Microbiota-Dependent Hepatic Lipogenesis Mediated by Stearoyl CoA Desaturase 1 (SCD1) Promotes Metabolic Syndrome in TLR5-Deficient Mice

Vishal Singh; Benoit Chassaing; Limin Zhang; Beng San Yeoh; Xia Xiao; Manish Kumar; Mark T. Baker; Jingwei Cai; Rachel Walker; Kamil Borkowski; Kevin J. Harvatine; Nagendra Singh; Gregory C. Shearer; James M. Ntambi; Bina Joe; Andrew D. Patterson; Andrew T. Gewirtz; Matam Vijay-Kumar

doi:10.1016/j.cmet.2015.09.028

Microbiota-Dependent Hepatic Lipogenesis Mediated by Stearoyl CoA Desaturase 1 (SCD1) Promotes Metabolic Syndrome in TLR5-Deficient Mice

Vishal Singh, Benoit Chassaing, Limin Zhang, Beng San Yeoh, Xia Xiao, Manish Kumar, Mark T. Baker, Jingwei Cai, Rachel Walker, Kamil Borkowski, Kevin J. Harvatine, Nagendra Singh, Gregory C. Shearer, James M. Ntambi, Bina Joe, Andrew D. Patterson, Andrew T. Gewirtz, Matam Vijay-Kumar

Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

79 Scopus citations

Abstract

The gut microbiota plays a key role in host metabolism. Toll-like receptor 5 (TLR5), a flagellin receptor, is required for gut microbiota homeostasis. Accordingly, TLR5-deficient (T5KO) mice are prone to develop microbiota-dependent metabolic syndrome. Here we observed that T5KO mice display elevated neutral lipids with a compositional increase of oleate [C18:1 (n9)] relative to wild-type littermates. Increased oleate contribution to hepatic lipids and liver SCD1 expression were both microbiota dependent. Analysis of short-chain fatty acids (SCFAs) and ¹³C-acetate label incorporation revealed elevated SCFA in ceca and hepatic portal blood and increased liver de novo lipogenesis in T5KO mice. Dietary SCFAs further aggravated metabolic syndrome in T5KO mice. Deletion of hepatic SCD1 not only prevented hepatic neutral lipid oleate enrichment but also ameliorated metabolic syndrome in T5KO mice. Collectively, these results underscore the key role of the gut microbiota-liver axis in the pathogenesis of metabolic diseases.

Original language	English (US)
Pages (from-to)	983-996
Number of pages	14
Journal	Cell Metabolism
Volume	22
Issue number	6
DOIs	https://doi.org/10.1016/j.cmet.2015.09.028
State	Published - 2015

Keywords

Toll-like receptor 5
gut bacteria
hepatic neutral lipids
low-grade inflammation
metabolic diseases
monounsaturated fatty acids
short-chain fatty acids

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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Singh, V., Chassaing, B., Zhang, L., San Yeoh, B., Xiao, X., Kumar, M., Baker, M. T., Cai, J., Walker, R., Borkowski, K., Harvatine, K. J., Singh, N., Shearer, G. C., Ntambi, J. M., Joe, B., Patterson, A. D., Gewirtz, A. T., & Vijay-Kumar, M. (2015). Microbiota-Dependent Hepatic Lipogenesis Mediated by Stearoyl CoA Desaturase 1 (SCD1) Promotes Metabolic Syndrome in TLR5-Deficient Mice. Cell Metabolism, 22(6), 983-996. https://doi.org/10.1016/j.cmet.2015.09.028

Microbiota-Dependent Hepatic Lipogenesis Mediated by Stearoyl CoA Desaturase 1 (SCD1) Promotes Metabolic Syndrome in TLR5-Deficient Mice. / Singh, Vishal; Chassaing, Benoit; Zhang, Limin; San Yeoh, Beng; Xiao, Xia; Kumar, Manish; Baker, Mark T.; Cai, Jingwei; Walker, Rachel; Borkowski, Kamil; Harvatine, Kevin J.; Singh, Nagendra; Shearer, Gregory C.; Ntambi, James M.; Joe, Bina; Patterson, Andrew D.; Gewirtz, Andrew T.; Vijay-Kumar, Matam.

In: Cell Metabolism, Vol. 22, No. 6, 2015, p. 983-996.

