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

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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 languageEnglish (US)
Pages (from-to)983-996
Number of pages14
JournalCell Metabolism
Volume22
Issue number6
DOIs
StatePublished - Jan 1 2015

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All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

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