1. Gut Microbiota-Associated Activation of TLR5 Induces Apolipoprotein A1 Production in the Liver.
- Author
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Yiu JHC, Chan KS, Cheung J, Li J, Liu Y, Wang Y, Fung WWL, Cai J, Cheung SWM, Dorweiler B, Wan EYF, Tso P, Xu A, and Woo CW
- Subjects
- Animals, Apolipoprotein A-I genetics, Cholesterol, HDL metabolism, Dietary Fats metabolism, Flagellin metabolism, Flagellin pharmacology, Mice, NF-kappa B metabolism, Toll-Like Receptor 5 drug effects, Apolipoprotein A-I metabolism, Gastrointestinal Microbiome, Liver metabolism, Toll-Like Receptor 5 metabolism
- Abstract
Rationale: Dysbiosis of gut microbiota plays an important role in cardiovascular diseases but the molecular mechanisms are complex. An association between gut microbiome and the variance in HDL-C (high-density lipoprotein-cholesterol) level was suggested in a human study. Besides, dietary fat was shown to increase both HDL-C and LDL-C (low-density lipoprotein-cholesterol) levels. We speculate that certain types of gut bacteria responding to dietary fat may help to regulate HDL-C level and potentially affect atherosclerotic development., Objective: We aimed to investigate whether and how high-fat diet (HFD)-associated gut microbiota regulated HDL-C level., Methods and Results: We found that HFD increased gut flagellated bacteria population in mice. The increase in HDL-C level was adopted by mice receiving fecal microbiome transplantation from HFD-fed mouse donors. HFD led to increased hepatic but not circulating flagellin, and deletion of TLR5 (Toll-like receptor 5), a receptor sensing flagellin, suppressed HFD-stimulated HDL-C and ApoA1 (apolipoprotein A1) levels. Overexpression of TLR5 in the liver of TLR5-knockout mice was able to partially restore the production of ApoA1 and HDL-C levels. Mechanistically, TLR5 activation by flagellin in primary hepatocytes stimulated ApoA1 production through the transcriptional activation responding to the binding of NF-κB (nuclear factor-κB) on Apoa1 promoter region. Furthermore, oral supplementation of flagellin was able to stimulate hepatic ApoA1 production and HDL-C level and decrease atherosclerotic lesion size in apolipoprotein E-deficient ( Apoe
-/- ) mice without triggering hepatic and systemic inflammation. The stimulation of ApoA1 production was also seen in human ApoA1-transgenic mice treated with oral flagellin., Conclusions: Our finding suggests that commensal flagellated bacteria in gut can facilitate ApoA1 and HDL-C productions in liver through activation of TLR5 in hepatocytes. Hepatic TLR5 may be a potential drug target to increase ApoA1.- Published
- 2020
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