Abstract
Aims/hypothesisIn mammals, the evolutionary conserved family of Mg2+-dependent phosphatidate phosphatases (PAP1), involved in phospholipid and triacylglycerol synthesis, consists of lipin-1, lipin-2 and lipin-3. While mutations in the murine Lpin1 gene cause lipodystrophy and its knockdown in mouse 3T3-L1 cells impairs adipogenesis, deleterious mutations of human LPIN1 do not affect adipose tissue distribution. However, reduced LPIN1 and PAP1 activity has been described in participants with type 2 diabetes. We aimed to characterise the roles of all lipin family members in human adipose tissue and adipogenesis.MethodsThe expression of the lipin family was analysed in adipose tissue in a cross-sectional study. Moreover, the effects of lipin small interfering RNA (siRNA)-mediated depletion on in vitro human adipogenesis were assessed.ResultsAdipose tissue gene expression of the lipin family is altered in type 2 diabetes. Depletion of every lipin family member in a human Simpson–Golabi–Behmel syndrome (SGBS) pre-adipocyte cell line, alters expression levels of adipogenic transcription factors and lipid biosynthesis genes in early stages of differentiation. Lipin-1 knockdown alone causes a 95% depletion of PAP1 activity. Despite the reduced PAP1 activity and alterations in early adipogenesis, lipin-silenced cells differentiate and accumulate neutral lipids. Even combinatorial knockdown of lipins shows mild effects on triacylglycerol accumulation in mature adipocytes.Conclusions/interpretationOverall, our data support the hypothesis of alternative pathways for triacylglycerol synthesis in human adipocytes under conditions of repressed lipin expression. We propose that induction of alternative lipid phosphate phosphatases, along with the inhibition of lipid hydrolysis, contributes to the maintenance of triacylglycerol content to near normal levels.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-4018-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
Triacylglycerols (TAGs) are neutral lipids that act as the major energy storage molecules, repository for fatty acids, and phospholipid precursors [1]
Conclusions/interpretation Overall, our data support the hypothesis of alternative pathways for triacylglycerol synthesis in human adipocytes under conditions of repressed lipin expression
Adipose tissue expression levels of the lipin family is altered in type 2 diabetes To investigate the roles of lipin paralogues in adipose tissue, we started by examining their gene expression in paired abdominal subcutaneous (SAT) and visceral (VAT) adipose tissue biopsies
Summary
Triacylglycerols (TAGs) are neutral lipids that act as the major energy storage molecules, repository for fatty acids, and phospholipid precursors [1]. Nematodes and insects express one lipin, whereas mammals express three paralogues called lipin-1, -2 and -3 that exhibit distinct but overlapping expression in many mouse and human tissues [5]. Consistent with their key metabolic role, loss of lipin function disrupts TAG production, membrane organisation and phospholipid synthesis in several model organisms [7]. Besides their enzymatic functions, lipins regulate transcription [8,9,10,11,12,13]. Lipin-1 transcriptional co-regulation of the peroxisome proliferator activated receptor (PPAR)A/PPAR coactivator 1α axis modulates fatty acid oxidation (FAO) in liver [9]
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