and Western blots.

RESULTS: HF mice weighed more, had insulin resistance, hepatic steatosis, and focal pericellular hepatic fibrosis. Hepatic expression of sterol regulatory element-binding protein-1c, carbohydrate response element-binding protein, liver X receptor-alpha, acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) decreased during fasting in SF and HF mice; however, FAS expression and protein content were higher in the liver of fasted HF mice than of fasted SF mice. In adipose tissue, expression of sterol response element-binding protein-1c, carbohydrate response element-binding protein, liver X receptor-alpha, peroxisome proliferator-activated receptor-gamma, ACC, and FAS decreased with fasting in mice fed SF, but not in HF mice. ACC and FAS expression and protein content remained higher during fasting in HF than in SF mice.

CONCLUSION: Feeding a nutritionally complete diet containing a moderate increase in fat produces obesity and steatohepatitis. During fasting, hepatic FAS expression and protein content are increased in HF mice. Transcription factor expression, and lipogenic enzyme expression and protein concentration do not decline during fasting in adipose tissue from HF mice. De-novo lipogenesis may persist in liver and adipose tissue during fasting in obesity/nonalcoholic fatty liver disease.

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Altered expression of transcription factors and genes regulating lipogenesis in liver and adipose tissue of mice with high fat diet-induced obesity and nonalcoholic fatty liver disease

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