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.
|Number of pages||11|
|State||Published - Aug 3 2011|
Bibliographical noteFunding Information:
We gratefully acknowledge support from NIH DK062948 (M.E.P.), DK060837 (M.E.P. and A.B.G.), and DK70648 (A.B.G.); M01 RR001032 (General Clinical Research Center), D36836 (Joslin Diabetes and Endocrinology Research Center), Lilly Foundation (M.E.P.), Graetz Fund (M.E.P.), Academy of Finland (M.L. and J.P.), Finnish Diabetes Research Foundation (J.P. and M.L.), EVO Fund of Kuopio University Hospital (5167, M.L.), European Union (EUGENE2 LSHM-CT-2004-512013, M.L.), and EURASNET (S.S.). J.P. also received support from Sigrid Juselius Foundation, Maud Kuistila Foundation, Northern Savo Cultural Foundation, and Viipuri Tuberculosis Foundation. A.M. is supported by RO1GM50388 and P20RR021964. H.R. is the recipient of an American Heart Association postdoctoral fellowship. We thank Amit Khanna for technical help with the minigene construction and EURASNET (S.S.) for funding. We appreciate the assistance of Chris Burge and Xinshu Xiao, Massachusetts Institute of Technology, with computational identification of splicing targets. We also thank Joyclyn Yee and Martha Vokes for assistance with microarray analysis.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology