Bile acids as metabolic regulators

Abstract

Purpose of review: This review focuses on the latest understanding of the molecular mechanisms underlying the complex interactions between intestine and liver bile acid signaling, gut microbiota, and their impact on whole-body lipid, glucose and energy metabolism.

Recent findings: Hepatic bile acid synthesis is tightly regulated by the bile acid negative feedback mechanisms. Modulating the enterohepatic bile acid signaling greatly impacts the whole-body metabolic homeostasis. Recently, a positive feedback mechanism through intestine farnesoid X receptor (FXR) antagonism has been proposed to link gut microbiota to the regulation of bile acid composition and pool size. Two studies identified intestine Diet1 and hepatic SHP-2 as novel regulators of CYP7A1 and bile acid synthesis through the gut-liver FXR-fibroblast growth factor 15/19-FGF receptor four signaling axis. New evidence suggests that enhancing bile acid signaling in the distal ileum and colon contributes to the metabolic benefits of bile acid sequestrants and bariatric surgery.

Summary: Small-molecule ligands that target TGR5 and FXR have shown promise in treating various metabolic and inflammation-related human diseases. New insights into the mechanisms underlying the bariatric surgery and bile acid sequestrant treatment suggest that targeting the enterohepatic circulation to modulate gut-liver bile acid signaling, incretin production and microbiota represents a new strategy to treat obesity and type 2 diabetes.

Figure 1. Bile acid biosynthetic pathways

Two major bile acid biosynthetic pathways are shown. The classic pathway is the major bile acid synthetic pathway in the liver. In this pathway, cholesterol is converted to 7α-hydroxycholesterol (7α-HOC) by the rate-limiting enzyme cholesterol 7α-hydroxylase (CYP7A1), which is located in the endoplasmic reticulum. The sterol 12α-hydroxylase (CYP8B1) converts the intermediate 7α-hydroxy-4 cholesten-3-one (C4) to 7α, 12α-dihydroxy-4- cholesten-3-one, leading to synthesis of cholic acid (CA). Without 12αhydroxylation by CYP8B1, C4 is eventually converted to chenodeoxycholic acid (CDCA). The mitochondrial sterol 27-hydroxylase (CYP27A1) catalyzes the steroid side-chain oxidation in both CA and CDCA synthesis. In the alternative pathway, CYP27A1 converts cholesterol to 27hydroxycholesterol (27-HOC), which eventually is converted to CDCA. In mouse liver, most CDCA is converted to α- and β-muricholic acid (MCA). MCA is only found in trace amount in humans. In the large intestine, bacterial 7-dehydroxylase removes a hydroxyl group from C-7 and converts CA to deoxycholic acid (DCA) and converts CDCA to lithocholic acid (LCA). CYP3A1 and epimerases also convert CDCA to the secondary bile acids, including hyocholic acid (HCA), murideoxycholic acid (MDCA), ω-muricholic acid (ω-MCA), hyodeoxycholic acid (HDCA) and ursodeoxycholic acid (UDCA). Most LCA and ω-MCA are excreted into feces.

Figure 2. Mechanisms of bile acid feedback inhibition of bile acid synthesis

Bile acidactivated signaling inhibits CYP7A1 and therefore reduces hepatic bile acid synthesis. Nuclear receptors HNF4α and LRH1 bind to the bile acid response element (BARE) located in the CYP7A1 gene promoter and stimulate CYP7A1 gene transcription. In hepatocytes, bile acids activate FXR, which induces the repressor SHP. SHP interacts with and represses the transactivating action of HNF4α and LRH. In the intestine, bile acid-activated FXR induces the transcription of FGF15 (FGF19 in humans). Diet1 may promote FGF15/19 secretion from the intestine. Diet1 may also regulate FGF15 mRNA levels. FGF15/19 binds and activates FGFR4 on the hepatocytes. FGFR4 activates intracellular signaling pathways such as ERK, which leads to the repression of CYP7A1 gene transcription. SHP2 and FRS2 are identified as key components of the FGFR4 signaling complex that activates ERK1/2 in response to FGF15. The intracellular event downstream of ERK1/2 in CYP7A1 inhibition is less well understood, but may involve the inhibition of HNF4α or LRH. ERK has also been shown to stabilize SHP via direct phosphorylation. Disruption of the bile acid feedback signaling caused increased hepatic CYP7A1 expression and enlarged bile acid pool size.