Pharmacology and therapeutics of bile acid synthesis and modification enzymes in metabolic diseases.

Bile acids (BAs) are mainly synthesized in the liver as end products of cholesterol catabolism through the classic (neutral) and alternative (acidic) pathways. BA synthesis requires a coordinated series of enzymes, in which CYP7A1 catalyzes the rate-limiting step, whereas CYP8B1 determines the proportion of the 2 primary BAs-cholic acid and chenodeoxycholic acid. Enterohepatic circulation of BAs is essential not only for nutrient absorption but also for maintaining systemic metabolic homeostasis. The expanding catalog of BA-responsive receptors throughout the gastrointestinal tract and peripheral metabolic tissues underscores the hormone-like nature of BAs in metabolic regulation. Moreover, dynamic and bidirectional interactions between BAs and the gut microbiota introduce an additional layer of complexity that shapes physiological and pathological metabolic processes. Targeting BA synthesis and microbial modification offers substantial therapeutic potential for a wide spectrum of metabolism-related diseases. SIGNIFICANCE STATEMENT: Bile acids (BAs) comprise a large family of endogenous steroid metabolites with diverse chemical structures. They can activate or inhibit a panel of BA-responsive receptors to elicit distinct cellular signaling programs integral to metabolic regulation. Their reciprocal interactions with gut microbiota further amplify the complexity of host metabolic control. Therapeutic strategies that modulate BA synthesis and microbial BA transformation, leveraging both BA synthesis enzymes and microbial partners, hold great promise for treating metabolic disorders.