Perilipin 2 (PLIN2) is the most abundant lipid droplet (LD)-associated protein in nonadipose tissue, and its expression correlates with intracellular lipid accumulation. Here we identified a missense polymorphism, Ser251Pro, that has major effect on protein structure and function, along with an influence on human plasma triglyceride concentration. The evolutionarily conserved Ser251Pro polymorphism was identified with the ClustalW program. Structure modeling using 3D-JigSaw and the Chimera package revealed that the Pro251 allele disrupts a predicted α-helix in PLIN2. Analyses of macrophages from individuals carrying Ser251Pro variants and human embryonic kidney 293 (HEK293) cells stably transfected with either of the alleles demonstrated that the Pro251 variant causes increased lipid accumulation and decreased lipolysis. Analysis of LD size distribution in stably transfected cells showed that the minor Pro251 allele resulted in an increased number of small LDs per cell and increased perilipin 3 protein expression levels as compared with cells carrying the major Ser251 allele. Genotyping of 2113 individuals indicated that the Pro251 variant is associated with decreased plasma triglyceride and very low-density lipoprotein concentrations. Altogether, these data provide the first evidence of a polymorphism in PLIN2 that affects PLIN2 function and may influence the development of metabolic and cardiovascular diseases.

Aims: We investigated whether polymorphisms in candidate genes involved in lipid metabolism and type 2 diabetes are related to liver fat content. Methods: Liver fat content was measured using proton magnetic resonance spectroscopy ( 1 H-MRS) in 302 Finns, in whom single nucleotide polymorphisms (SNPs) in acyl-CoA synthetase long-chain family member 4 (ACSL4), adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2), and the three peroxisome proliferator-activated receptors (PPARA, PPARD, and PPARG) were analyzed. To validate our findings, SNPs significantly associated with liver fat content were studied in two independent cohorts and related to surrogate markers of liver fat content. Results: In the Finnish subjects, polymorphisms in ACSL4 (rs7887981), ADIPOR2 (rs767870), and PPARG (rs3856806) were significantly associated with liver fat content measured with 1 H-MRS after adjusting for age, gender, and BMI. Anthropometric and circulating parameters were comparable between genotypes. In the first validation cohort of w 600 Swedish men, ACSL4 rs7887981 was related to fasting insulin and triglyceride concentrations, and ADIPOR2 rs767870 to serum g glutamyltransferase concentrations after adjusting for BMI. The SNP in PPARG (rs3856806) was not significantly associated with any relevant metabolic parameter in this cohort. In the second validation cohort of w3000 subjects from Western Finland, ADIPOR2 rs767870, but not ACSL4 rs7887981 was related to fasting triglyceride concentrations. Conclusions: Genetic variation, particularly in the ADIPOR2 gene, contributes to variation in hepatic fat accumulation in humans.

The microsomal triglyceride transfer protein (MTTP) is essential for formation of apolipoprotein B (apoB)-containing lipoproteins. The liver and the intestine have the highest tissue expression of MTTP and secrete triacylglycerol (TAG)-rich VLDLs and chylomicrons, respectively ( 1 ). MTTP is also expressed in other cells such as cardiomyocytes ( 2 ) and macrophages ( 3 ). The heart secretes apoB100-containing lipoproteins and it has been proposed that cardiac lipoprotein secretion protects the heart against accumulation of lipids that are toxic to the myocardium ( 4 ). This theory is supported by the fi nding that MTTP exAbstract Promoter polymorphisms in microsomal triglyceride transfer protein ( MTTP ) have been associated with decreased plasma lipids but an increased risk for ischemic heart disease (IHD), indicating that MTTP infl uences the susceptibility for IHD independent of plasma lipids. The objective of this study was to characterize the functional promoter polymorphism in MTTP predisposing to IHD and its underlying mechanism. Use of pyrosequencing technology revealed that presence of the minor alleles of the promoter polymorphisms -493G>T and -164T>C result in lower transcription of MTTP in vivo in the heart, liver, and macrophages. In vitro experiments indicated that the minor -164C allele mediates the lower gene expression and that C/ EBP binds to the polymorphic region in an allele-specifi c manner. Furthermore, homozygous carriers of the -164C were found to have increased risk for IHD as shown in a case-control study including a total of 544 IHD patients and 544 healthy control subjects. We concluded that carriers of the minor -164C allele have lower expression of MTTP in the heart, mediated at least partly by the transcription factor CCAAT/enhancer binding protein, and that reduced concentration of MTTP in the myocardium may contribute to IHD upon ischemic damage. -Aminoff, A

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