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

Cell Metab. 2015 Dec 1;22(6):983-96. doi: 10.1016/j.cmet.2015.09.028. Epub 2015 Oct 29.


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 (13)C-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight
  • Caloric Restriction
  • Diet, High-Fat
  • Fatty Acids, Volatile / blood
  • Feces / chemistry
  • Female
  • Insulin Resistance
  • Intestines / microbiology
  • Lipogenesis
  • Liver / metabolism*
  • Magnetic Resonance Spectroscopy
  • Male
  • Metabolic Syndrome / metabolism
  • Metabolic Syndrome / pathology*
  • Mice
  • Mice, Knockout
  • Microbiota
  • Oleic Acid / metabolism
  • Stearoyl-CoA Desaturase / deficiency
  • Stearoyl-CoA Desaturase / genetics
  • Stearoyl-CoA Desaturase / metabolism*
  • Toll-Like Receptor 5 / deficiency
  • Toll-Like Receptor 5 / genetics*
  • Up-Regulation


  • Fatty Acids, Volatile
  • Toll-Like Receptor 5
  • Oleic Acid
  • Scd1 protein, mouse
  • Stearoyl-CoA Desaturase