Loss of hepatic PPARα promotes inflammation and serum hyperlipidemia in diet-induced obesity

David E. Stec, Darren M. Gordon, Jennifer A. Hipp, Stephen Hong, Zachary L. Mitchell, Natalia R. Franco, J. Walker Robison, Christopher D. Anderson, Donald F. Stec, Terry D. Hinds

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Agonists for PPARα are used clinically to reduce triglycerides and improve high-density lipoprotein (HDL) cholesterol levels in patients with hyperlipidemia. Whether the mechanism of PPARα activation to lower serum lipids occurs in the liver or other tissues is unknown. To determine the function of hepatic PPARα on lipid profiles in diet-induced obese mice, we placed hepatocyte-specific peroxisome proliferator-activated receptor-α (PPARα) knockout (PparaHepKO) and wild-type (Pparafl/fl) mice on high-fat diet (HFD) or normal fat diet (NFD) for 12 wk. There was no significant difference in weight gain, percent body fat mass, or percent body lean mass between the groups of mice in response to HFD or NFD. Interestingly, the PparaHepKO mice on HFD had worsened hepatic inflammation and a significant shift in the proinflammatory M1 macrophage population. These changes were associated with higher hepatic fat mass and decreased hepatic lean mass in the PparαHepKO on HFD but not in NFD as measured by Oil Red O and noninvasive EchoMRI analysis (31.1 ± 2.8 vs. 20.2 ± 1.5, 66.6 ± 2.5 vs. 76.4 ± 1.5%, P < 0.05). We did find that this was related to significantly reduced peroxisomal gene function and lower plasma β-hydroxybutyrate in the PparaHepKO on HFD, indicative of reduced metabolism of fats in the liver. Together, these provoked higher plasma triglyceride and apolipoprotein B100 levels in the PparaHepKO mice compared with Pparafl/fl on HFD. These data indicate that hepatic PPARα functions to control inflammation and liver triglyceride accumulation that prevent hyperlipidemia.

Original languageEnglish
Pages (from-to)R733-R745
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume317
Issue number5
DOIs
StatePublished - 2019

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grant L32MD009154 (to T. D. Hinds, Jr.), National Heart, Lung and Blood Institute Grants K01HL-125445 (to T. D. Hinds, Jr.) and P01 HL05197-11 (to D. E. Stec), and the National Institute of General Medical Sciences Grant P20GM104357-02 (to D. E. Stec). Nuclear magnetic resonance instrumentation was supported in part by National Science Foundation Grant 0922862, National Institutes of Health Grant S10 RR025677, and Vanderbilt University matching funds. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
Copyright © 2019 the American Physiological Society.

Keywords

  • Apolipoprotein
  • Cholesterol
  • Nonalcoholic fatty liver disease
  • Obesity
  • Peroxisomes

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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