PPARα-deficient ob/ob obese mice become more obese and manifest severe hepatic steatosis due to decreased fatty acid oxidation

Qian Gao, Yuzhi Jia, Gongshe Yang, Xiaohong Zhang, Prajwal C. Boddu, Bryon Petersen, Saiprasad Narsingam, Yi Jun Zhu, Bayar Thimmapaya, Yashpal S. Kanwar, Janardan K. Reddy*

*Corresponding author for this work

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

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 (PPARαΔob/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 PPARαΔob/ob mice as they fail to up-regulate FAO systems. PPARαΔob/ob mice also do not respond to peroxisome proliferative and mitogenic effects of PPARα agonist Wy-14,643. Although PPARαΔob/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.

Original languageEnglish (US)
Article number1984
Pages (from-to)1396-1408
Number of pages13
JournalAmerican Journal of Pathology
Volume185
Issue number5
DOIs
StatePublished - May 1 2015

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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