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

Abstract

for the STOP-NIDDM Study Group* Peroxisome proliferator-activated receptor (PPAR) ␣, a transcription factor of the nuclear receptor superfamily, regulates fatty acid oxidation. We evaluated the association of single nucleotide polymorphisms (SNPs) of the PPAR-␣ gene (PPARA) with the conversion from impaired glucose tolerance to type 2 diabetes in 767 subjects of the STOP-NIDDM trial in order to investigate the effect of acarbose in comparison with placebo on the prevention of diabetes. In the placebo group, the G (162V) allele of rs1800206 increased the risk for diabetes by 1.9-fold (95% CI 1.05-3.58) and was associated with elevated levels of plasma glucose and insulin. The effect of this allele on the risk of diabetes in the placebo group was enhanced by the simultaneous presence of the risk alleles of the PPAR-␥2, PPAR-␥ coactivator 1␣, and hepatic nuclear factor 4␣ genes (odds ratios 2.2, 2.5, and 3.4, respectively). In the acarbose group, subjects carrying the minor G allele of rs4253776 and the CC genotype of rs4253778 of PPARA had a 1.7-and 2.7-fold increased risk for diabetes. Our data indicate that SNPs of PPARA increase the risk of type 2 diabetes alone and in combination with the SNPs of other genes acting closely with PPAR-␣. Diabetes

Associations between Lifestyle-Related Diseases and Transporters Involved in Intestinal Absorption and Biliary Excretion of Cholesterol

“…Regarding the regulatory mechanism of NPC1L1 expression, we demonstrated that, in addition to SREBP2, several transcriptional factors such as hepatocyte nuclear factor 4α (HNF4α/NR2A1), peroxisome proliferator-activated receptor α (PPARα/NR1C1), and PPARγ coactivator 1α (PGC1α) positively regulate the mRNA expression of NPC1L1. 15,49) Taken together with facts that both HNF4α and PPARα are involved in the pathogenesis of diabetes [50][51][52] and that intestinal expression of PGC1α is increased under diabetic conditions, 53) our findings indicate that these transcriptional factors may play important roles in the regulation of NPC1L1 expression under diabetic conditions and at least partly account for clinical associations between progressions of T2DM and other cholesterol-related diseases such as dyslipidemia and NAFLD/ NASH. 54,55) …”

Human NPC1L1 Expression is Positively Regulated by PPARα

“…Additionally, PGC1α is suggested to have stimulatory effects on the SREBP2/HNF4α-and PPARα/RXRα-mediated transactivation of the human NPC1L1 promoter. Taken together with the involvement of HNF4α, PPARα and PGC1α in the pathogenesis of diabetes (20,21,27), these findings may provide new insights into the close relationship of glucose, fatty acids and cholesterol homeostasis.…”

“…6). Because HNF4α and PPARα are also involved in the pathogenesis of diabetes (20,21,27), it is possible that these factors play important roles in the regulation of NPC1L1 expression under (patho)physiological conditions.…”

“…PPARα recognizes fatty acids as a physiological ligand (19), and clinical studies have shown that genetic variation in this receptor is involved in the risk and progression of diabetes (20,21). Together with the profound relationship between fatty acids and cholesterol in lipid homeostasis and the increased expression of NPC1L1 in diabetic patients (22,23), we hypothesized and characterized in the present study that PPARα and its major cofactor, PPARγ coactivator 1α (PGC1α), contribute to the transcriptional regulation of human NPC1L1.…”

Efficacy of peroxisome proliferator-activated receptor agonists in diabetes and coronary artery disease

“…Although clinical studies did not reveal any effect of PPARα ligands on glucose parameters in patients with T2DM, PPARα ligands have the intriguing potential to prevent the progression from prediabetes to T2DM as suggested by post hoc analysis of the Bezafi brate Infarction Protection (BIP) study [13]. Moreover, PPARα gene variations have been reported to associate with the onset of and progression to T2DM in humans [14,15].…”