Targeting the alternative bile acid synthetic pathway for metabolic diseases

Abstract

The gut microbiota is profoundly involved in glucose and lipid metabolism, in part by regulating bile acid (BA) metabolism and affecting multiple BA-receptor signaling pathways. BAs are synthesized in the liver by multi-step reactions catalyzed via two distinct routes, the classical pathway (producing the 12α-hydroxylated primary BA, cholic acid), and the alternative pathway (producing the non-12α-hydroxylated primary BA, chenodeoxycholic acid). BA synthesis and excretion is a major pathway of cholesterol and lipid catabolism, and thus, is implicated in a variety of metabolic diseases including obesity, insulin resistance, and nonalcoholic fatty liver disease. Additionally, both oxysterols and BAs function as signaling molecules that activate multiple nuclear and membrane receptor-mediated signaling pathways in various tissues, regulating glucose, lipid homeostasis, inflammation, and energy expenditure. Modulating BA synthesis and composition to regulate BA signaling is an interesting and novel direction for developing therapies for metabolic disease. In this review, we summarize the most recent findings on the role of BA synthetic pathways, with a focus on the role of the alternative pathway, which has been under-investigated, in treating hyperglycemia and fatty liver disease. We also discuss future perspectives to develop promising pharmacological strategies targeting the alternative BA synthetic pathway for the treatment of metabolic diseases.

Keywords: alternative pathway; bile acids; gut microbiota; metabolic diseases.

Figure 1

The mechanism of activation of alternative pathway by exogenous molecules and endogenous BAs. Oral administration of exogenous molecules suppresses the activity of intestinal BSH enzymes, and causes accumulation of predominantly conjugated non-12-OH BAs. Meanwhile, endogenous conjugated or unconjugated CDCA or UDCA could increase the abundance of non-12-OH BAs directly or indirectly (via enterohepatic circulation). These BAs inhibit intestinal FXR and therefore, downstream FGF15/19-FGFR4 signaling resulting in upregulation of the hepatic BA synthesis genes CYP7A1, CYP8B1, CYP27A1 and CYP7B1 in both classical and alternative pathways. Meanwhile, hepatic FXR expression as well as downstream SHP signaling is increased and the BA synthetic enzymes are inhibited, mainly CYP8B1, in the classical pathway. Ultimately, the combined regulation of intestinal FXR-FGF15 and hepatic FXR-SHP on hepatic BA synthesis results in increased expression of CYP7B1 in the alternative pathway. The metabolites, proteins, and pathways in blue indicate their down-regulation, whereas in red indicate up-regulation after oral treatment of exogenous and endogenous agents

Figure 2

Diagram of a simplified alternative BA synthetic pathway and its effect on cholesterol metabolism and the importance of oxysterols in lipid metabolism. (A) Cholesterol is chaperoned into the mitochondria via STARD1 and CYP27A1 converts it to two important bioactive oxysterols, 25OHC and 26OHC. Treatment with the BAs, TCDCA and TUDCA, have been associated with higher expression levels of CYP27A1. The OHCs are then acted on by CYP7B1 to form dihydroxylated species and ultimately, CDCA as the primary product. It is also possible to form CA via CYP8B1 activity in this pathway. In CLD such as T2DM and NAFLD/early NASH, the expression of CYP7B1 is suppressed. Cold temperatures, BA treatment with TCDCA and TUDCA, theobrownin and anything which increases insulin sensitivity induces higher expression of CYP7B1. Decreased GLP-1 (increased insulin resistance), CA and DCA treatment can increase expression of CYP8B1 which has poor patient outcomes. (B) Oxysterols are the first products formed in the alternative BA synthetic pathway and are important endogenous agonists for LXR. LXR activation leads to upregulation of important enzymes in the glycolysis pathway (GK, PK) and also upregulation of enzymes for de novo lipogenesis (ATP citrate lyase, ACC, FAS, SCD1). When this pathway becomes overactive as in NAFLD, there is increased fat accumulation in the liver leading to NASH. OHC induced activation of LXR can also cause an increase in RCT as the transporters, ABCA1 and ABCA5/8 are downstream targets of LXR. Activation of LXR also upregulates CYP7A1, the regulatory enzyme that governs BA synthesis in the classical pathway. OHCs can also directly activate INSIG which then forms a complex with SCAP to block the transcription action of SRBEBP-1c. OHCs can also directly activate SRBEBP-1c. BA activation of FXR also acts in an antagonistic way towards LXR activation. The endogenously produced OHC-3S and the synthetically produced 22(S) OHC are also both antagonists to LXR activation. When CYP7B1 is repressed as in insulin resistant metabolic diseases such as CLD, then more cholesterol ends up as oxysterols which in overabundance can cause lipotoxicity and inflammation in the liver

Figure 3

Alternative BA synthetic pathway manipulated by gut microbiota. (1) Gut bacteria express 7-hydroxysteroid dehydrogenase (7-HSDH) which catalyzes the epimerization of BA 7-hydroxyl groups and converts the primary non-12-OH BA (CDCA) to UDCA. (2) Non-12-OH BAs can be produced by a non-bacteria metabolic process. (3) Gut bacterial species might also express 12α-dehydroxylase activity, which would convert 12-OH BAs to non-12-OH BAs. The activation of the alternative pathway accelerates BA circulation and fecal excretion and suppresses hepatic cholesterol and lipid metabolism