title: Expression of the splicing factor gene SFRS10 is reduced in human obesity and contributes to enhanced lipogenesis.
abstract: Alternative mRNA splicing provides transcript diversity and may contribute to human disease. We demonstrate that expression of several genes regulating RNA processing is decreased in both liver and skeletal muscle of obese humans. We evaluated a representative splicing factor, SFRS10, downregulated in both obese human liver and muscle and in high-fat-fed mice, and determined metabolic impact of reduced expression. SFRS10-specific siRNA induces lipogenesis and lipid accumulation in hepatocytes. Moreover, Sfrs10 heterozygous mice have increased hepatic lipogenic gene expression, VLDL secretion, and plasma triglycerides. We demonstrate that LPIN1, a key regulator of lipid metabolism, is a splicing target of SFRS10; reduced SFRS10 favors the lipogenic β isoform of LPIN1. Importantly, LPIN1β-specific siRNA abolished lipogenic effects of decreased SFRS10 expression. Together, our results indicate that reduced expression of SFRS10, as observed in tissues from obese humans, alters LPIN1 splicing, induces lipogenesis, and therefore contributes to metabolic phenotypes associated with obesity.
authors.affiliation: Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Jussi
authors.initials: J
authors.lastname: Pihlajamäki
authors.forename: Carles
authors.initials: C
authors.lastname: Lerin
authors.forename: Paula
authors.initials: P
authors.lastname: Itkonen
authors.forename: Tanner
authors.initials: T
authors.lastname: Boes
authors.forename: Thomas
authors.initials: T
authors.lastname: Floss
authors.forename: Joshua
authors.initials: J
authors.lastname: Schroeder
authors.forename: Farrell
authors.initials: F
authors.lastname: Dearie
authors.forename: Sarah
authors.initials: S
authors.lastname: Crunkhorn
authors.forename: Furkan
authors.initials: F
authors.lastname: Burak
authors.forename: Josep C
authors.initials: JC
authors.lastname: Jimenez-Chillaron
authors.forename: Tiina
authors.initials: T
authors.lastname: Kuulasmaa
authors.forename: Pekka
authors.initials: P
authors.lastname: Miettinen
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Park
authors.forename: Imad
authors.initials: I
authors.lastname: Nasser
authors.forename: Zhenwen
authors.initials: Z
authors.lastname: Zhao
authors.forename: Zhaiyi
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Hongmei
authors.initials: H
authors.lastname: Ren
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.forename: Stefan
authors.initials: S
authors.lastname: Stamm
authors.forename: Allison B
authors.initials: AB
authors.lastname: Goldfine
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Mary Elizabeth
authors.initials: ME
authors.lastname: Patti
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008055:Lipids / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D050155:Lipogenesis / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010711:Phosphatidate Phosphatase / Q000235:genetics*; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D000068103:Serine-Arginine Splicing Factors
chemical_list: D008055:Lipids; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; C097083:TRA2B protein, human; D000068103:Serine-Arginine Splicing Factors; C485999:LPIN1 protein, human; D010711:Phosphatidate Phosphatase