Role of peroxisome proliferators-activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and can result in nonalcoholic steatohepatitis (NASH) and progressive liver disease including cirrhosis and hepatocellular carcinoma. A growing body of literature implicates the peroxisome proliferators-activated receptors (PPARs) in the pathogenesis and treatment of NAFLD. These nuclear hormone receptors impact on hepatic triglyceride accumulation and insulin resistance. The aim of this review is to describe the data linking PPAR alpha and PPAR gamma to NAFLD/NASH and to discuss the use of PPAR ligands for the treatment of NASH.

Figure 1

Liver histology ranging from normal liver to steatohepatitis with fibrosis. A: Normal liver. Cytoplasmic fat globules are absent in hepatocytes and there is no fibrosis in this trichrome stained specimen (× 20); B: Steatosis without steatohepatitis. Moderate cytoplasmic fat infiltration (arrow) is present without fibrosis (× 20); C: Steatohepatitis with minimal fibrosis. There is focal hepatocyte ballooning, inflammation, and minimal fibrosis (accentuated in blue by trichrome stain); D: Steatohepatitis with fibrosis. There is nodular scarring in this fat laden liver with advanced fibrosis depicted in blue by trichrome stain (× 20).

Figure 2

Mechanisms by which PPARs and their ligands can modulate triglyceride accumulation are highlighted by letters in the figure. A: PPARγ increases expression of genes associated with fatty acid uptake and triglyceride storage in adipocytes. Release of adiponectin from adipocytes improves insulin sensitivity and activates PPARα; B: PPARγ increases lipoprotein lipase expression, liberating circulating fatty acids from lipoproteins for import into adipocytes; C: PPARα activity up regulates β-oxidation of fatty acids in the liver; D: PPARα and TZDs upregulate stearoyl-CoA desaturase-1, a necessary enzyme for VLDL synthesis and export, and TZDs increase arachidonic acid content in triglycerides, which is associated with increased insulin sensitivity.