Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Sep 26, 2018; 6(10): 355-364
Published online Sep 26, 2018. doi: 10.12998/wjcc.v6.i10.355
PNPLA3 rs139051 is associated with phospholipid metabolite profile and hepatic inflammation in nonalcoholic fatty liver disease
Ji-Jun Luo, Hai-Xia Cao, Rui-Xu Yang, Rui-Nan Zhang, Qin Pan
Ji-Jun Luo, Hai-Xia Cao, Rui-Xu Yang, Rui-Nan Zhang, Qin Pan, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
Author contributions: Pan Q conceived and designed the experiments; Luo JJ, Yang RX and Zhang RN performed the experiments; Luo JJ and Cao HX analyzed the data; Pan Q wrote the paper; Luo JJ and Cao HX contributed equally to this work.
Supported by National Key Research and Development Plan “Precision Medicine Research” , No. 2017YFC0908903; National Natural Science Foundation of China, No. 81070346, No. 81270492, No. 81470859, No. 81270491 and No. 81470840; State Key Development Program for Basic Research of China, No. 2012CB517501; 100 Talents Program, No. XBR2011007h; and Program of the Committee of Science and Technology, No. 09140903500.
Institutional review board statement: The study was reviewed and approved by the Xinhua Hospital Ethics Committee Affiliated to Shanghai Jiaotong University School of Medicine.
Conflict-of-interest statement: No potential conflicts 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: Qin Pan, MD, PhD, Professor, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Kongjiang Road NO. 1665, Yangpu District, Shanghai 200092, China. panqin@xinhuamed.com.cn
Telephone: +86-21-63846590 Fax: +86-21-25077340
Received: June 19, 2018
Peer-review started: June 19, 2018
First decision: July 11, 2018
Revised: July 16, 2018
Accepted: August 3, 2018
Article in press: August 4, 2018
Published online: September 26, 2018
Processing time: 100 Days and 4.3 Hours
Abstract
AIM

To investigate the effect of PNPLA3 polymorphisms on serum lipidomics and pathological characteristics in nonalcoholic fatty liver disease (NAFLD).

METHODS

Thirty-four biopsy-proven NAFLD patients from Northern, Central, and Southern China were subjected to stratification by genotyping their single nucleotide polymorphisms (SNPs) in PNPLA3. Ultra performance liquid chromatographytandem mass spectrometry was then employed to characterize the effects of PNPLA3 SNPs on serum lipidomics. In succession, correlation analysis revealed the association of PNPLA3-related lipid profile and hepatic pathological characteristics on a basis of steatosis, activity, and fibrosis assessment. The variant-based scoring of hepatocyte steatosis, ballooning, lobular inflammation, and liver fibrosis was finally performed so as to uncover the actions of lipidomics-affecting PNPLA3 SNPs in NAFLD-specific pathological alterations.

RESULTS

PNPLA3 SNPs (rs139051, rs738408, rs738409, rs 2072906, rs2294918, rs2294919, and rs4823173) demonstrated extensive association with the serum lipidomics, especially phospholipid metabolites [lysophosphatidylcholine (LPC), lysophosphatidylcholine plasmalogen (LPCO), lysophosphatdylethanolamine (LPE), phosphatidylcholine (PC), choline plasmalogen (PCO), phosphatidylethanolamine (PE), ethanolamine plasmalogen (PEO)], of NAFLD patients. PNPLA3 rs139051 (A/A genotype) and rs2294918 (G/G genotype) dominated the up-regulatory effect on phospholipids of LPCs (LPC 17:0, LPC 18:0, LPC 20:0, LPC 20:1, LPC 20:2) and LPCOs (LPC O-16:1, LPC O-18:1). Moreover, subjects with high-level LPCs/LPCOs were predisposed to low-grade lobular inflammation of NAFLD (rho: -0.407 to -0.585, P < 0.05-0.001). The significant correlation of PNPLA3 rs139051 and inflammation grading [A/A vs A/G + G/G: 0.50 (0.00, 1.75) vs 1.50 (1.00, 2.00), P < 0.05] further demonstrated its pathological role based on the modulation of phospholipid metabolite profile.

CONCLUSION

The A/A genotype at PNPLA3 rs139051 exerts an up-regulatory effect on serum phospholipids of LPCs and LPCOs, which are associated with low-grade lobular inflammation of NAFLD.

Keywords: Nonalcoholic fatty liver disease; Patatin-like phospholipase domain containing 3; Single nucleotide polymorphism; Phospholipid; Inflammation

Core tip:PNPLA3 single nucleotide polymorphisms reflect an important genetic basis of serum lipidomics, especially phospholipid metabolites, in nonalcoholic fatty liver disease (NAFLD) patients. PNPLA3 rs139051 (A/A genotype) exerts an up-regulatory effect on phospholipids of lysophosphatidylcholines (LPCs) and lysophosphatidylcholine plasmalogens (LPCOs). Moreover, both the A/A genotype at PNPLA3 rs139051 and high-level LPCs/LPCOs share an association with the low-grade lobular inflammation of NAFLD. Therefore, PNPLA3 rs139051 may underlie the inflammatory progress of NAFLD with its modulation of phospholipid metabolite profiles.