Variation in the PPARα gene is associated with altered function in vitro and plasma lipid concentrations in Type II diabetic subjects

Abstract

Risk of coronary artery disease (CAD) is determined by a combination of genetic and environmental factors which influence plasma lipid homeostasis, haemostasis and inflammation. Peroxisome proliferator activated receptor alpha (PPARa) is a ligand-inducible transcription factor [1] which regulates the expression of genes involved in fatty acid oxidation, extracellular lipid metabolism, haemostasis [2] and inflammation [3]. Ligands for PPARa include long chain fatty acids, eicosanoids, peroxisome proliferators, non-steroidal anti-inflammatory drugs and the fibrate class of hypolipidaemic drugs [4±6]. PPARa is highly expressed in tissues with a high rate of fatty Diabetologia (2000) Methods. The human PPARa gene was isolated and screened for variation by single strand conformation polymorphism analysis. Genotypes were determined for 129 Type II diabetic subjects and 2508 healthy men. The association with plasma lipid concentrations was examined. The function of the V162 variant was examined in co-transfection assays.Results. We identified two polymorphisms, one in intron 3 and a missense mutation, leucine 162 to valine, in the DNA binding domain. In Type II diabetic patients, V162 allele carriers had higher total cholesterol, HDL cholesterol and apoAI whereas intron 3 rare allele carriers had higher apoAI concentrations. By contrast, no effect was observed in healthy rare allele carriers. In vitro, the V162 variant showed greater transactivation of a reporter gene construct. Conclusion/interpretation. Naturally occurring variation alters PPARa function, influencing plasma lipid concentrations in Type II diabetic patients but not healthy people. This demonstrates that PPARa is a link between diabetes and dyslipidaemia, and so could influence the risk of coronary artery disease, the greatest cause of morbidity and mortality in Type II diabetes. [Diabetologia (2000) 43: 673±680]

Single Nucleotide Polymorphisms of the Peroxisome Proliferator–Activated Receptor-α Gene (PPARA) Influence the Conversion From Impaired Glucose Tolerance to Type 2 Diabetes

“…However, the L162V polymorphism has different effects on gene transcription depending on the concentration of ligand. In the presence of high concentrations, transcriptional activity of the G (162V) allele is higher compared with that of the C allele (8,20), whereas at low concentrations results are the opposite (20). In our study and a previous study (10) the presence of the G (162V) allele increased the risk of diabetes.…”

“…rs1800206 of PPARA is likely to be functional. Transcriptional studies have demonstrated that the C to G change in codon 162 (L162V) of exon 5 encodes a more active PPAR-␣ in vitro (8,20). However, the L162V polymorphism has different effects on gene transcription depending on the concentration of ligand.…”

Peroxisome Proliferator-activated Receptor α (PPARα) Agonist Treatment Reverses PPARα Dysfunction and Abnormalities in Hepatic Lipid Metabolism in Ethanol-fed Mice

“…Of these, the L162V variant showed decreased non-ligand-dependent transactivation activity and decreased sensitivity to low concentrations of ligand in tissue culture experiments (46). In human studies, it was reported to be associated with elevated plasma low density lipoprotein concentration and increased risk for atherosclerosis and ischemic heart disease (33,47,48). Our study suggests that carriers of this allele might be more susceptible to the toxic hepatic effects of ethanol.…”

Central role of PPARα-dependent hepatic lipid turnover in dietary steatohepatitis in mice

“…49 Furthermore, the L162V polymorphism in the human PPAR␣ gene that increases PPAR␣ activity has been associated with increased sensitivity of type II diabetic patients to the lipid-lowering effects of fibrates. 50 Until the role of PPAR␣ in humans and mode of fibrate action are discerned, it can be assumed that the effect of PPAR␣ activation in humans is less than in rodents, and that the dramatic effect of potent PPAR␣ activation in preventing steatohepatitis in this rodent model is unlikely to be replicated in humans with risk factors for NASH. However, a better understanding of whether the prevention of steatohepatitis by PPAR␣ agonists in this and other models is the direct consequence of depleted intrahepatic lipid, or results from enhanced degradation of lipid inflammatory mediators will be valuable in the design of effective therapeutic strategies for clinically relevant forms of steatohepatitis.…”