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PubMed · 16049017

Alternatively spliced lipin isoforms exhibit distinct expression pattern, subcellular localization, and role in adipogenesis.

Miklós Péterfy·Jack Phan·Karen Reue
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Abstract

We recently identified mutations in the Lpin1 (lipin) gene to be responsible for lipodystrophy in the fatty liver dystrophy (fld) mouse strain. Previous studies revealed that lipin plays a critical role in adipogenesis, explaining the adipose-deficient phenotype of the fld mouse. In the current study, we demonstrate that alternative mRNA splicing generates two lipin isoforms, lipin-alpha and lipin-beta, which are differentially expressed during adipocyte differentiation. Lipin-alpha expression peaks at day 2 of 3T3-L1 cell differentiation, after which its levels gradually decrease. In contrast, lipin-beta expression is transiently elevated at 10 h, followed by a drop to background levels at 20 h and a gradual increase between days 2 and 6 of differentiation. The two lipin isoforms also exhibit differences in subcellular localization. Lipin-alpha is predominantly nuclear, whereas lipin-beta is primarily located in the cytoplasm of 3T3-L1 adipocytes, suggesting distinct cellular functions. Using primary mouse embryonic fibroblasts expressing either lipin-alpha or lipin-beta, we demonstrate functional differences between the two isoforms. Whereas lipin-alpha is required for adipocyte differentiation, the predominant effect of lipin-beta expression is the induction of lipogenic genes. In vivo, overexpression of lipin-beta specifically in mature adipocytes leads to elevated expression of lipogenic genes and adipocyte hypertrophy, confirming a role of lipin-beta in the regulation of lipogenesis. In conclusion, our data suggest that the two lipin isoforms have distinct, but complementary, functions in adipogenesis, with lipin-alpha playing a primary role in differentiation and lipin-beta being predominantly involved in lipogenesis.

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3T3-L1 CellsAdipocytesAdipose TissueAlternative SplicingAnimalsBlotting, WesternCell DifferentiationCell LineCell NucleusCells, CulturedExonsFibroblastsInsulinIntronsLipid MetabolismMiceMice, Inbred C57BLMicroscopy, FluorescenceModels, GeneticOrganic ChemicalsPlasmidsProtein IsoformsRNA, MessengerRetroviridaeReverse Transcriptase Polymerase Chain ReactionTime FactorsTissue DistributionJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.

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Miklós Péterfy, Jack Phan, Karen Reue. 2005-07-27. Alternatively spliced lipin isoforms exhibit distinct expression pattern, subcellular localization, and role in adipogenesis.. https://doi.org/10.1074/jbc.m503885200

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