Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Oct 28;11(11):2588.
doi: 10.3390/nu11112588.

Polyphenol Effects on Cholesterol Metabolism via Bile Acid Biosynthesis, CYP7A1: A Review

Karen F Chambers  1 , Priscilla E Day  2 , Hassan T Aboufarrag  3 , Paul A Kroon  4
Affiliations
Review

Polyphenol Effects on Cholesterol Metabolism via Bile Acid Biosynthesis, CYP7A1: A Review

Karen F Chambers et al. Nutrients. .

Abstract

Atherosclerosis, the main contributor to coronary heart disease, is characterised by an accumulation of lipids such as cholesterol in the arterial wall. Reverse cholesterol transport (RCT) reduces cholesterol via its conversion into bile acids (BAs). During RCT in non-hepatic peripheral tissues, cholesterol is transferred to high-density lipoprotein (HDL) particles and returned to the liver for conversion into BAs predominantly via the rate-limiting enzyme, cholesterol 7 α-hydroxylase (CYP7A1). Numerous reports have described that polyphenol induced increases in BA excretion and corresponding reductions in total and LDL cholesterol in animal and in-vitro studies, but the process whereby this occurs has not been extensively reviewed. There are three main mechanisms by which BA excretion can be augmented: (1) increased expression of CYP7A1; (2) reduced expression of intestinal BA transporters; and (3) changes in the gut microbiota. Here we summarise the BA metabolic pathways focusing on CYP7A1, how its gene is regulated via transcription factors, diurnal rhythms, and microRNAs. Importantly, we will address the following questions: (1) Can polyphenols enhance BA secretion by modulating the CYP7A1 biosynthetic pathway? (2) Can polyphenols alter the BA pool via changes in the gut microbiota? (3) Which polyphenols are the most promising candidates for future research? We conclude that while in rodents some polyphenols induce CYP7A1 expression predominantly by the LXRα pathway, in human cells, this may occur through FXR, NF-KB, and ERK signalling. Additionally, gut microbiota is important for the de-conjugation and excretion of BAs. Puerarin, resveratrol, and quercetin are promising candidates for further research in this area.

Keywords: ASBT; anthocyanin; atherosclerosis; catechin; diurnal rhythms; flavonoid; microRNA; phenolic acid; reverse cholesterol transport.

PubMed Disclaimer

Conflict of interest statement

K.F.C. Chambers, H.T.A. Aboufarrag, P.E.D., P.A.K., no conflicts of interest.

Figures

Figure 1
Figure 1
The enterohepatic re-circulation of bile acids via reverse cholesterol transport. Cholesterol laden macrophages in the arterial wall deliver cholesterol via the ABCA1 transporter to lipid free apoA-I, preventing foam cell formation and also forming nascent HDL particles. Further lipidation of the nascent HDLs occurs via ABCG1. Cholesterol is delivered to the liver from mature HDL particles via specific HDL cholesterol efflux (CE) uptake by a scavenger receptor class B type I (SR-BI). In the liver, cholesterol is converted into BAs predominantly by the CYP7A1 neutral (classic) pathway. The BAs travel via the bile duct to the intestine, where they are de-conjugated via the bacteria and excreted or re-circulated (95%), usually in their conjugated form via passive diffusion or via active transport via the apical sodium dependent BA transporter (ASBT).
Figure 2
Figure 2
A summary of the main enzymes involved in the classic and alternative bile acid biosynthesis pathways. The classic pathway is controlled by the rate limiting enzyme CYP7A1 and the alternative pathway is controlled by CYP27A1; both pathways culminate in the production of cholic acid (CA) and chenodexoycholic acid (CDCA), the ratio of which depends on the activity of CYP8B1. Briefly, bile-acid biosynthesis begins with the modification of the ring structure of cholesterol, which involves oxidation and shortening of the side chain [2]. In the classic pathway, cholesterol is converted into 7 α-hydroxycholesterol by CYP7A1 and in subsequent steps, cytochrome P450 Family 8 Subfamily B Member 1a (CYP8B1) and sterol 27-hydroxylase (CYP27A1) are required for the synthesis of cholic acid (CA). Without CYP8B1, the product is chenodeoxycholic acid (CDCA), which is formed via the activity of CYP27A1 alone. The acidic pathway (or alternative pathway) is initiated by CYP27A1 and relies on 25-hydroxycholesterol 7-alpha-hydroxylase (CYP7B1) to produce CDCA.
Figure 3
Figure 3
Putative mechanisms through which polyphenols modulate CYP7A1 to promote cholesterol metabolism and bile acid deconjugation, consequently attenuating atherosclerosis plaque development. Resveratrol, epigallocatechin gallate (EGCG), and quercetin increase cyp7a1 by employing SIRT1 to acetylate FXR/LXRα; preventing its dimerisation with RXR, which then inhibits its binding and activation of CYP7A1 repressor [75,91]. Resveratrol can activate circadian proteins [116,117] and genes that subsequently upregulate cyp7a1 and together with C-3-G, procyanidins, and naringin, can downregulate or upregulate certain microRNAs to promote CYP7A1 expression [44,118,119,120,121]. Alternatively, these may also increase bile acid hydrolases and certain gut microbiota species involved in the deconjugation and excretion of bile acids [122,123,124]. Dashed lines indicate mechanisms not completely known.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Gistera A., Hansson G.K. The immunology of atherosclerosis. Nat. Rev. Nephrol. 2017;13:368–380. doi: 10.1038/nrneph.2017.51. - DOI - PubMed
    1. Russell D.W. The enzymes, regulation, and genetics of bile acid synthesis. Annu. Rev. Biochem. 2003;72:137–174. doi: 10.1146/annurev.biochem.72.121801.161712. - DOI - PubMed
    1. Schwarz M., Russell D.W., Dietschy J.M., Turley S.D. Marked reduction in bile acid synthesis in cholesterol 7alpha-hydroxylase-deficient mice does not lead to diminished tissue cholesterol turnover or to hypercholesterolemia. J. Lipid Res. 1998;39:1833–1843. - PubMed
    1. Duane W.C., Javitt N.B. 27-hydroxycholesterol: Production rates in normal human subjects. J. Lipid Res. 1999;40:1194–1199. - PubMed
    1. De Aguiar Vallim T.Q., Tarling E.J., Edwards P.A. Pleiotropic Roles of Bile Acids in Metabolism. Cell Metab. 2013;17:657–669. doi: 10.1016/j.cmet.2013.03.013. - DOI - PMC - PubMed

MeSH terms