Atherosclerosis is the leading cause of cardio-cerebrovascular disease, which is the most prevalent illness and cause of death interiorly and worldwide. Atherosclerosis is a progressive metabolic disease characterized by lipid accumulation in the arteries and is highly correlated with metabolic abnormalities. It is revealed that disordered intestinal microbial metabolism induces the occurrence and development of cardio-cerebrovascular disease. Resveratrol, a natural plant polyphenol, can alleviate and even abrogate the occurrence and development of atherosclerosis by intervening in various pathophysiological processes, including intestinal microbial metabolism. However, most of current researches focus on the effects of intestinal microbial metabolic disorders on cardio-cerebrovascular disease and the effects of resveratrol. Therefore, we suspect that whether there are metabolites in the intestine that are not related to bacterial metabolism but play key roles in the occurrence and development of atherosclerosis, and that how resveratrol works.

The Environmental Health and Molecular Toxicology Research Group of the Institute of Urban Environment, Chinese Academy of Sciences (Sijun Dong Team) and Associate Prof. Guoyou Chen and Associate Prof. Yuhua Fan from Harbin Medical University (Daqing) constructed an atherosclerosis and the resveratrol intervention model. GC-MS based metabolomics revealed that multiple metabolic pathways were altered in the intestine of atherosclerotic mice, which was responsive to resveratrol intervention. Oleate, a main fatty acid in the intestine, accumulated in the intestine and serum, and induced lipid accumulation in RAW 264.7 macrophages. PCR and Western blot results showed that oleate could inhibit ABCA1/G1-mediated cholesterol efflux via suppressing PPARA/G activity, leading to the accumulation of total cholesterol, cholesterol ester and neutral lipids in macrophages, but above effects were inhibited or even eliminated by the intervention of resveratrol, WY14643 (PPARA specific agonist) or pioglitazone (PPARG specific agonist). Extracellular cholesterol changes confirmed that oleate exposure reduced the contents of extracellular total cholesterol, free cholesterol and cholesterol ester, but above effects were abolished by the intervention of resveratrol, WY14643 or pioglitazone. This study provides the first evidence that resveratrol abolishes intestinal fatty acid and monoglyceride accumulation in atherosclerotic mice, and that resveratrol suppresses oleate-induced accumulation of total cholesterol, esterified cholesterol and neutral lipids in macrophages by activating PPARA/G.

This study entitled “Resveratrol inhibits lipid accumulation in the intestine of atherosclerotic mice and macrophages” was published in Journal of Cellular and Molecular Medicine, 2019, 23(6)，4313-4325. Dr. Guozhu Ye and Ph.D. Candidate Han Gao from Institute of Urban Environment and Associate Prof. Guoyou Chen from Harbin Medical University (Daqing) are co-first authors, meanwhile, Associate Prof. Yuhua Fan from Harbin Medical University (Daqing) and Prof. Sijun Dong from Institute of Urban Environment are co-corresponding authors. This study was supported by the National Natural Science Foundation of China (Nos. 21507128, 41390240, 21777158, 21477124 and 21677140) and other funding.

Schematic diagram of molecular mechanisms by which resveratrol inhibits the occurrence and development of atherosclerosis.