Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. May 18, 2015; 7(8): 1012-1019
Published online May 18, 2015. doi: 10.4254/wjh.v7.i8.1012
Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease
Vanessa Souza-Mello
Vanessa Souza-Mello, Biomedical Centre, Institute of Biology, Department of Anatomy, State University of Rio de Janeiro, Rio de Janeiro 20551-030, Brazil
Author contributions: Souza-Mello V solely contributed to this paper.
Conflict-of-interest: The author discloses any conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Vanessa Souza-Mello, RD, PhD, Biomedical Centre, Institute of Biology, Department of Anatomy, State University of Rio de Janeiro, Av. 28 de Setembro 87, Fundos, Vila Isabel, Rio de Janeiro 20551-030, Brazil. souzamello.uerj@gmail.com
Telephone: +55-21-28688689 Fax: +55-21-28688033
Received: January 27, 2015
Peer-review started: January 28, 2015
First decision: February 7, 2015
Revised: February 21, 2015
Accepted: March 30, 2015
Article in press: April 2, 2015
Published online: May 18, 2015

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.