Expression of the splicing factor gene SFRS10 is reduced in human obesity and contributes to enhanced lipogenesis

Jussi Pihlajamäki, Carles Lerin, Paula Itkonen, Tanner Boes, Thomas Floss, Joshua Schroeder, Farrell Dearie, Sarah Crunkhorn, Furkan Burak, Josep C. Jimenez-Chillaron, Tiina Kuulasmaa, Pekka Miettinen, Peter J. Park, Imad Nasser, Zhenwen Zhao, Zhaiyi Zhang, Yan Xu, Wolfgang Wurst, Hongmei Ren, Andrew J. MorrisStefan Stamm, Allison B. Goldfine, Markku Laakso, Mary Elizabeth Patti

Research output: Contribution to journalArticle

72 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)208-218
Number of pages11
JournalCell Metabolism
Volume14
Issue number2
DOIs
StatePublished - Aug 3 2011

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Pihlajamäki, J., Lerin, C., Itkonen, P., Boes, T., Floss, T., Schroeder, J., Dearie, F., Crunkhorn, S., Burak, F., Jimenez-Chillaron, J. C., Kuulasmaa, T., Miettinen, P., Park, P. J., Nasser, I., Zhao, Z., Zhang, Z., Xu, Y., Wurst, W., Ren, H., ... Patti, M. E. (2011). Expression of the splicing factor gene SFRS10 is reduced in human obesity and contributes to enhanced lipogenesis. Cell Metabolism, 14(2), 208-218. https://doi.org/10.1016/j.cmet.2011.06.007