Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), represent the most common cause of chronic liver disease in Western countries. MASLD patients are at increased risk for developing clinically meaningful cardiovascular diseases (CVD), including stroke and coronary artery disease and its fatal and nonfatal ischemic complications. It is widely established that the CV component dictates the patient outcomes more frequently and to a greater extent than does the progression of the liver component and it is the most common cause of death for MASLD patients. There are no drugs specifically approved for the treatment of CVD and liver components of MASLD. In this scenario, there is therefore a constant search for new therapeutic targets and new therapies for the treatment of CVD in patients with MASLD. GPBAR1is a receptor, belonging to the family of bile acid receptors (BARs), activated by secondary bile acids and their derivatives. Activation of GPBAR1 increases energy expenditure in the adipose tissue and promotes the release of Glucagon-like peptide (GLP)-1 and FGF15. Furthermore, GPBAR1 is expressed by cells of innate immunity and endothelial cells and their systemic activation counter-regulates leukocytes/endothelial cells adhesion and contribute to the vasodilatory properties of bile acids. The purpose of this study was to evaluate the effect of GPBAR1 activation in a mouse model of atherosclerosis.

Methods: Apolipoprotein E deficient mice (ApoE^−/−), a standard model of atherosclerosis, were fed with HFD-F alone or with BAR501 for 14 weeks and then sacrificed. The aortic rings, aorta and liver were isolated and analyzed.

Results: The GPBAR1 expression in the atherosclerotic plaques in rodent and patient’s aorta, highlighted by IF staining, confirmed the involvement of the receptor in the atherosclerotic process. BAR501 in ApoE^-/- mice exposed to HFD-F decreased body weight gain and increased insulin sensitivity. Furthermore, the administration of BAR501 induced an increase in the plasma concentration of GLP-1 and FGF15. Activation of GPBAR1 also resulted in the reduction of thickness and atheroma area in the aorta with a decrease in infiltrating GPBAR1⁺ immune cells. The transcriptome analysis of the aorta showed a anti-inflammatory activity of BAR501 that down-regulated the expression of many genes belonging to inflammatory pathways. Macrophages represent the main actors of the atherosclerosis process; the analysis of macrophage subpopulations extracted from the spleen of mice from the different experimental groups showed a systemic anti-inflammatory activity exerted by BAR501, with an increase of IL10⁺/IL6⁺ macrophages ratio.

Conclusion: GPBAR1 activation reduces systemic inflammation induced by a high-fat diet thereby reducing atherosclerotic lesions in the aorta, suggesting that BAR501 therapy may represent a potent new treatment for MASLD-related CVD.