Hepatic lipid homeostasis by peroxisome proliferator-activated receptor gamma 2

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ or PPARG) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. It plays a master role in the differentiation and proliferation of adipose tissues. It has two major isoforms, PPARγ1 and PPARγ2, encoded from a single gene using two separate promoters and alternative splicing. Among them, PPARγ2 is most abundantly expressed in adipocytes and plays major adipogenic and lipogenic roles in the tissue. Furthermore, it has been shown that PPARγ2 is also expressed in the liver, specifically in hepatocytes, and its expression level positively correlates with fat accumulation induced by pathological conditions such as obesity and diabetes. Knockout of the hepatic Pparg gene ameliorates hepatic steatosis induced by diet or genetic manipulations. Transcriptional activation of Pparg in the liver induces the adipogenic program to store fatty acids in lipid droplets as observed in adipocytes. Understanding how the hepatic Pparg gene expression is regulated will help develop preventative and therapeutic treatments for non-alcoholic fatty liver disease (NAFLD). Due to the potential adverse effect of hepatic Pparg gene deletion on peripheral tissue functions, therapeutic interventions that target PPARγ for fatty liver diseases require fine-tuning of this gene's expression and transcriptional activity.

Keywords: Adipogenesis; Gene expression; High fat diet (HFD); Non-alcoholic fatty liver disease (NAFLD); Peroxisome proliferator-activated receptor; gamma (PPARγ).

Fig. 1. Gene and protein structures of mouse and human PPARγ isoforms.

Genomic structures of mouse Pparg1 and Pparg2 (middle left), and human PPARG1 and PPARG2 (middle right) are depicted, based on the earlier reports.^, Purple solid rectangles are common exons for Pparg1 and Pparg2 isoforms. Orange (A1 and A2) and brown rectangles (B) are specific for Pparg1 and Pparg2 isoforms, respectively. PPARγ1 protein structures are shown at the top and PPARγ2 structures are presented at the bottom. The functional domains of mouse and human PPARγs are based on sequence alignment reported in an earlier review. Abbreviations: PPARγ, peroxisome proliferator-activated receptor gamma; AF, activation function.

Fig. 2. Upstream regulators and downstream targets of PPARγ2-mediated hepatic lipid homeostasis.

Increased ghrelin by chronic HFD consumption induces Pparg2 gene expression through mTOR signaling. Similarly, external stresses (i.e., nutritional stress) induce or inhibit Pparg2 transcription via AP1 depending on the specific heterodimer formation. Increased PPARγ2 activates downstream target genes such as LPL and CD36 for FA uptake, aP2 for intracellular FA trafficking, MOGAT1 for synthesis of diacylglycerol, and ADRP and FSP27 for lipid droplet accumulation. These targets are not major genes in hepatic TG synthesis during normal conditions. However, when PPARγ2 expression is increased by HFD feeding, these target genes contribute to lipid accumulation in the liver. Abbreviations: PPARγ2, peroxisome proliferator-activated receptor gamma 2; Chylm, chylomicron remnants; FFA, free fatty acids; FA-CoA, fatty acyl-Coenzyme A; MG, monoacylglycerol; DG, diacylglycerol; TG, triacylglycerol; GHRL, ghrelin; GHSR1, ghrelin receptor; LPL, lipoprotein lipase; CD36, cluster of differentiation 36; aP2, adipocyte protein 2; AP1, activator protein 1; mTOR, mammalian target of rapamycin; ADRP, adipose differentiation-related protein; FSP27, fat specific protein 27; MOGAT1, monoacylglycerol O-acyltransferase 1.