Gut Microbiota-Associated Activation of TLR5 Induces Apolipoprotein A1 Production in the Liver. Issue 10 (23rd October 2020)

• Record Type: Journal Article
• Authors: Yiu, Jensen H.C.; Chan, Kam-Suen; Cheung, Jamie; Li, Jin; Liu, Yan; Wang, Yao; Fung, William W.L.; Cai, Jieling; Cheung, Samson W.M.; Dorweiler, Bernhard; Wan, Eric Y.F.; Tso, Patrick; Xu, Aimin; Woo, Connie W.
• Is Part Of: Circulation research. Volume 127:Issue 10(2020)
• Publication Date: 2020-10-23
• Subjects: apolipoproteins -- atherosclerosis -- gastrointestinal microbiome -- hepatocytes -- lipoproteins -- pharmacology -- Toll-like receptors; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.120.317362
• Languages: English
• ISSNs: 0009-7330

Abstract

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. Abstract : Supplemental Digital Content is available in the text.