Regulation of Bile Acid Metabolism and Signaling in Metabolic Diseases

Bile acids are both physiological detergents and signaling molecules that are critically involved in regulating liver and gut functions. Common forms of human cholestasis (primary biliary cholangitis, PBC, and primary sclerosing cholangitis, PSC) are chronic liver diseases due to immune-mediated bile duct injury that impairs bile flow. Reducing hepatobiliary bile acid toxicity is a major therapeutic goal in all forms of cholestasis. Currently, bile acid-based therapeutics ursodeoxycholic acid (UDCA) and obeticholic acid are the only available treatments to promote bile flow and alleviate bile acid toxicity in PBC. Therapeutic options are still limited for PBC patients who do not adequately respond to or cannot tolerate these treatments. UDCA is not approved for treating PSC. Muricholic acids (MCAs) are 6-hydroxylated hydrophilic bile acids abundantly produced in mice but not in humans. Glycine-conjugated -MCA (Gly--MCA), a none naturally occurring MCA derivative, has recently been developed as a “gut-restricted” FXR antagonist. Gly--MCA has been shown to possess anti-obesity and insulin- sensitizing effect in mice and a potential treatment for metabolic diseases. However, despite its unique physicochemical and signaling properties, no studies have investigated the potential anti-cholestasis effect of Gly--MCA. By using Cyp2c70 KO mice that do not synthesize MCAs and exhibit a “human-like” hydrophobic bile acid pool-induced hepatobiliary injury as a clinically relevant model of cholestasis, we have demonstrated that Gly--MCA shows potent anti-cholestasis efficacy via mechanisms independent of its intestine FXR antagonism. Notably, our studies have revealed that Gly--MCA undergoes a unique microbiome-dependent enterohepatic circulation within which it modulates bile acid metabolism in both the hepatobiliary system and the small and large intestine. The overall goal of this project is to investigate the efficacy and mechanisms of action of Gly--MCA as an effective anti-cholestasis agent. To achieve this goal, we will comprehensively characterize the therapeutic efficacy of incremental doses of Gly--MCA in close comparison to that of UDCA in male and female Cyp2c70 KO mice and Mdr2 KO mice. We have designed mechanistic studies to characterize the metabolism of Gly--MCA in vivo and delineate the effects and mechanisms of Gly--MCA modulation of bile acid composition and hydrophobicity, bile flow, intestine bile acid absorption, and gut barrier function. Furthermore, we will investigate if enhanced efficacy can be achieved by combining Gly--MCA with AAV-FGF15 (mimicking FGF15/19 analog) or GalNac-siCYP7A1 in treating advanced cholestasis by concomitant inhibition of hepatic bile acid production and intestine bile acid absorption. Upon successful completion of this project, we expect that new mechanistic insights will be obtained to demonstrate that Gly--MCA processes several unique bile acid modulating properties in the enterohepatic circulation, which supports its potential clinical use as a new hepatobiliary protective agent to treat human cholestasis.