Research output: Contribution to journal › Article › peer-review

Singh, V, Chassaing, B, Zhang, L, San Yeoh, B, Xiao, X, Kumar, M, Baker, MT, Cai, J, Walker, R, Borkowski, K, Harvatine, KJ, Singh, N, Shearer, GC, Ntambi, JM, Joe, B, Patterson, AD, Gewirtz, AT & Vijay-Kumar, M 2015, 'Microbiota-Dependent Hepatic Lipogenesis Mediated by Stearoyl CoA Desaturase 1 (SCD1) Promotes Metabolic Syndrome in TLR5-Deficient Mice', Cell Metabolism, vol. 22, no. 6, pp. 983-996. https://doi.org/10.1016/j.cmet.2015.09.028

Singh, Vishal ; Chassaing, Benoit ; Zhang, Limin ; San Yeoh, Beng ; Xiao, Xia ; Kumar, Manish ; Baker, Mark T. ; Cai, Jingwei ; Walker, Rachel ; Borkowski, Kamil ; Harvatine, Kevin J. ; Singh, Nagendra ; Shearer, Gregory C. ; Ntambi, James M. ; Joe, Bina ; Patterson, Andrew D. ; Gewirtz, Andrew T. ; Vijay-Kumar, Matam. / Microbiota-Dependent Hepatic Lipogenesis Mediated by Stearoyl CoA Desaturase 1 (SCD1) Promotes Metabolic Syndrome in TLR5-Deficient Mice. In: Cell Metabolism. 2015 ; Vol. 22, No. 6. pp. 983-996.

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title = "Microbiota-Dependent Hepatic Lipogenesis Mediated by Stearoyl CoA Desaturase 1 (SCD1) Promotes Metabolic Syndrome in TLR5-Deficient Mice",

abstract = "The gut microbiota plays a key role in host metabolism. Toll-like receptor 5 (TLR5), a flagellin receptor, is required for gut microbiota homeostasis. Accordingly, TLR5-deficient (T5KO) mice are prone to develop microbiota-dependent metabolic syndrome. Here we observed that T5KO mice display elevated neutral lipids with a compositional increase of oleate [C18:1 (n9)] relative to wild-type littermates. Increased oleate contribution to hepatic lipids and liver SCD1 expression were both microbiota dependent. Analysis of short-chain fatty acids (SCFAs) and 13C-acetate label incorporation revealed elevated SCFA in ceca and hepatic portal blood and increased liver de novo lipogenesis in T5KO mice. Dietary SCFAs further aggravated metabolic syndrome in T5KO mice. Deletion of hepatic SCD1 not only prevented hepatic neutral lipid oleate enrichment but also ameliorated metabolic syndrome in T5KO mice. Collectively, these results underscore the key role of the gut microbiota-liver axis in the pathogenesis of metabolic diseases.",

keywords = "Toll-like receptor 5, gut bacteria, hepatic neutral lipids, low-grade inflammation, metabolic diseases, monounsaturated fatty acids, short-chain fatty acids",

author = "Vishal Singh and Benoit Chassaing and Limin Zhang and {San Yeoh}, Beng and Xia Xiao and Manish Kumar and Baker, {Mark T.} and Jingwei Cai and Rachel Walker and Kamil Borkowski and Harvatine, {Kevin J.} and Nagendra Singh and Shearer, {Gregory C.} and Ntambi, {James M.} and Bina Joe and Patterson, {Andrew D.} and Gewirtz, {Andrew T.} and Matam Vijay-Kumar",

note = "Funding Information: M.V.-K. is supported by NIH grants K01, (DK083275), R03 (DK094864), and R01 (DK097865-01A1); A.T.G. by DK061417 and DK083890; and B.C. by Crohn{\textquoteright}s and Colitis Foundation of America (CCFA) Research Fellowship award. B.S.Y. is supported by NIH grant T32AI07445. A.D.P. is supported by NIH grant ES022186 and grant with the Pennsylvania Department of Health using Tobacco CURE Funds. B.J. is supported by NIH grants R01HL11264 and R01HL020176. We thank the Mouse Metabolic Phenotyping Center (MMPC)/DTRC Lipid laboratory (DK59637), Vanderbilt University, Nashville, TN. We thank Philip Smith, Director, Penn State Metabolomics Core Facility. We thank Jesse Aitken, Gayathri Srinivasan, Alyssa Grube, Jackie Yun Ying, and Rodrigo Aguilera for technical assistance. ",

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doi = "10.1016/j.cmet.2015.09.028",

language = "English (US)",

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pages = "983--996",

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AU - Singh, Vishal

AU - Chassaing, Benoit

AU - Zhang, Limin

AU - San Yeoh, Beng

AU - Xiao, Xia

AU - Kumar, Manish

AU - Baker, Mark T.

