Cholesterol-lowering effects and mechanisms in view of bile acid pathway of resveratrol and resveratrol-glucuronides

Authors: SHAO, DONGYAN - University Of California; WANG, YILIN - Northwest University; HUANG, QINGSHENG - Northwest University; SHI, JUNLING - Northwest University; YANG, HUI - Northwest University; Pan, Zhongli; ZHAO, HAOBIN - Northwest University; XU, XIAGUANG - Northwest University

Submitted to: Journal of Food Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/11/2016
Publication Date: 10/13/2016
Citation: Shao, D., Wang, Y., Huang, Q., Shi, J., Yang, H., Pan, Z., Zhao, H., Xu, X. 2016. Cholesterol-lowering effects and mechanisms in view of bile acid pathway of resveratrol and resveratrol-glucuronides. Journal of Food Science. 81:H2841-H2848. doi:10.1111/1750-3841.13528.

Interpretive Summary: High levels of plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) are proven to be the biomarkers of high risk of CVD. Resveratrol (Res) was a natural polyphenolic compound in grapes and red wine. It has been reported that Res could significantly lower the plasma TC and/or LDL-C content by, at least partially, increasing the excretion of neutral sterols and bile acids from liver to feces. The cycling of bile acids is recognized as an enterohepatic circulation. The overall efficiency of cholesterol secretion out of body would highly depend on the efficiency of each step of the process in the cycling. Although there have been reports on the effect of Res on the synthesis of bile acids, the results turn out to be contradictory. Res could actively and efficiently go directly into the liver and mainly be metabolized into resveratrol-glucuronides (Gres). However, little is known about the function of Gres in lowering cholesterol in liver. Therefore, the individual effect of Res and Gres on the cholesterol in the liver was investigated. Through the data and observations of gene expression, this study demonstrated that Gres and Res might have potential capabilities in lowering cholesterol level in liver. Furthermore, Gres would have preferred potential than Res because of its lower cytotoxicity.

Technical Abstract: Resveratrol (Res) was previously reported to be capable of lowering plasma TC and LDL-C. The mechanism behind Res is not clearly understood, although it is presumed to have an effect on bile acid metabolism in the liver: a significant way in eliminating cholesterol from the body. As one of the major metabolites of Res in the liver, resveratrol-glucuronides (Gres) is suspected to also contribute to the overall cholestrol-lowering activity of Res, which needs to be studied. In this research, when HepG2 steatosis hepatic cells were treated with Res and Gres at different concentration levels, Res and Gres showed similar activity in lowering cellular TC content. The presence of Res and Gres caused a significant increase in hepatic CYP7A1 and BSEP, indicating the increase in the synthesis and efflux of bile acids, respectively. The reduction of HMG-CoAR tied to a decrease in de novo synthesis of cholesterol and the increase of ABCG5 suggested the increase of direct efflux of cholesterol. The changes reduced hepatic cholesterol level, which triggered the significant enhancement of LDLR, illustrating the improvement of clearance of LDL-C from the plasma and prevention of atherosclerosis. Overall, this study demonstrated both Res and Gres might have capabilities in lowering hepatic cholesterol through increasing in the synthesis and efflux of bile acids, and decreasing in synthesis and increasing in the efflux of cholesterol. Gres would have preferred potential than Res because of its lower cytotoxicity, which indicated that the action of the metabolites should also be considered in the future studies.