Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease

Abstract

Lately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease (NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that modulate the expression of genes involved in lipid metabolism, energy homeostasis and inflammation, being altered in diet-induced obesity. Experimental evidences show that PPAR-alpha is the master regulator of hepatic beta-oxidation (mitochondrial and peroxisomal) and microsomal omega-oxidation, being markedly decreased by high-fat (HF) intake. PPAR-beta/delta is crucial to the regulation of forkhead box-containing protein O subfamily-1 expression and, hence, the modulation of enzymes that trigger hepatic gluconeogenesis. In addition, PPAR-beta/delta can activate hepatic stellate cells aiming to the hepatic recovery from chronic insult. On the contrary, PPAR-gamma upregulation by HF diets maximizes NAFLD through the induction of lipogenic factors, which are implicated in the fatty acid synthesis. Excessive dietary sugars also upregulate PPAR-gamma, triggering de novo lipogenesis and the consequent lipid droplets deposition within hepatocytes. Targeting PPARs to treat NAFLD seems a fruitful approach as PPAR-alpha agonist elicits expressive decrease in hepatic steatosis by increasing mitochondrial beta-oxidation, besides reduced lipogenesis. PPAR-beta/delta ameliorates hepatic insulin resistance by decreasing hepatic gluconeogenesis at postprandial stage. Total PPAR-gamma activation can exert noxious effects by stimulating hepatic lipogenesis. However, partial PPAR-gamma activation leads to benefits, mainly mediated by increased adiponectin expression and decreased insulin resistance. Further studies are necessary aiming at translational approaches useful to treat NAFLD in humans worldwide by targeting PPARs.

Keywords: Peroxisome proliferator-activated receptors; Non-alcoholic fatty liver disease; Obesity; Treatment; Insulin resistance; Beta-oxidation; Lipogenesis

Core tip: Multiple pathways disrupted in obesity and non-alcoholic fatty liver disease (NAFLD) are regulated by genes encoded by peroxisome proliferator-activated receptors (PPARs). Thus, PPARs emerged as potential targets to alleviate NAFLD. The use of PPAR-alpha agonist yields increased mitochondrial beta-oxidation coupled with reduced lipogenesis. Both of them are essential to tackle insulin resistance and hepatic steatosis. PPAR-beta/delta agonist is still not available as a medicine, but PPAR-beta/delta agonist elicited expressive reduction in hepatic glucose production in murine models. PPAR-gamma agonist is extensively used, and beneficial effects come from partial activation as total PPAR-gamma activation leads to hepatic lipogenesis, being harmful to the liver.