Role of hepatic peroxisome proliferator-activated receptor γ in non-alcoholic fatty liver disease

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) belongs to a family of nuclear receptors that could serve as lipid sensors. PPARγ is the target of a group of insulin sensitizers called thiazolidinediones (TZDs) which regulate the expression of genes involved in glucose and lipid metabolism as well as adipokines that regulate metabolic function in other tissues. Non-alcoholic fatty liver disease (NAFLD) has a high prevalence worldwide and is even higher in patients with obesity and insulin resistance. TZD-mediated activation of PPARγ could serve as a good treatment for NAFLD because TZDs have shown anti-fibrogenic and anti-inflammatory effectsin vitro and increase insulin sensitivity in peripheral tissues which improves liver pathology. However, mechanistic studies in mouse models suggest that the activation of PPARγ in hepatocytes might reduce or limit the therapeutic potential of TZD against NAFLD. In this review, we briefly describe the short history of PPAR isoforms, the relevance of their expression in different tissues, as well as the pathogenesis and potential therapeutics for NAFLD. We also discuss some evidence derived from mouse models that could be useful for endocrinologists to assess tissue-specific roles of PPARs, complement reverse endocrinology approaches, and understand the direct role that PPARγ has in hepatocytes and non-parenchymal cells.

Keywords: Cre-LoxP-knockout models; fatty acids; liver; mouse; nuclear receptor.

Figure 1.. Tissue-specific expression level of PPARα, PPARβ/δ, and PPARγ.

A) Normalized gene expression data: reads per kilobase of transcripts, per million mapped reads (RPKM) of PPARα, PPARβ/δ, and PPARγ in mouse (M) and human (H) tissues. Values were obtained from Gene database of the National Center for Biotechnology Information: Gene IDs 19013, 19015, 19016, 5465, 5467, 5468, using expression data of Bioproject #PRJNA66167 (RNA profiling data sets generated by the Mouse ENCODE project) and #PRJEB4337 (RNA-seq of tissue samples from 95 human individuals). B) Representation of percentage expression level of mouse and human PPAR isoforms by tissue.

Figure 2.. Representation of the changes in the hepatic phenotype during the progression of obesity-related nonalcoholic fatty liver disease (NAFLD).

In obese individuals, insulin resistance increases adipose tissue lipolysis resulting in increased availability of non-esterified fatty acids (1, green), and recycled lipoproteins (2, green). In addition, increased food intake and content of carbohydrates and fat in the diet, increases availability of chylomicrons remnants (3, green) and carbohydrates that will fuel de novo lipogenesis (DNL, 4, green). These mechanisms increase the production of triglycerides (TG) and store of fat as lipid droplets in the cytosol. Also, increased fat accumulation in hepatocytes could be associated with impaired fatty acid β-oxidation (1, red) and reduced production of very low density lipoprotein release (VLDL, 2, red). Excess accumulation of fat in hepatocytes leads to steatosis, and promotes lipid-related stress that promotes the generation of damage-associated molecular patterns (DAMPs). These DAMP will be released by hepatocytes to activate the non-parenchymal cells: Kupffer cells and hepatic stellate cells (HSC), which promote the development of inflammation and fibrosis, respectively, and the progression of NAFLD to non-alcoholic steatohepatitis (NASH). TZD activate PPARγ in hepatocytes, Kupffer cells, and HSC. In hepatocytes, PPARγ is also activated by incoming fatty acids and accumulated lipids. PPARγ activates steatogenic mechanisms (green circles 1–4), and may increase the production of DAMPs to activate non-parenchymal cells. In Kupffer cells, PPARγ acts as an anti-inflammatory agent. In HSC, PPARγ acts as an anti-fibrogenic agent.