PPARα-Deficient ob/ob Obese Mice Become More Obese and Manifest Severe Hepatic Steatosis Due to Decreased Fatty Acid Oxidation.

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 (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.

• Authors: 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
• Journal: The American journal of pathology (Am J Pathol) Vol. 185 Issue 5 Pg. 1396-408 (May 2015) ISSN: 1525-2191 [Electronic] United States
• PMID: 25773177 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Fatty Acids
• PPAR alpha

Topics

• Animals
• Disease Models, Animal
• Fatty Acids (metabolism)
• Immunoblotting
• Liver Neoplasms (etiology, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Non-alcoholic Fatty Liver Disease (etiology, metabolism)
• Obesity (complications, metabolism)
• Oxidation-Reduction
• PPAR alpha (deficiency)
• Real-Time Polymerase Chain Reaction