PPARα-Deficient ob/ob Obese Mice Become More Obese and Manifest Severe Hepatic Steatosis Due to Decreased Fatty Acid Oxidation.
paper
Cited
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- Authors
- Gao, Qian; Jia, Yuzhi; Yang, Gongshe; Zhang, Xiaohong; Boddu, Prajwal C; Petersen, Bryon; Narsingam, Saiprasad; Zhu, Yi-Jun; Thimmapaya, Bayar; Kanwar, Yashpal S; Reddy, Janardan K
- Year
- 2015
- Journal
- The American journal of pathology
- PMID
- 25773177
- DOI
- 10.1016/j.ajpath.2015.01.018
- PMCID
- PMC4419205
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 α (PPARα) 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 PPARα-regulated hepatic FAO and energy burning in the progression of fatty liver disease, we generated PPARα-deficient ob/ob (PPARα(Δ)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 PPARα(Δ)ob/ob mice as they fail to up-regulate FAO systems. PPARα(Δ)ob/ob mice also do not respond to peroxisome proliferative and mitogenic effects of PPARα agonist Wy-14,643. Although PPARα(Δ)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 PPARα activation-related increase in FAO in fatty livers of obese ob/ob mice increases liver cancer risk, whereas deletion of PPARα 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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