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. Morris; Stefan Stamm; Allison B. Goldfine; Markku Laakso; Mary Elizabeth Patti

doi:10.1016/j.cmet.2011.06.007

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 journal › Article › peer-review

124 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 language	English
Pages (from-to)	208-218
Number of pages	11
Journal	Cell Metabolism
Volume	14
Issue number	2
DOIs	https://doi.org/10.1016/j.cmet.2011.06.007
State	Published - Aug 3 2011

Bibliographical note

Funding 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.

Funding

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.

Funders	Funder number
EURASNET
Northern Savo Cultural Foundation
Sigrid Juselius Foundation
Viipuri Tuberculosis Foundation	RO1GM50388, P20RR021964
National Institutes of Health (NIH)	M01 RR001032, DK060837, DK062948, D36836, DK70648
National Center for Research Resources	S10RR024598
American the American Heart Association
Joslin Diabetes Center
Maud Kuistilan Muistosäätiö
European Commission	EUGENE2 LSHM-CT-2004-512013
Academy of Finland
Kuopion Yliopistollinen Sairaala	5167
Diabetestutkimussäätiö
Fundación Lilly

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2011.06.007

Cite this

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

@article{bbd9882cccd14e34970ea0635d0400a6,

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.",

author = "Jussi Pihlajam{\"a}ki and Carles Lerin and Paula Itkonen and Tanner Boes and Thomas Floss and Joshua Schroeder and Farrell Dearie and Sarah Crunkhorn and Furkan Burak and Jimenez-Chillaron, {Josep C.} and Tiina Kuulasmaa and Pekka Miettinen and Park, {Peter J.} and Imad Nasser and Zhenwen Zhao and Zhaiyi Zhang and Yan Xu and Wolfgang Wurst and Hongmei Ren and Morris, {Andrew J.} and Stefan Stamm and Goldfine, {Allison B.} and Markku Laakso and Patti, {Mary Elizabeth}",

note = "Funding 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. ",

year = "2011",

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doi = "10.1016/j.cmet.2011.06.007",

language = "English",

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Pihlajamäki, J, Lerin, C, Itkonen, P, Boes, T, Floss, T, Schroeder, J, Dearie, F, Crunkhorn, S, Burak, F, Jimenez-Chillaron, JC, Kuulasmaa, T, Miettinen, P, Park, PJ, Nasser, I, Zhao, Z, Zhang, Z, Xu, Y, Wurst, W, Ren, H, Morris, AJ, Stamm, S, Goldfine, AB, Laakso, M & Patti, ME 2011, 'Expression of the splicing factor gene SFRS10 is reduced in human obesity and contributes to enhanced lipogenesis', Cell Metabolism, vol. 14, no. 2, pp. 208-218. https://doi.org/10.1016/j.cmet.2011.06.007

TY - JOUR

T1 - Expression of the splicing factor gene SFRS10 is reduced in human obesity and contributes to enhanced lipogenesis

AU - Pihlajamäki, Jussi

AU - Lerin, Carles

AU - Itkonen, Paula

AU - Boes, Tanner

AU - Floss, Thomas

AU - Schroeder, Joshua

AU - Dearie, Farrell

AU - Crunkhorn, Sarah

AU - Burak, Furkan

AU - Jimenez-Chillaron, Josep C.

AU - Kuulasmaa, Tiina

AU - Miettinen, Pekka

AU - Park, Peter J.

AU - Nasser, Imad

AU - Zhao, Zhenwen

AU - Zhang, Zhaiyi

AU - Xu, Yan

AU - Wurst, Wolfgang

AU - Ren, Hongmei

AU - Morris, Andrew J.

AU - Stamm, Stefan

AU - Goldfine, Allison B.

AU - Laakso, Markku

AU - Patti, Mary Elizabeth

N1 - Funding 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.

PY - 2011/8/3

Y1 - 2011/8/3

N2 - 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.

AB - 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.

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JO - Cell Metabolism

JF - Cell Metabolism

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ER -

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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