Abstract
Disordered intestinal metabolism is highly correlated with atherosclerotic diseases. Resveratrol protects against atherosclerotic diseases. Accordingly, this study aims to discover novel intestinal proatherosclerotic metabolites and potential therapeutic targets related to the anti‐atherosclerotic effects of resveratrol. An untargeted metabolomics approach was employed to discover novel intestinal metabolic disturbances during atherosclerosis and resveratrol intervention. We found that multiple intestinal metabolic pathways were significantly disturbed during atherosclerosis and responsive to resveratrol intervention. Notably, resveratrol abolished intestinal fatty acid and monoglyceride accumulation in atherosclerotic mice. Meanwhile, oleate accumulation was one of the most prominent alterations in intestinal metabolism. Moreover, resveratrol attenuated oleate‐triggered accumulation of total cholesterol, esterified cholesterol and neutral lipids in mouse RAW 264.7 macrophages by activating ABC transporter A1/G1‐mediated cholesterol efflux through PPAR (peroxisome proliferator‐activated receptor) α/γ activation. Furthermore, we confirmed that PPARα and PPARγ activation by WY14643 and pioglitazone, respectively, alleviated oleate‐induced accumulation of total cholesterol, esterified cholesterol and neutral lipids by accelerating ABC transporter A1/G1‐mediated cholesterol efflux. 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 PPARα/γ signalling.
Highlights
Atherosclerosis (AS) is the leading cause of cardiovascular and cerebrovascular diseases, which are the most prevalent illnesses and causes of death worldwide.[1,2] the mortality rate for cardiovascular and cerebrovascular disease are declining globally, the absolute number of deaths is still growing.[1]
An untargeted metabolomics approach was employed to discover intestinal metabolic perturbation and potential thera‐ peutic targets related to AS and the anti‐atherosclerotic effects of RSV
We found that many metabolites involved in carbohydrate me‐ tabolism, amino acid metabolism and lipid metabolism were signifi‐ cantly altered during AS and RSV intervention
Summary
Atherosclerosis (AS) is the leading cause of cardiovascular and cerebrovascular diseases, which are the most prevalent illnesses and causes of death worldwide.[1,2] the mortality rate for cardiovascular and cerebrovascular disease are declining globally, the absolute number of deaths is still growing.[1]. Resveratrol (RSV), a natural plant polyphenol, can alleviate and even abrogate AS by intervening in various patho‐ physiological processes, including intestinal metabolism.[11,16,17] RSV decreased intestinal microbial trimethylamine content, subse‐ quently resulting in reduced liver trimethylamine N‐oxide synthe‐ sis and preventing AS.[11] RSV promotes faecal bile acid excretion by activating bile salt hydrolase, leading to decreased ileal bile acid content and subsequent suppression of the enterohe‐ patic farnesoid X receptor‐fibroblast growth factor 15 axis.[11] The subsequent activation of liver cholesterol 7a‐hydroxylase triggers bile acid neosynthesis and facilitates cholesterol homeostasis, ulti‐ mately alleviating AS.[11]. The effects of proath‐ erosclerotic metabolites and potential therapeutic targets were further confirmed in vitro
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