Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 7, 2015; 21(45): 12787-12799
Published online Dec 7, 2015. doi: 10.3748/wjg.v21.i45.12787
Peroxisome proliferator-activated receptor-delta agonist ameliorated inflammasome activation in nonalcoholic fatty liver disease
Hyun Jung Lee, Jong Eun Yeon, Eun Jung Ko, Eileen L Yoon, Sang Jun Suh, Keunhee Kang, Hae Rim Kim, Seoung Hee Kang, Yang Jae Yoo, Jihye Je, Beom Jae Lee, Ji Hoon Kim, Yeon Seok Seo, Hyung Joon Yim, Kwan Soo Byun
Hyun Jung Lee, Jong Eun Yeon, Eun Jung Ko, Eileen L Yoon, Sang Jun Suh, Keunhee Kang, Hae Rim Kim, Seoung Hee Kang, Yang Jae Yoo, Jihye Je, Beom Jae Lee, Ji Hoon Kim, Yeon Seok Seo, Hyung Joon Yim, Kwan Soo Byun, Department of Internal Medicine, Korea University College of Medicine, Seoul 152-703, South Korea
Author contributions: Lee HJ and Yeon JE designed the research; Lee HJ and Ko EJ performed the research; Yoon EL, Suh SJ, Kang K, Lee BJ, Kim JH, Seo YS, Yim HJ and Byun KS contributed reagents/analytic tools; Kim HR, Kang SH, Yoo YJ and Je J anlyazed the data; Lee HJ and Yeon JE wrote the paper.
Institutional review board statement: This study was approved by the institutional review board Korea University and conducted in compliance with the Guide for the care and Use of Laboratory Animals.
Institutional animal care and use committee statement: All procedure involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Korea University, Seoul, Korea, KUIACUC-2013-66 and carried out according to the Guide for the Care and Use of Laboratory Animals.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: No additional data are available.
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: Jong Eun Yeon, MD, PhD, Department of Internal Medicine, Korea University College of Medicine, 97 Guro-Dong Gil, Guro-Dong, Guro-Ku, Seoul 152-703, South Korea. jeyyeon@hotmail.com
Telephone: +82-2-26263010 Fax: +82-2-26261038
Received: May 7, 2015
Peer-review started: May 11, 2015
First decision: June 2, 2015
Revised: July 24, 2015
Accepted: October 13, 2015
Article in press: October 13, 2015
Published online: December 7, 2015
Processing time: 213 Days and 0.6 Hours
Abstract

AIM: To evaluate the inflammasome activation and the effect of peroxisome proliferator-activated receptors (PPAR)-δ agonist treatment in nonalcoholic fatty liver disease (NAFLD) models.

METHODS: Male C57BL/6J mice were classified according to control or high fat diet (HFD) with or without PPAR-δ agonist (GW) over period of 12 wk [control, HFD, HFD + lipopolysaccharide (LPS), HFD + LPS + GW group]. HepG2 cells were exposed to palmitic acid (PA) and/or LPS in the absence or presence of GW.

RESULTS: HFD caused glucose intolerance and hepatic steatosis. In mice fed an HFD with LPS, caspase-1 and interleukin (IL)-1β in the liver were significantly increased. Treatment with GW ameliorated the steatosis and inhibited overexpression of pro-inflammatory cytokines. In HepG2 cells, PA and LPS treatment markedly increased mRNA of several nucleotide-binding and oligomerization domain-like receptor family members (NLRP3, NLRP6, and NLRP10), caspase-1 and IL-1β. PA and LPS also exaggerated reactive oxygen species production. All of the above effects of PA and LPS were reduced by GW. GW also enhanced the phosphorylation of AMPK-α.

CONCLUSION: PPAR-δ agonist reduces fatty acid-induced inflammation and steatosis by suppressing inflammasome activation. Targeting the inflammasome by the PPAR-δ agonist may have therapeutic implication for NAFLD.

Keywords: Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Inflammasome; Nucleotide-binding and oligomerization domain-like receptor; Peroxisome proliferator-activated receptors delta

Core tip: Until now, the underlying mechanisms of disease progression and therapeutic targets were uncertain in nonalcoholic fatty liver disease (NAFLD). Our study were to evaluate the inflammasome activation and the effect of peroxisome proliferator-activated receptors (PPAR)-δ agonist treatment in NAFLD models. In our NAFLD models, mRNA of several NOD-like receptor family members, caspase-1 and interleukin-1β were markedly increased. All of those effects were reduced by PPAR-δ agonist treatment. It also ameliorated the steatosis and inhibited overexpression of pro-inflammatory cytokines. In conclusion, PPAR-δ agonist reduces fatty acid-induced inflammation and steatosis by suppressing inflammasome activation.