期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 185, 期 5, 页码 1396-1408出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2015.01.018
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资金
- NIH [DK083163, DK097240, R21A1094296, DK60015, DK58614, DK60635]
- China Scholarship Council grant [CSC 2011630169]
Obesity poses an increased risk of developing metabolic syndrome and closely associated nonalcoholic fatty liver disease, including liver cancer. Satiety hormone leptin-deficient (ob/ob) mice, considered paradigmatic of nutritional obesity, develop hepatic steatosis but are less prone to developing liver tumors. Sustained activation of peroxisome proliferator-activated receptor alpha (PPAR alpha) in ob/ob mouse liver increases fatty acid oxidation (FAO), which contributes to attenuation of obesity but enhances liver cancer risk. To further evaluate the role of PPAR alpha-regulated hepatic FAO and energy burning in the progression of fatty liver disease, we generated PPAR alpha-deficient ob/ob (PPAR alpha(Delta)ob/ob) mice. These mice become strikingly more obese compared to ob/ob littermates, with increased white and brown adipose tissue content and severe hepatic steatosis. Hepatic steatosis becomes more severe in fasted PPAR alpha(Delta)ob/ob mice as they fail to up-regulate FAO systems. PPAR alpha(Delta)ob/ob mice also do not respond to peroxisome proliferative and mitogenic effects of PPAR alpha agonist Wy-14,643. Although PPAR alpha(Delta)ob/ob mice are severely obese, there was no significant increase in liver tumor incidence, even when maintained on a diet containing Wy-14,643. We conclude that sustained PPAR alpha activation-related increase in FAO in fatty livers of obese ob/ob mice increases liver cancer risk, whereas deletion of PPAR alpha in ob/ob mice aggravates obesity and hepatic steatosis. However, it does not lead to liver tumor development because of reduction in FAO and energy burning.
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