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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    • "Nevertheless, single nucleotide polymorphisms in LPIN1, or specific haplotypes composed of several such polymorphisms, are significantly associated with body mass index, insulin sensitivity, obesity, and other metabolic traits in several ethnic groups (Suviolahti et al., 2006; Loos et al., 2007; Fawcett et al., 2008; Wiedmann et al., 2008; Chang et al., 2010; Zhang et al., 2013). Moreover, a correlation between metabolic phenotypes and LPIN1 mRNA abundance in adipose tissue has been consistently observed (Suviolahti et al., 2006; Chang et al., 2010). The mechanism that drives rhabdomyolysis in LPIN1-deficient mice was recently established to be impaired autophagy of damaged mitochondria (Zhang et al., 2014). "
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    ABSTRACT: Recessive mutations in LPIN1, which encodes a phosphatidate phosphatase enzyme, are a frequent cause of severe rhabdomyolysis in childhood. Hence, we sequenced the 19 coding exons of the gene in eight patients with recurrent hereditary myoglobinuria from four unrelated families in Jordan. The long-term goal is to facilitate molecular genetic diagnosis without the need for invasive procedures such as muscle biopsies. Three different mutations were detected, including the novel missense mutation c.2395G>C (Gly799Arg), which was found in two families. The two other mutations, c.2174G>A (Arg725His) and c.1162C>T (Arg388X), have been previously identified, and were found to cosegregate with the disease phenotype in the other two families. Intriguingly, patients homozygous for Arg725His were also homozygous for the c.1828C>T (Pro610Ser) polymorphism, and were exercise-intolerant between myoglobinuria episodes. Notably, patients homozygous for Arg388X were also homozygous for the c.2250G>C silent variant (Gly750Gly). Taken together, the data provide family-based evidence linking hereditary myoglobinuria to pathogenic variations in the C-terminal lipin domain of the enzyme. This finding highlights the functional significance of this domain in the absence of structural information. This is the first analysis of LPIN1 in myoglobinuria patients of Jordanian origin, and the fourth such analysis worldwide.
    Full-text · Article · Feb 2016 · Meta Gene
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    • "Lipin 1-deficient mice exhibit insulin resistance and elevated insulin levels, whereas over-expression in adipose tissue increases insulin sensitivity (Phan and Reue, 2005; Reue et al., 2000). Similarly, in humans, lipin 1 levels in adipose tissue are inversely correlated with glucose and insulin levels as well as insulin resistance (Suviolahti et al., 2006; Yao-Borengasser et al., 2006). While these data indicate that adipose tissue expression of lipin 1 is an important determinant of insulin sensitivity, the underlying mechanism remains poorly understood. "
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    ABSTRACT: Lipin proteins have key functions in lipid metabolism, acting as both phosphatidate phosphatases (PAPs) and nuclear regulators of gene expression. We show that the insulin and TORC1 pathways independently control functions of Drosophila dLipin. Reduced signaling through the insulin receptor strongly enhances defects caused by dLipin deficiency in fat body development, whereas reduced signaling through TORC1 leads to translocation of dLipin into the nucleus. Reduced expression of dLipin results in decreased signaling through the insulin receptor-controlled PI3K/Akt pathway and increased hemolymph sugar levels. Consistent with this, downregulation of dLipin in fat body cell clones causes a strong growth defect. The PAP, but not the nuclear activity of dLipin is required for normal insulin pathway activity. Reduction of other enzymes of the glycerol-3 phosphate pathway similarly affects insulin pathway activity, suggesting an effect mediated by one or more metabolites associated with the pathway. Together, our data show that dLipin is subject to intricate control by the insulin and TORC1 pathways and that the cellular status of dLipin impacts how fat body cells respond to signals relayed through the PI3K/Akt pathway.
    Full-text · Article · Oct 2015 · Journal of Cell Science
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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.
    Preview · Article · Jul 2012 · animal
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