Fig. 8
Proposed mechanism for theabrownin reduce cholesterol level. a Theabrownin promoted alternative bile acids synthetic pathway by simultaneous inhibition of intestinal FXR-FGF15 signaling with TCDCA or TUDCA and activation of hepatic FXR-SHP signaling with CDCA.Intestinal FXR-FGF15 signaling inhibits hepatic bile acid synthesis genes CYP7A1, CYP8B1, CYP27A1 and CYP7B1 with no selectivity, whereas hepatic FXR-SHP signaling selectively inhibits CYP8B1 in the classic pathway. Theabrownin in Pu-erh tea induced TCDCA and TUDCA in distal ileum to inhibit FGF15 production and thus, activated bile acid synthesis enzymes. Additionally, increased CDCA production in the liver promoted nuclear FXR expression as well as SHP to inhibit CYP8B1 expression. Ultimately, the combined regulation of decreased intestinal FXR-FGF15 and increased hepatic FXR-SHP on bile acid synthesis enzymes resulted in increased expression of CYP7B1 in alternative pathway and decreased expression of CYP8B1 in classic pathway leading to increased production of CDCA rather than CA. b Proposed mechanism for theabrownin induced attenuation of hepatic cholesterol levels via modulation of gut microbiome-mediated bile acid metabolism. Primary BAs, mainly CA and CDCA, were produced in the liver from cholesterol and conjugated to glycine or taurine to form conjugated BAs and then secreted to the intestinal. BSH enzymes are produced in intestinal microbes and function to hydrolyze conjugated BAs into unconjugated BAs. BSH microbes were suppressed by theabrownin in Pu-erh tea resulting in the accumulation of conjugated BAs in distal ileum. Conjugated BAs inhibited intestinal FXR-FGF15 signaling which subsequently alleviated the suppression of BA synthesis gene expression by this signaling pathway, resulting in increased BA production in alternative synthetic pathway and fecal BA excretion and ultimately, decreased cholesterol levels
