Abstract
Cholestatic liver disease is caused by the obstruction of bile synthesis, transport, and excretion in or outside the liver by a variety of reasons. Long-term persistent cholestasis in the liver can trigger inflammation, necrosis, or apoptosis of hepatocytes. Bile acid nuclear receptors have received the most attention for the treatment of cholestasis, while the drug development for bile acid nuclear receptors has made considerable progress. However, the targets regulated by bile acid receptor drugs are limited. Thus, as anticipated, intervention in the expression of bile acid nuclear receptors alone will not yield satisfactory clinical results. Therefore, this review comprehensively summarized the literature related to cholestasis, analyzed the molecular mechanism that bile acid damages cells, and status of drug development. It is hoped that this review will provide some reference for the research and development of drugs for cholestasis treatment in the future.
Highlights
Bile acid is an important component of bile, accounting for about 85% of the solid composition of bile, is the main metabolite of cholesterol metabolism, which can participate in the regulation of physiological function, such as cholesterol, sugar, and lipid metabolism (Song et al, 2015)
We speculate that drugs that can simultaneously regulate farnesoid X receptor (FXR) and pregnane X receptor (PXR)/constitutive androstane receptor (CAR) may be more promising for the treatment of cholestatic liver disease
Bile acid receptor agonists are recognized as the most promising drugs for the treatment of cholestatic liver diseases, such as FXR agonist obeticholic acid (OCA), which can significantly improve patients who do not respond to ursodeoxycholic acid (UDCA)
Summary
Bile acid is an important component of bile, accounting for about 85% of the solid composition of bile, is the main metabolite of cholesterol metabolism, which can participate in the regulation of physiological function, such as cholesterol, sugar, and lipid metabolism (Song et al, 2015). FXR agonist obeticholic acid (OCA) can significantly improve the symptoms and liver function of patients with cholestasis who do not respond to ursodeoxycholic acid (UDCA) (Bowlus et al, 2019) This gives us new hope for cholestatic liver diseases. Some evidence has found that OCA can aggravate the symptoms of itching (Mayer et al, 2020) This leads us to rethink whether bile acid receptor drugs are the most promising treatments for patients with cholestatic liver disease. This review focuses on the latest research progress about non-bile acid nuclear receptor mechanisms that regulate bile acid synthesis, hydrophobic bile acid toxicity mechanism, and current main drugs targeting bile acid receptor, hoping to provide some reference for the pathogenesis research and drug discovery research of cholestatic liver disease
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