Role of Peroxisome Proliferator-activated Receptor δ/β in Hepatic Metabolic Regulation

Minghui Zhao,Matthew R. Gangl,Ben Hatano,Sihao Liu,Chih-Hao Lee,James A. Balschi,James M. Ntambi,Cem Gorgun,Kihwa Kang,Shannon M. Reilly,Chen-Chung Yen

doi:10.1074/jbc.m110.138115

Abstract

Pharmacological activation of peroxisome proliferator-activated receptor δ/β (PPARδ/β) improves glucose handling and insulin sensitivity. The target tissues of drug actions remain unclear. We demonstrate here that adenovirus-mediated liver-restricted PPARδ activation reduces fasting glucose levels in chow- and high fat-fed mice. This effect is accompanied by hepatic glycogen and lipid deposition as well as up-regulation of glucose utilization and de novo lipogenesis pathways. Promoter analyses indicate that PPARδ regulates hepatic metabolic programs through both direct and indirect transcriptional mechanisms partly mediated by its co-activator, PPARγ co-activator-1β. Assessment of the lipid composition reveals that PPARδ increases the production of monounsaturated fatty acids, which are PPAR activators, and reduces that of saturated FAs. Despite the increased lipid accumulation, adeno-PPARδ-infected livers exhibit less damage and show a reduction in JNK stress signaling, suggesting that PPARδ-regulated lipogenic program may protect against lipotoxicity. The altered substrate utilization by PPARδ also results in a secondary effect on AMP-activated protein kinase activation, which likely contributes to the glucose-lowering activity. Collectively, our data suggest that PPARδ controls hepatic energy substrate homeostasis by coordinated regulation of glucose and fatty acid metabolism, which provide a molecular basis for developing PPARδ agonists to manage hyperglycemia and insulin resistance.

Highlights

A series of metabolic studies were conducted within a week following the injection. These mice were first placed in metabolic cages, and the respiratory exchange ratio (RER) was examined to determine whether increased hepatic PPAR␦ altered fuel substrate usage
We found a moderate but significant increase in the RER at the resting period in adPPAR␦ mice (Fig. 1A and supplemental Fig. S2), indicating that PPAR␦ may increase glucose utilization in the liver
Insulin tolerance tests demonstrated that adPPAR␦ mice had improved insulin sensitivity, supporting the notion that hepatic PPAR␦ overexpression enhances glucose handling (Fig. 1C)

Summary

Introduction

Examination of liver sections showed that ϳ70% of hepatocytes were infected as determined by GFP expression, resulting in a 4 –5-fold increase in the PPAR␦ protein level (supplemental Fig. S1A). To determine how hepatic PPAR␦ regulates glucose metabolism, liver samples were collected for histological and gene expression studies.

Results

Conclusion