Gut Microbiota-Associated Activation of TLR5 Induces Apolipoprotein A1 Production in the Liver

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-cholesterol (HDL-C) level was suggested in a human study. Besides, dietary fat was shown to increase both HDL-C and LDL-C 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 level. Methods and Results: We found that HFD increased gut flagellated bacteria population in mice. The increase in HDL-C levels was adopted by mice receiving fecal microbiome transplantion from HFD-fed mouse donors. HFD led to increased hepatic but not circulating flagellin, and deletion of TLR5, a receptor sensing flagellin, suppressed HFD-stimulated HDL-C and apolipoprotein A1 (ApoA1) 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 NFkappaB 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 productions in liver through activation of TLR5 in hepatocytes. Hepatic TLR5 may be a potential drug target to increase ApoA1.

TLR5 Supports Development of Placental Labyrinthine Zone in Mice

“…Fecal DNA was extracted using the QIAamp DNA Stool Mini Kit (Qiagen, Netherlands), and subjected to whole genome shotgun metagenomic sequencing by Beijing Genomics Institute (Hong Kong, China) as previously described ( Yiu et al, 2020 ). In brief, DNA fragments were sequenced using Illumina HiSeq 4000 (150 bp; paired-end).…”

“…CCL-98, American Type Culture Collection), were routinely maintained in DMEM/F12K supplemented with 10% FBS. Adenovirus encoding TLR5 (Ad-TLR5) was constructed by Welgen Inc. (MA, United States) as previously described ( Yiu et al, 2020 ). In brief, murine Tlr5 cDNA (GE-Dharmacon, Lafayette, United States) was inserted into pEntCMV-Ef1aGFP vector followed by adenovirus packaging in HEK293 cells.…”

“…Immunoblotting was conducted as described previously ( Yiu et al, 2020 ). Primary antibodies, anti-Akt (Cat.…”

The microbiome and rodent models of immune mediated diseases

“…Dietary lipid intake, gut microbiota and development of atherosclerosis is linked in mice, which seems to be mediated through the production of inducing metabolites, such as trimethylamine N-oxide (TMAO) (Wang et al 2011 ). TMAO promotes the release of pro-inflammatory cytokines, such as IL-1 β , IL-6 and IL-18 (Seldin et al 2016 ; Yue et al 2017 ), which may be mediated by stimulation of TLR5 by flagellin, which promotes hepatic production of ApoE (Yiu et al 2020 ).…”

ApoPred: Identification of Apolipoproteins and Their Subfamilies With Multifarious Features

“…Apolipoprotein (Apo), a protein component of plasma lipoprotein, can bind and transport blood lipids to various tissues of the body for metabolism and utilization. It is mainly synthesized in the liver and partly in the small intestine ( Yiu et al, 2020 ). A large number of studies have found that apolipoprotein gene mutation, the formation of different allelic polymorphisms, and further the generation of different phenotypes of apolipoprotein, can affect the metabolism and utilization of blood lipid, thereby triggering the occurrence and development of hyperlipidemia, atherosclerosis, cardiovascular and cerebrovascular diseases ( Richardson et al, 2020 ).…”