Peroxisome Proliferator-activated Receptor-γ Coactivator-1α (PGC-1α) Stimulates VLDL Assembly through Activation of Cell Death-inducing DFFA-like Effector B (CideB)

Zhouji Chen,Jin Y Norris,Brian N Finck

doi:10.1074/jbc.m110.141598

Abstract

Abnormalities in very low density lipoprotein (VLDL) assembly and secretion impact intrahepatic lipid homeostasis, plasma lipoprotein profile, and energy metabolism of distal peripheral tissues. We have evaluated the role of the transcriptional coactivator, the peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), in VLDL assembly and secretion. PGC-1alpha overexpression in HepG2 cells led to diminished rates of triglyceride (TG) synthesis but strongly stimulated VLDL-TG secretion, markedly increasing the efficiency of secretion of newly synthesized TG. PGC-1alpha overexpression increased the rate of secretion of apoB100 and promoted secretion of larger, less dense VLDL particles. PGC-1alpha overexpression in intact mouse liver also stimulated rates of VLDL TG secretion and attenuated hepatic TG accumulation resulting from high fat diet feeding. To determine the molecular mechanisms mediating the effect of PGC-1alpha on VLDL assembly, we evaluated the expression of several candidate mediators known to be involved in VLDL assembly or hepatic lipid homeostasis. Cell death-inducing DFFA-like effector B (CideB) expression was greatly induced by PGC-1alpha, and siRNA against CideB reversed the effects of PGC-1alpha on the secretion of TG and VLDL-sized particles by HepG2 cells, indicating that CideB is a critical mediator of stimulatory effects of PGC-1alpha on VLDL secretion. Collectively, these data suggest that PGC-1alpha plays an important role in partitioning cytoplasmic TG toward the VLDL secretory compartments and promoting VLDL secretion via transcriptional induction of CideB.

Highlights

Liver disease in humans [2,3,4] and mice [5,6,7]
We further demonstrate that the stimulatory effect of PGC-1␣ on very low density lipoprotein (VLDL) secretion is mediated, at least in part, by inducing the expression of the cell death-inducing DFFA-like effector B (CideB), a lipid droplet-associated protein recently identified in VLDL maturation in the endoplasmic reticulum (ER) [36]
PGC-1␣ Overexpression Decreases TG Synthesis but Robustly Stimulates TG Secretion in HepG2—We chose HepG2 cells to evaluate the gain-of-function effect of PGC-1␣ on VLDL assembly and secretion because previous studies have suggested that this cell line is deficient in PGC-1␣ activity [42, 43]

Summary

Introduction

Liver disease in humans [2,3,4] and mice [5,6,7]. overproduction of VLDL is frequently a co-morbidity of obesity, peripheral insulin resistance, and type 2 diabetes mellitus and is a key mechanism leading to the development of dyslipidemia in metabolic syndrome (8 –10). We have determined the effects of PGC-1␣ on TG and VLDL secretion in vitro by using human hepatoma HepG2 cells, primary mouse hepatocytes, and in vivo in intact mice.

Results

Conclusion