Endocrine Abstracts

Introduction: Atherosclerosis is a chronic inflammatory arterial disease and is currently one of the most common causes of cardiovascular morbidity and mortality worldwide. Therefore, there is an urgent need to discover new therapeutic targets for treatment of this fatal chronic disease. Fatty acid binding protein 4 (FABP4), a pro-inflammatory adipokine that links obesity with its related metabolic diseases, has been implicated in the development of atherosclerosis. This study aims to investigate whether FABP4 potentiates atherosclerosis by mediating the crosstalk between gut microbiota and immunity and to explore whether targeting FABP4 is therapeutically effective for treatment of this disease.

Method: FABP4^+/+ApoE^−/− and FABP4^−/−ApoE^−/− mice were generated for the study and fed with high fat and high cholesterol diet (HFHC) for 12 weeks. Biochemical, immunological, flow cytometry and denaturing gradient gel electrophoresis (DGGE) analysis were conducted to determine the pathophysiological roles of FABP4 in potentiating diet-induced atherosclerosis by altering gut microbiota and immunity. Fecal microbiota transplantation (FMT) were performed to further investigate the role of FABP4 in atherosclerosis mediated through microbiota. The FABP4 chemical inhibitor BMS309403 was used to evaluate the effects of FABP4 inhibition in alleviating atherosclerosis.

Result: The aortic trees stained with Oil Red exhibited significantly reduced atherosclerosis in FABP4^−/−ApoE^−/− mice comparing to FABP4^+/+ApoE^−/− littermates. Likewise, FMT of FABP4^−/− feces to FABP4^+/+ mice significantly attenuated the development of atherosclerosis. DGGE analysis of fecal DNA showed that the pattern of bacterial phyla was obviously changed in FABP4^−/− mice comparing to FABP4^+/+ littermates. These changes in FABP4^−/− mice were accompanied by significantly increased expression of zona occuldens protein-1 (ZO-1) and occludin in intestinal villa, suggesting that FABP4 may enhance the intestinal permeability in mice in response to HFHC diet. Furthermore, FABP4 promoted macrophage infiltration and the polarization of macrophage from M0 to pro-inflammatory M1 subtype in the intestine of mice. Treatment with the FABP4 inhibitor BMS309403 dramatically alleviated the inflammatory response in the gut and atherosclerotic plaque formation, and elevated the intestinal expression of ZO1 and occludin in FABP4^+/+ mice.

Conclusion: FABP4, which is elevated during obesity, alters the composition of gut microbiota and intestinal permeability by creating a pro-inflammatory microenvironment, leading to endotoxinemia and subsequently contributing to the development of atherosclerosis. Targeting FABP4 with small-molecule inhibitors such as BMS303409 is a promising therapeutic strategy for treatment and prevention of atherosclerosis by modulating gut microbiota and intestinal immunity.

Acknowledgement: Hong Kong Health and Medical Research Fund (06172596)