1. Expression of the Splicing Factor Gene SFRS10 is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis
- Author
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Joshua Schroeder, Sarah Crunkhorn, Andrew J. Morris, Josep C. Jimenez-Chillaron, Zhaiyi Zhang, Tiina Kuulasmaa, Hongmei Ren, Mary-Elizabeth Patti, Thomas Floss, Imad Nasser, Paula Itkonen, Zhenwen Zhao, Tanner Boes, Allison B. Goldfine, Markku Laakso, Wolfgang Wurst, Carles Lerin, Stefan Stamm, Peter J. Park, Pekka Miettinen, Furkan Burak, Farrell Dearie, Jussi Pihlajamäki, and Yan Xu
- Subjects
Male ,Very low-density lipoprotein ,metabolism [Muscle, Skeletal] ,Physiology ,RNA-binding protein ,Mice ,0302 clinical medicine ,genetics [Obesity] ,Genome-wide association ,Pre-messenger-RNA ,Adipose-tissue ,Insulln-resistance ,Skeletal-muscle ,Diabetic mice ,Lipin ,Metabolism ,Receptor ,Protein ,Gene expression ,blood [Lipids] ,genetics [RNA-Binding Proteins] ,genetics [Nerve Tissue Proteins] ,2. Zero hunger ,Regulation of gene expression ,0303 health sciences ,Mice, Inbred ICR ,Serine-Arginine Splicing Factors ,RNA-Binding Proteins ,Middle Aged ,Lipids ,TRA2B protein, human ,Liver ,030220 oncology & carcinogenesis ,Lipogenesis ,RNA splicing ,biosynthesis [Lipids] ,Female ,genetics [Phosphatidate Phosphatase] ,Adult ,medicine.medical_specialty ,genetics [Lipogenesis] ,RNA Splicing ,Phosphatidate Phosphatase ,Mice, Transgenic ,Nerve Tissue Proteins ,Biology ,Article ,biosynthesis [RNA-Binding Proteins] ,03 medical and health sciences ,Splicing factor ,Internal medicine ,ddc:570 ,Cell Line, Tumor ,metabolism [Obesity] ,medicine ,Animals ,Humans ,LPIN1 protein, human ,Obesity ,genetics [Lipids] ,biosynthesis [Nerve Tissue Proteins] ,Muscle, Skeletal ,Molecular Biology ,030304 developmental biology ,Aged ,Lipid metabolism ,Cell Biology ,Endocrinology ,Gene Expression Regulation ,metabolism [Liver] - 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.
- Published
- 2011