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Review
. 2020 Jan 29;7:15.
doi: 10.3389/fmed.2020.00015. eCollection 2020.

Bile Acid Receptor Therapeutics Effects on Chronic Liver Diseases

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Free PMC article
Review

Bile Acid Receptor Therapeutics Effects on Chronic Liver Diseases

Vik Meadows et al. Front Med (Lausanne). .
Free PMC article

Abstract

In the past ten years, our understanding of the importance of bile acids has expanded from fat absorption and glucose/lipid/energy homeostasis into potential therapeutic targets for amelioration of chronic cholestatic liver diseases. The discovery of important bile acid signaling mechanisms, as well as their role in metabolism, has increased the interest in bile acid/bile acid receptor research development. Bile acid levels and speciation are dysregulated during liver injury/damage resulting in cytotoxicity, inflammation, and fibrosis. An increasing focus to target bile acid receptors, responsible for bile acid synthesis and circulation, such as Farnesoid X receptor and apical sodium-dependent bile acid transporter to reduce bile acid synthesis have resulted in clinical trials for treatment of previously untreatable chronic liver diseases such as non-alcoholic steatohepatitis and primary sclerosing cholangitis. This review focuses on current bile acid receptor mediators and their effects on parenchymal and non-parenchymal cells. Attention will also be brought to the gut/liver axis during chronic liver damage and its treatment with bile acid receptor modulators. Overall, these studies lend evidence to the importance of bile acids and their receptors on liver disease establishment and progression.

Keywords: bile acid; bile acid receptor; chronic liver disease; obeticholic acid; ursodeoxycholic acid.

Figures

Figure 1
Figure 1
Human and mouse bile acid synthesis and conjugation. Cholesterol catabolism results in the creation of primary bile acids (BAs) through either the classical pathway, accomplished by Cytochrome P450 7A1 (CYP7A1), or the alternative/acidic pathway, conducted by Cytochrome P450 27A1 (CYP27A1). Alteration by various cytochrome P450 family of enzymes allows for the creation of cholic acid (CA) and chenodeoxycholic acid (CDCA). Primary BAs can become conjugated to glycine or taurine prior to secretion to the biliary ductules. Deconjugation and reconjugation occurs in the distal ileum through bacterial intervention creating secondary BAs: lithocholic acid (LCA) or deoxycholic acid (DCA). Mice have additional primary BAs: Ursodeoxycholic acid (UDCA) and α- and β-muricholic acid. The murine specific primary BAs created by cytochrome P450 2C70 (CYP2C70) can also be conjugated to glycine or taurine prior to secretion into bile duct and alteration by gut microbiota into secondary BAs. Figure reprinted with permission from Molinaro et al. Trends Endocrinol Metab.
Figure 2
Figure 2
Current bile acid receptor therapeutics and their effects in bile acid signaling. Briefly, Obeticholic acid (OCA) reduces bile acid (BA) synthesis, circulating BA levels, and hepatic inflammation. This treatment may cause adverse effects such as pruritus and jaundice (in decompensated PBC patients). Ursodeoxycholic acid (UDCA) alters BA pool and reduced hepatic inflammation and damage. In some cases, UDCA treatment has led to development of pruritus. Apical sodium bile acid transporter (ASBT) inhibitors affect bile acid synthesis, circulation, secretion, and microbial composition in the intestine.

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