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. 2018 Sep 26;6(10):355-364.
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  1 , Hai-Xia Cao  1 , Rui-Xu Yang  1 , Rui-Nan Zhang  1 , Qin Pan  2
Affiliations

PNPLA3 rs139051 is associated with phospholipid metabolite profile and hepatic inflammation in nonalcoholic fatty liver disease

Ji-Jun Luo et al. World J Clin Cases. .

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

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Conflict of interest statement

Conflict-of-interest statement: No potential conflicts of interest.

Figures

Figure 1
Figure 1
Dynamic distribution of quality control samples throughout the Ultra-high performance liquid chromatography-tandem mass spectrometry analysis. Colored bars indicate the quality control samples that are projected onto the first principal component with a range from -2 SD to +2 SD. QC: Quality control; SD: Standard deviation.
Figure 2
Figure 2
Nonalcoholic fatty liver disease patients carrying the A/A genotype at PNPLA3 rs139051 demonstrated low-grade lobular inflammation. Box plots indicate the difference in pathologic characteristics of steatosis (A); lobular inflammation (B); ballooning (C); and fibrosis (D) between nonalcoholic fatty liver disease patients with the A/A or A/G + G/G genotype at PNPLA3 rs139051. Results are presented as medians and Interquartile Range. aP < 0.05.
Figure 3
Figure 3
PNPLA3 rs2294918 showed no association with pathologic characteristics of nonalcoholic fatty liver disease patients. Box plots indicate the grade of steatosis (A); lobular inflammation (B); ballooning (C); and fibrosis (D) in nonalcoholic fatty liver disease patients with the G/G or A/A + A/G genotype at PNPLA3 rs2294918. Results are presented as medians and Interquartile Range.
See this image and copyright information in PMC

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