Bile acids: regulation of synthesis

Abstract

Bile acids are physiological detergents that generate bile flow and facilitate intestinal absorption and transport of lipids, nutrients, and vitamins. Bile acids also are signaling molecules and inflammatory agents that rapidly activate nuclear receptors and cell signaling pathways that regulate lipid, glucose, and energy metabolism. The enterohepatic circulation of bile acids exerts important physiological functions not only in feedback inhibition of bile acid synthesis but also in control of whole-body lipid homeostasis. In the liver, bile acids activate a nuclear receptor, farnesoid X receptor (FXR), that induces an atypical nuclear receptor small heterodimer partner, which subsequently inhibits nuclear receptors, liver-related homolog-1, and hepatocyte nuclear factor 4alpha and results in inhibiting transcription of the critical regulatory gene in bile acid synthesis, cholesterol 7alpha-hydroxylase (CYP7A1). In the intestine, FXR induces an intestinal hormone, fibroblast growth factor 15 (FGF15; or FGF19 in human), which activates hepatic FGF receptor 4 (FGFR4) signaling to inhibit bile acid synthesis. However, the mechanism by which FXR/FGF19/FGFR4 signaling inhibits CYP7A1 remains unknown. Bile acids are able to induce FGF19 in human hepatocytes, and the FGF19 autocrine pathway may exist in the human livers. Bile acids and bile acid receptors are therapeutic targets for development of drugs for treatment of cholestatic liver diseases, fatty liver diseases, diabetes, obesity, and metabolic syndrome.

Fig. 1.

Bile acid synthesis. Cholesterol is converted to two primary bile acids in human liver, CA and CDCA. Key regulated enzymes, CYP7A1, CYP8B1, CYP27A1, and CYP7B1, in the pathways are indicated. CYP7A1 initiates the classic (neutral) bile acid biosynthetic pathway in the liver. CYP27A1 initiates the alternative (acidic) pathway in the liver and macrophages. CA and CDCA are conjugated to glycine (G) and taurine (T). BACS and BAT are two key enzymes involved in amino conjugation of bile acids. In the intestine, conjugated CA and CDCA are deconjugated and then dehydroxylated at the 7α-position to the secondary bile acids DCA and LCA, respectively.

Fig. 2.

Enterohepatic circulation of bile acids. In humans, about 0.2–0.6 g (averaging 0.5 g) bile acids are synthesized daily in human liver. Conjugated bile acids are secreted into bile and stored in the gallbladder. Some bile acids are spilled over into sinusoid blood and reabsorbed when passing through the renal tubules in the kidney and circulated back to the liver through mensenteric and arterial blood flow. Some bile acids secreted in the bile duct are reabsorbed in the cholangiocytes and recycled back to hepatocytes (cholangiohepatic shunt). After each meal, gallbladder contraction empties bile acids into the intestinal tract. When passing through the intestinal tract, some bile acids are reabsorbed in the upper intestine by passive diffusion, but most bile acids (95%) are reabsorbed in the ileum. Bile acids are transdiffused across the enterocyte to the basolateral membrane and excreted into portal blood circulation back to the sinusoid of hepatocytes. In the colon, DCA is reabsorbed by passive transport and recycled with CA and CDCA to the liver. A bile acid pool of about 3 g is recycled 4–12 times a day. Bile acids lost in the feces (0.2–0.6 g/day) are replenished by de novo synthesis in the liver to maintain a constant bile acid pool.

Fig. 3.

Mechanisms of FXR regulation of enterohepatic circulation of bile acid. Bile acids synthesized in the liver are excreted into bile via BSEP and stored in the gallbladder. After each meal, bile acids are excreted into the intestinal tract. In the ileum, bile acids are reabsorbed by ASBT in the brush border membrane. Bile acids activate FXR to induce IBABP in enterocytes. OSTα/β transporter in the basolateral membrane effluxes bile acids to portal circulation to hepatocytes where they are taken up by NTCP. In the liver, bile acids activate FXR, which induces SHP expression. SHP then inhibits LRH-1 (or human FTF) and HNF4α transactivation of CYP7A1 (FXR/SHP pathway 1). In the endocrine pathway, intestinal bile acids activate FXR, which induces FGF19 expression. FGF19 may be transported to the liver to activate a liver-specific receptor tyrosine kinase FGFR4 (FXR/FGF19/FGFR4 pathway 2). In the autocrine pathway (pathway 3), cholestatic bile acids may activate FXR and FGF19/FGFR4 signaling, which activates the MAPK/ERK1/2 pathway to inhibit CYP7A1 transcription. It is not clear how the FGF19/ERK1/2 pathway downregulates CYP7A1 transcription. The endocrine pathway may be a physiological pathway for bile acid inhibition of bile acid synthesis, while the autocrine pathway may be an adaptive response to protect liver from cholestatic injury. BARE-II contains 18 bp sequence of overlapping HNF4α and FTF (α-fetoprotein transcription factor, a human homolog of mouse LRH-1) binding site, which is completely conserved in all species.

Fig. 4.

FXR-independent and bile acid-activated cell signaling pathways in regulation of CYP7A1 transcription. 1) LCA activates PXR, CAR (indirectly), and VDR, which inhibit CYP7A1 transcription by interacting with HNF4α and blocking PGC-1α activation of HNF4α. 2) Bile acids stimulate inflammatory cytokines TNFα and IL-1β in Kupffer cells, which activate the TNF receptor and the MAPK/JNK pathways to inhibit CYP7A1 transcription. 3) TGFβ1 secreted from the HSC cells activates TGFβ1 receptor and the MAPK/Smad pathway. Smad3 interacts with HNF4α and recruitment of HDAC and mSin3A to inhibit CYP7A1 transcription. 4) Bile acids and TGFβ1 induce reactive oxidizing species (ROS) and activate p53, which interacts with HNF4α and inhibits HNF4α transactivation of CYP7A1. 5) Bile acids also activate epidermal growth factor receptor (EGFR) and the Raf-1/MEK/ERK signaling pathway to inhibit CYP7A1. 6) Bile acids enhance the insulin receptor signaling to phosphorylate and activate insulin receptor substrate, PI3K and AKT, which phosphorylates FoxO1 and inhibits CYP7A1. 7) Bile acids also activate protein kinase C, which phosphorylates cJun to inhibit CYP7A1. 8) During liver injury and regeneration, HGF secreted from HSC cells activates the HGF receptor cMet and the MAPK pathways to inhibit CYP7A1. All these signaling pathways may converge to regulate chromatin structure by the epigenetic mechanism.