While patients with
nonalcoholic fatty liver disease (
NAFLD) are at increased risk to develop clinically meaningful
cardiovascular diseases (CVD), there are no approved
drug designed to target the liver and CVD component of
NAFLD. GPBAR1, also known as TGR5, is a
G protein coupled receptor for secondary
bile acids. In this study we have investigated the effect of GPBAR1 activation by
BAR501, a selective GPBAR1 agonist, in
Apolipoprotein E deficient (
ApoE-/-) mice fed a high fat diet and
fructose (Western diet), a validated model of
NAFLD-associated
atherosclerosis. Using aortic samples from patients who underwent surgery for abdominal aneurism, and ex vivo experiments with endothelial cells and human macrophages, we were able to co-localize the expression of GPBAR1 in CD14+ and PECAM1+ cells. Similar findings were observed in the aortic plaques from
ApoE-/- mice. Treating
ApoE-/- mice with
BAR501, 30 mg/kg for 14 weeks, attenuated the
body weight gain while ameliorated the
insulin sensitivity by increasing the plasma concentrations of
GLP-1 and FGF15. Activation of GPBAR1 reduced the aorta thickness and severity of atherosclerotic lesions and decreased the amount of plaques macrophages. Treating
ApoE-/- mice reshaped the aortic transcriptome promoting the expression of anti-inflammatory genes, including
IL-10, as also confirmed by tSNE analysis of spleen-derived macrophages. Feeding
ApoE-/- mice with
BAR501 redirected the
bile acid synthesis and the composition of the intestinal microbiota. In conclusion, GPBAR1 agonism attenuates systemic
inflammation and improve metabolic profile in a genetic/dietetic model of
atherosclerosis.
BAR501 might be of utility in the treatment for
NAFLD-related CVD.