The regulation of apolipoprotein-A1 production by hepatic toll-like receptor-5

Abstract

Atherosclerotic cardiovascular diseases are the leading killers around the world. High-density lipoprotein (HDL) promotes the clearance of cholesterol from arterial wall and low in HDL-cholesterol (HDL-C) level is one of the major predictors of cardiovascular risks. However, none of the current anti-atherosclerotic agents confers the atheroprotective effect through the induction of HDL-C level. Dietary fat intake can stimulate HDL-C level in human studies, but the underlying mechanism remains elusive. Gut microbiota is intimately linked with the physiology of the host and plays complex roles in cardiovascular health. A previous study shows the composition of gut microbiota can partially explain the variance of the host HDL-C level. Hence, the hypothesis that dietary fat intake stimulates HDL-C level by altering gut microbiota composition was tested in this study. Through gut microbiota manipulation including fecal microbiome transplantation and antibiotic treatment in murine models, the induction of HDL-C level by high-fat diet (HFD) was found to be attributed to a favored occupancy of flagellated bacteria in the gut and the resulting accumulation of flagellin, the structural monomer of flagella, in liver. Such correlation between the abundance of flagellar genes in feces and serum HDL-C level was also observed in overweight men. Further molecular studies using murine and human cells revealed that flagellin acted on toll-like receptor-5 (TLR5) in hepatocyte which, in turn, induced transcription of apolipoprotein-A1 (ApoA1) through the classical myeloid differentiation primary response gene-88/nuclear factor-κB-mediated pathway. As a proof-of-concept study for testing the anti-atherogenic potential of TLR5 agonism, chow-fed ApoE-deficient mice were orally gavaged with flagellin. Significant reduction in atherosclerotic lesions associated with increases in HDL-C level and ApoA1-mediated cholesterol efflux capacity in serum were observed in the absence of any apparent inflammatory induction following a 4-week flagellin treatment. Altogether, this study identified a commensal action of flagellated gut bacteria on host HDL metabolism during HFD. The induction of ApoA1 synthesis following TLR5 activation represents a novel strategy for HDL induction, and development of flagellin analogues or small molecules selectively activating hepatocyte TLR5 for treatment of dyslipidemia and atherosclerosis is prompted.