4.8 Article

Expression of the Splicing Factor Gene SFRS10 Is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis

Journal

CELL METABOLISM
Volume 14, Issue 2, Pages 208-218

Publisher

CELL PRESS
DOI: 10.1016/j.cmet.2011.06.007

Keywords

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Funding

  1. NIH [DK062948, DK060837, DK70648]
  2. General Clinical Research Center [M01 RR001032]
  3. Joslin Diabetes and Endocrinology Research Center [D36836]
  4. Lilly Foundation
  5. Graetz Fund
  6. Academy of Finland
  7. Finnish Diabetes Research Foundation
  8. Kuopio University Hospital [5167]
  9. European Union [LSHM-CT-2004-512013]
  10. EURASNET
  11. Sigrid Juselius Foundation
  12. Maud Kuistila Foundation
  13. Northern Savo Cultural Foundation
  14. Viipuri Tuberculosis Foundation
  15. American Heart Association
  16. [RO1GM50388]
  17. [P20RR021964]

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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 beta isoform of LPIN1. Importantly, LPIN1 beta-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.

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