title: Alternatively spliced lipin isoforms exhibit distinct expression pattern, subcellular localization, and role in adipogenesis.
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.
authors.affiliation: Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, California 90095, USA.
authors.forename: Miklós
authors.initials: M
authors.lastname: Péterfy
authors.forename: Jack
authors.initials: J
authors.lastname: Phan
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
mesh_terms: D041721:3T3-L1 Cells / Q000166:cytology; D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology; D017398:Alternative Splicing; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D005091:Exons; D005347:Fibroblasts / Q000166:cytology; D007328:Insulin / Q000378:metabolism; D007438:Introns; D050356:Lipid Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009930:Organic Chemicals / Q000737:chemistry / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D007328:Insulin; D009930:Organic Chemicals; D020033:Protein Isoforms; D012333:RNA, Messenger; C088310:lipine