Phospholipid Biosynthesis Genes and Susceptibility to Obesity: Analysis of Expression and Polymorphisms

Neeraj K Sharma,Ashis K Mondal,Swapan K Das,Kurt A Langberg,Struan Frederick Airth Grant

doi:10.1371/journal.pone.0065303

Neeraj K Sharma, Ashis K Mondal + Show 3 more

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https://doi.org/10.1371/journal.pone.0065303

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Journal: PloS one	Publication Date: May 28, 2013
Citations: 40	License type: CC BY 4.0

Affiliation: Wake Forest University

Abstract

Recent studies have identified links between phospholipid composition and altered cellular functions in animal models of obesity, but the involvement of phospholipid biosynthesis genes in human obesity are not well understood. We analyzed the transcript of four phospholipid biosynthesis genes in adipose and muscle from 170 subjects. We examined publicly available genome-wide association data from the GIANT and MAGIC cohorts to investigate the association of SNPs in these genes with obesity and glucose homeostasis traits, respectively. Trait-associated SNPs were genotyped to evaluate their roles in regulating expression in adipose. In adipose tissue, expression of PEMT, PCYT1A, and PTDSS2 were positively correlated and PCYT2 was negatively correlated with percent fat mass and body mass index (BMI). Among the polymorphisms in these genes, SNP rs4646404 in PEMT showed the strongest association (p = 3.07E-06) with waist-to-hip ratio (WHR) adjusted for BMI. The WHR-associated intronic SNP rs4646343 in the PEMT gene showed the strongest association with its expression in adipose. Allele “C” of this SNP was associated with higher WHR (p = 2.47E-05) and with higher expression (p = 4.10E-04). Our study shows that the expression of PEMT gene is high in obese insulin-resistant subjects. Intronic cis-regulatory polymorphisms may increase the genetic risk of obesity by modulating PEMT expression.

Highlights

Endoplasmic reticulum (ER) is the major site of protein and lipid biosynthesis in cells [1]
Expression of phospholipid remodeling genes in adipose tissue is correlated with adiposity Expression of PCYT1A (r = 0.36, p = 1.0961025), phosphatidylethanolamine N-methyltransferase (PEMT) (r = 0.46, p = 9.5761029) and phosphatidylserine synthase 2 (PTDSS2) (r = 0.29, p = 4.7261024) in adipose showed significant positive correlations, while phosphate cytidylyltransferase 2 (PCYT2) (r = 20.30, p = 4.1561024) was negatively correlated with percent of fat mass (PFAT) and body mass index (BMI) in 142 non-diabetic subjects (Table 2)
Further examination in adipose tissue fractions from a subset of 40 non-diabetic subjects indicated that the correlation of PEMT with adiposity was conferred by adipocytes (r = 0.38, p = 0.02) but not by cells in the stromal vascular fraction (Table 2)

Summary

Introduction

Endoplasmic reticulum (ER) is the major site of protein and lipid biosynthesis in cells [1]. A recent proteomic analysis revealed a shift in ER function from protein to lipid synthesis and metabolism in obese mice compared to lean animals. Further analysis revealed an increase in the phosphatidylcholine/phosphatidylethanolamine (PC/PE) ratio due to a shift in de novo lipogenesis in the obese ER lipidome [2]. This derangement in the composition of phospholipids was caused by transcriptional modulation of genes involved in phospholipid biosynthesis and remodeling [2]. An increased PC/PE ratio in the hepatic ER membrane perturbed ER calcium retention and homeostasis (by modulating sarco-endoplasmic reticulum calcium ATPAse – SERCA activity) leading to compromised protein folding and ER stress [2]. The molecular and genetic regulatory mechanisms that lead to activation of chronic ER stress in obesity are not well understood

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