Cross-species analyses implicate Lipin 1 involvement in human glucose metabolism

Department of Dental Public Health, University of Helsinki, Helsinki, Uusimaa, Finland
Human Molecular Genetics (Impact Factor: 6.39). 03/2006; 15(3):377-86. DOI: 10.1093/hmg/ddi448
Source: PubMed


Recent studies in the mouse have demonstrated that variations in lipin expression levels in adipose tissue have marked effects on adipose tissue mass and insulin sensitivity. In the mouse, lipin deficiency prevents normal adipose tissue development, resulting in lipodystrophy and insulin resistance, whereas excess lipin levels promote fat accumulation and insulin sensitivity. Here, we investigated the effects of genetic variation in lipin levels on glucose homeostasis across species by analyzing lipin transcript levels in human and mouse adipose tissues. A strong negative correlation was observed between lipin mRNA levels and fasting glucose and insulin levels, as well as an indicator of insulin resistance (HOMA-IR), in both mice and humans. We subsequently analyzed the allelic diversity of the LPIN1 gene in dyslipidemic Finnish families, as well as in a case-control sample of obese (n = 477) and lean (n = 821) individuals. Alleles were defined by genotyping seven single nucleotide polymorphisms (SNPs) of the critical DNA region over the LPIN1 gene. Intragenic SNPs and corresponding allelic haplotypes exhibited associations with serum insulin levels and body mass index (P = 0.002-0.04). Both the expression levels in adipose tissue across species and genetic data in human study samples highlight the importance of lipin in glucose homeostasis and imply that allelic variants of this gene have significance in human metabolic traits.

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    • "In accordance with the reports from natural human population, in our experiment chicken hepatic Lpin1 gene mRNA expression level presented significantly negative correlation with abdominal adipose deposition (AFR; P , 0.01). It was reported that Lpin1 mRNA expression had a strong negative correlation with GLU and INS levels in mouse and human, TG levels in human (Suviolahti et al., 2006). Lpin1 "
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    ABSTRACT: Lpin1 was a gene with important effects on controlling lipid/energy metabolism in humans and mice. However, little was known about chicken Lpin1 gene. In the present study, two transcript isoforms of chicken Lpin1 were identified. Lpin1-α was predicted encoding one 902 amino acid protein, whereas Lpin1-δ was predicted encoding one 918 amino acid protein with an insertion of 48-bp fragment from intron 12 of chicken Lpin1-α, and a conservative element was found to be located in intron 12 of chicken Lpin1-α genomic sequence. Ten variants were identified from chicken Lpin1-α coding sequence, and two missense mutations were predicted to affect the protein function of Lpin1. Reverse transcription PCR (RT-PCR) analysis revealed that chicken total Lpin1, Lpin1-α and Lpin1-δ were expressed in all analyzed tissues, and presented clear tissue expression differences. Real-time quantitative RT-PCR revealed that 30% energy restriction significantly elevated the total Lpin1 mRNA expression level in hepatic (P < 0.01) and adipose (P < 0.01) tissues of birds. Chicken total Lpin1 gene mRNA expression level presented a significantly inverse correlation with some traits including abdominal fat rate (P < 0.01), serum high-density lipoprotein (P < 0.05) and total cholesterol (P < 0.05), which would make a foundation for the further study on chicken Lpin1 gene function.
    animal 07/2012; 6(12):1897-903. DOI:10.1017/S1751731112001358 · 1.84 Impact Factor
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    • "Furthermore, although a number of studies have evaluated the role of common variation in LPIN1 and metabolic quantitative phenotypes (12–14), the results have been inconsistent across studies and sometimes within the same study. For example, rs2716610 and a SNP in high linkage disequilibrium, rs2716609, were associated with BMI in a Finnish obesity case-control study and in the Quebec Family Study (12,14) but not in a German population-based cohort (the the MONItoring of trends and determinants in CArdiovascular disease [MONICA] study) (13). Moreover, LPIN1 haplotypes were strongly associated with traits underlying the metabolic syndrome in the MONICA study, but these haplotypes often had the opposite effect on the same traits in a replication cohort (13). "
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    ABSTRACT: Loss of lipin 1 activity causes lipodystrophy and insulin resistance in the fld mouse, and LPIN1 expression and common genetic variation were recently suggested to influence adiposity and insulin sensitivity in humans. We aimed to conduct a comprehensive association study to clarify the influence of common LPIN1 variation on adiposity and insulin sensitivity in U.K. populations and to examine the role of LPIN1 mutations in insulin resistance syndromes. Twenty-two single nucleotide polymorphisms tagging common LPIN1 variation were genotyped in Medical Research Council (MRC) Ely (n = 1,709) and Hertfordshire (n = 2,901) population-based cohorts. LPIN1 exons, exon/intron boundaries, and 3' untranslated region were sequenced in 158 patients with idiopathic severe insulin resistance (including 23 lipodystrophic patients) and 48 control subjects. We found no association between LPIN1 single nucleotide polymorphisms and fasting insulin but report a nominal association between rs13412852 and BMI (P = 0.042) in a meta-analysis of 8,504 samples from in-house and publicly available studies. Three rare nonsynonymous variants (A353T, R552K, and G582R) were detected in severely insulin-resistant patients. However, these did not cosegregate with disease in affected families, and Lipin1 protein expression and phosphorylation in patients with variants were indistinguishable from those in control subjects. Our data do not support a major effect of common LPIN1 variation on metabolic traits and suggest that mutations in LPIN1 are not a common cause of lipodystrophy in humans. The nominal associations with BMI and other metabolic traits in U.K. cohorts require replication in larger cohorts.
    Diabetes 07/2008; 57(9):2527-33. DOI:10.2337/db08-0422 · 8.10 Impact Factor
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    • "Regarding human obesity, very few reports on human LPIN1 gene expression have been performed, suggesting a positive association with insulin sensitivity [12] [13] [14] and a negative one with body mass index (BMI) [13] [14]. On the other hand, human immunodeficiency virus (HIV)-infected patients who developed lipodystrophy had lower LPIN1 messenger RNA (mRNA) levels than those without lipodystrophy , in line with findings in the fld animal model [15]. "
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    ABSTRACT: The aim of this study was to analyze LPIN1 adipose tissue gene expression levels in 3 clinical insulin-resistant conditions-obesity, type 2 diabetes mellitus, and human immunodeficiency virus (HIV)-associated lipodystrophy-and its relationship with adipogenic and inflammatory markers. Subcutaneous adipose tissue samples were obtained from 2 cohorts: 98 subjects with different degrees of adiposity and with or without the presence of type 2 diabetes mellitus and 37 HIV-infected patients. Real-time polymerase chain reaction was used to measure gene expression of LPIN1 and adipogenic (PPARgamma, SREBP1c) and inflammatory markers (IL6, TNFalpha, TNFR1, and TNFR2). LPIN1 messenger RNA expression levels were significantly lower in the obese group (P = .002), were similar in type 2 diabetes mellitus patients and control subjects (P = .211), and were significantly higher in HIV-infected patients (P < .001). LPIN1 messenger RNA levels positively correlated with insulin sensitivity in all subjects. Moreover, an inverse correlation with proinflammatory cytokines was observed.
    Metabolism 11/2007; 56(11):1518-26. DOI:10.1016/j.metabol.2007.06.019 · 3.89 Impact Factor
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