AU - Cai, Jingwei

AU - Walker, Rachel

AU - Borkowski, Kamil

AU - Harvatine, Kevin J.

AU - Singh, Nagendra

AU - Shearer, Gregory C.

AU - Ntambi, James M.

AU - Joe, Bina

AU - Patterson, Andrew D.

AU - Gewirtz, Andrew T.

AU - Vijay-Kumar, Matam

N1 - Funding Information: M.V.-K. is supported by NIH grants K01, (DK083275), R03 (DK094864), and R01 (DK097865-01A1); A.T.G. by DK061417 and DK083890; and B.C. by Crohn’s and Colitis Foundation of America (CCFA) Research Fellowship award. B.S.Y. is supported by NIH grant T32AI07445. A.D.P. is supported by NIH grant ES022186 and grant with the Pennsylvania Department of Health using Tobacco CURE Funds. B.J. is supported by NIH grants R01HL11264 and R01HL020176. We thank the Mouse Metabolic Phenotyping Center (MMPC)/DTRC Lipid laboratory (DK59637), Vanderbilt University, Nashville, TN. We thank Philip Smith, Director, Penn State Metabolomics Core Facility. We thank Jesse Aitken, Gayathri Srinivasan, Alyssa Grube, Jackie Yun Ying, and Rodrigo Aguilera for technical assistance.

PY - 2015

Y1 - 2015

N2 - The gut microbiota plays a key role in host metabolism. Toll-like receptor 5 (TLR5), a flagellin receptor, is required for gut microbiota homeostasis. Accordingly, TLR5-deficient (T5KO) mice are prone to develop microbiota-dependent metabolic syndrome. Here we observed that T5KO mice display elevated neutral lipids with a compositional increase of oleate [C18:1 (n9)] relative to wild-type littermates. Increased oleate contribution to hepatic lipids and liver SCD1 expression were both microbiota dependent. Analysis of short-chain fatty acids (SCFAs) and 13C-acetate label incorporation revealed elevated SCFA in ceca and hepatic portal blood and increased liver de novo lipogenesis in T5KO mice. Dietary SCFAs further aggravated metabolic syndrome in T5KO mice. Deletion of hepatic SCD1 not only prevented hepatic neutral lipid oleate enrichment but also ameliorated metabolic syndrome in T5KO mice. Collectively, these results underscore the key role of the gut microbiota-liver axis in the pathogenesis of metabolic diseases.

AB - The gut microbiota plays a key role in host metabolism. Toll-like receptor 5 (TLR5), a flagellin receptor, is required for gut microbiota homeostasis. Accordingly, TLR5-deficient (T5KO) mice are prone to develop microbiota-dependent metabolic syndrome. Here we observed that T5KO mice display elevated neutral lipids with a compositional increase of oleate [C18:1 (n9)] relative to wild-type littermates. Increased oleate contribution to hepatic lipids and liver SCD1 expression were both microbiota dependent. Analysis of short-chain fatty acids (SCFAs) and 13C-acetate label incorporation revealed elevated SCFA in ceca and hepatic portal blood and increased liver de novo lipogenesis in T5KO mice. Dietary SCFAs further aggravated metabolic syndrome in T5KO mice. Deletion of hepatic SCD1 not only prevented hepatic neutral lipid oleate enrichment but also ameliorated metabolic syndrome in T5KO mice. Collectively, these results underscore the key role of the gut microbiota-liver axis in the pathogenesis of metabolic diseases.

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KW - metabolic diseases

KW - monounsaturated fatty acids

KW - short-chain fatty acids

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Microbiota-Dependent Hepatic Lipogenesis Mediated by Stearoyl CoA Desaturase 1 (SCD1) Promotes Metabolic Syndrome in TLR5-Deficient Mice

Abstract

Keywords

ASJC Scopus subject areas

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