Universität zu Köln

Yiu, Jensen H. C., Chan, Kam-Suen, Cheung, Jamie ORCID: 0000-0002-6731-3154, 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 and Woo, Connie W. (2020). Gut Microbiota-Associated Activation of TLR5 Induces Apolipoprotein A1 Production in the Liver. Circ.Res., 127 (10). S. 1236 - 1253. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1524-4571

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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-kappa B (nuclear factor-kappa B) 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Yiu, Jensen H. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Chan, Kam-Suen UNSPECIFIED UNSPECIFIED UNSPECIFIED Cheung, Jamie UNSPECIFIED orcid.org/0000-0002-6731-3154 UNSPECIFIED Li, Jin UNSPECIFIED UNSPECIFIED UNSPECIFIED Liu, Yan UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Yao UNSPECIFIED UNSPECIFIED UNSPECIFIED Fung, William W. L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cai, Jieling UNSPECIFIED UNSPECIFIED UNSPECIFIED Cheung, Samson W. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dorweiler, Bernhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Wan, Eric Y. F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tso, Patrick UNSPECIFIED UNSPECIFIED UNSPECIFIED Xu, Aimin UNSPECIFIED UNSPECIFIED UNSPECIFIED Woo, Connie W. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-314394
DOI:	10.1161/CIRCRESAHA.120.317362
Journal or Publication Title:	Circ.Res.
Volume:	127
Number:	10
Page Range:	S. 1236 - 1253
Date:	2020
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
Place of Publication:	PHILADELPHIA
ISSN:	1524-4571
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HIGH-DENSITY-LIPOPROTEIN; LOW-FAT DIET; LOW-CARBOHYDRATE-DIET; HDL-CHOLESTEROL; AKKERMANSIA-MUCINIPHILA; CARDIOVASCULAR-DISEASE; RISK-FACTORS; MICE; ATHEROSCLEROSIS; EXPRESSION Multiple languages Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/31439