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 (TZD) 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 TZD have shown anti-fibrogenic and anti-inflammatory effects in 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.

Multi-ancestry Polygenic Mechanisms of Type 2 Diabetes Elucidate Disease Processes and Clinical Heterogeneity

“…The novel Lipodystrophy 2 cluster included multiple variants related to adipocyte and hepatocyte function. For instance, the cluster included variants near PNPLA3 9 and PPARG 10 , which regulate fatty acid metabolism in both adipocytes and hepatocytes, and epigenomic analysis demonstrated that the Lipodystrophy 2 cluster was enriched in adipocytes ( Fig. 3B ).…”

A model of hepatic steatosis with declined viability and function in a liver-organ-on-a-chip

“…6 A and D). This is probably because in previous human studies, pioglitazone reduced FAs influx into the liver by enhancing lipid anabolism in adipose tissues 42 , 43 . We found no benefit of pioglitazone to OOC viability and albumin production under Condition A (Fig.…”

Multi-ancestry Polygenic Mechanisms of Type 2 Diabetes Elucidate Disease Processes and Clinical Heterogeneity

“…The top-weighted traits included increased hepatic enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], γ-glutamyl transferase [GGT]), increased Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and decreased insulin sensitivity index. The top-weighted loci included PNPLA3 and PPARG , which regulate the accumulation of fatty acids in the liver and adipose tissue 9,10 . Compared to our prior work, the previous single Lipodystrophy cluster appeared to split into two clusters (Extended Data Fig.…”

“…The novel Lipodystrophy 2 cluster included multiple variants related to adipocyte and hepatocyte function. For instance, the cluster included variants near PNPLA3 9 and PPARG 10 , which regulate fatty acid metabolism in both adipocytes and hepatocytes, and epigenomic analysis demonstrated that the Lipodystrophy 2 cluster was enriched in adipocytes (Fig. 3B).…”