Abstract
Adiponutrin (patatin-like phospholipase domain-containing 3; PNPLA3), encoded in humans by the PNPLA3 gene, is a protein associated with lipid droplet and endoplasmic reticulum membranes, where it is apparently involved in fatty acid redistribution between triglycerides and phospholipids. A common polymorphism of PNPLA3 (I148M, rs738409), linked to increased PNPLA3 presence on lipid droplets, is a strong genetic determinant of non-alcoholic fatty liver disease (NAFLD) and of its progression. P-glycoprotein (Pgp, MDR1—multidrug resistance protein 1, ABCB1—ATP-binding cassette sub-family B member 1), encoded by the ABCB1 gene, is another membrane protein implicated in lipid homeostasis and steatosis. In the past, common ABCB1 polymorphisms have been associated with the distribution of serum lipids but not with fatty acids (FA) profiles. Similarly, data on the effect of PNPLA3 I148M polymorphism on blood FAs are scarce. In this study, a gas chromatography-flame ionization detection (GC-FID) method was optimized, allowing us to analyze twenty FAs (C14: 0, C15: 0, C15: 1, C16: 0, C16: 1, C17: 0, C17: 1, C18: 0, C18: 1cis, C18: 2cis, C20: 0, C20: 1n9, C20: 2, C20: 3n6, C20: 4n6, C20: 5, C23: 0, C24: 0, C24: 1 and C22: 6) in whole blood, based on the indirect determination of the fatty acids methyl esters (FAMES), in 62 hyperlipidemic patients and 42 normolipidemic controls. FA concentrations were then compared between the different genotypes of the rs738409 and rs2032582 (ABCB1 G2677T) polymorphisms, within and between the hyperlipidemic and normolipidemic groups. The rs738409 polymorphism appears to exert a significant effect on the distribution of blood fatty acids, in a lipidemic and fatty acid saturation state-depending manner. The effect of rs2032582 was less pronounced, but the polymorphism did appear to affect the relative distribution of blood fatty acids between hyperlipidemic patients and normolipidemic controls.
Highlights
Patatin-like phospholipase domain-containing 3 (PNPLA3), known as adiponutrin (ADPN) or calcium independent phospholipase A2ε, is a protein tightly associated with lipid droplet and endoplasmic reticulum membranes; it displays in vitro triglyceride (TG) hydrolase as well as retinyl hydrolase activities and a modest acyltransferase activity was reported in some studies [1]
The I148M change confers to the protein resistance to proteasomal degradation [4] and reduction of the hydrolase activities [5], leading to accumulation of mainly monounsaturated fatty acids in the lipid droplet and decreased secretion of very low density lipoprotein (VLDL) from the hepatocyte; at the same time the transfer of polyunsaturated fatty acids (PUFAs) from TGs to PLs appears to be enhanced in presence of the mutant protein in genetically modified mice [2] albeit, paradoxically, the opposite was observed in the human liver [6]
Our findings indicate that (i) the PNPLA3 I148M polymorphism is associated with the total blood FA concentration in a group-dependent fashion, with GG (MM) genotypes displaying clearly higher concentrations compared to the PNPLA3 148C (I) carriers, but only in the hyperlipidemic group, (ii) a strong trend for allele-dosage effect of the ABCB1
Summary
Patatin-like phospholipase domain-containing 3 (PNPLA3), known as adiponutrin (ADPN) or calcium independent phospholipase A2ε (iPLA2ε), is a protein tightly associated with lipid droplet and endoplasmic reticulum membranes; it displays in vitro triglyceride (TG) hydrolase as well as retinyl hydrolase activities and a modest acyltransferase activity was reported in some studies [1]. The I148M change confers to the protein resistance to proteasomal degradation [4] and reduction of the hydrolase activities [5], leading to accumulation of mainly monounsaturated fatty acids in the lipid droplet and decreased secretion of very low density lipoprotein (VLDL) from the hepatocyte; at the same time the transfer of polyunsaturated fatty acids (PUFAs) from TGs to PLs appears to be enhanced in presence of the mutant protein in genetically modified mice [2] albeit, paradoxically, the opposite was observed in the human liver [6]. While the effect of PNPLA3 I148M on hepatic lipid homeostasis and NAFLD is being thoroughly studied, its association with serum lipids is much less examined; a small number of reports have suggested association of the PNPLA3 148M allele with decreased serum TG levels, in individuals with impaired glucose regulation [7], in the obese [8], and in patients with gallstones [9]. Information concerning the relative prevalence of individual fatty acids (FAs) in
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