人類LPIN1基因與肥胖、葡萄糖及脂肪代謝的相關性

Abstract

肥胖及其所導致的代謝症候群在近來的二十年逐漸成為公共衛生上重要的課題，其所帶來的醫療支出及死亡率的增加，使我們不得不重視此一疾病，然而肥胖的成因及其如何導致代謝症候群目前仍不清楚。利用3T3-L1此一preadipocyte cell line誘導為成熟脂肪細胞，並比較兩者一些基因表現量的變化，我們發現lipin mRNA的表現量會在第10小時被誘導而出現，但隨即迅速下降，接著PPAR

Adipose tissue plays a crucial role in the regulation of glucose homeostasis and lipid metabolism. Extreme increase or decrease in body mass index, seen in obesity and lipodystrophy, is associated with metabolic dysregulation. In the fatty liver dystrophy (fld) mouse, characterized by a loss of body fat and presence of fatty liver, hypertriglyceridemia and severe insulin resistance, a mutation in the Lpin1 gene has been identified. These studies demonstrated that lipin deficiency might impair adipocyte differentiation and cause lipodystrophy in mice. On the other hand, enhanced lipin expression in either mature adipose tissue or skeletal muscle promotes obesity in the tissue-specific transgenic mice. Although overexpression of lipin augments adiposity and accelerates diet-induced obesity in these mice, insulin sensitivity was found unaltered on a chow diet and even enhanced when feeding with high-fat diet. Due to the study results in mice are contradictory to our understanding that insulin sensitivity is usually decreased in humans with obesity, we decided to investigate the association of the human LPIN1 gene with obesity, glucose homeostasis and lipid metabolism. To assess lipin expression and its relation to clinical and metabolic variables of adiposity, glucose and lipid metabolism, we examined both the abdominal subcutaneous and omental depots total lipin mRNA levels in 98 obese individuals who were visited to accept gastric partition surgery, and compared the expression levels with BMI, glucose and insulin levels, and lipid profile. The LPIN1 expression levels in the subcutaneous depots were significantly correlated with the omental part expression levels (r = 0.76, p<0.0001). As age and sex may influence lipin expression levels, we matched age and sex and compared the different part of abdominal adipose tissue lipin expression levels. The expression levels in subcutaneous and omental depots showed no difference, but levels were higher in women as compared with men. A negative correlation was observed for both subcutaneous and omental LPIN1 mRNA levels with plasma glucose levels (r = -0.23, p = 0.02 in subcutaneous depot; r = -0.26, p = 0.01 in omental depot). Omental lipin expression levels correlated inversely with insulin sensitivity index as HOMA-IR. Our data indicate LPIN1 mRNA expression plays a role in glucose homeostasis associated with obesity. We hypothesized that sequence variants of LPIN1 gene might contribute to susceptibility of type 2 diabetes. Study subjects include 760 patients with type 2 diabetes and 760 normoglycemic controls. We genotyped 7 single nucleotide polymorphisms (SNPs) which spanned from the 5' upstream region to the 3' end of the LPIN1 gene. The correlation of each of the SNPs and their haplotypes with diabetes were analyzed with adjustment of covariates and permutation tests. No single variant was significantly associated with type 2 diabetes in our population. Haplotype analyses revealed a linkage disequilibrium (LD) block composed of 6 SNPs was located upstream of the gene. A rare haplotype (HapD) was significantly associated with risk to type 2 diabetes (OR= 2.03 [95% CI 1.93 - 2.14], p< 0.001). Our data suggest that the LPIN1 genetic polymorphism might not a major susceptibility gene in Taiwanese type 2 diabetes population.