Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) has been significantly increased due to the global epidemic of obesity. The disease progression from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is closely linked to inflammation, insulin resistance, and dysbiosis. Although extensive efforts have been aimed at elucidating the pathological mechanisms of NAFLD disease progression, current understanding remains incomplete, and no effective therapy is available. Bile acids (BAs) are not only important physiological detergents for the absorption of lipid-soluble nutrients in the intestine but also metabolic regulators. During the last two decades, BAs have been identified as important signaling molecules involved in lipid, glucose, and energy metabolism. Dysregulation of BA homeostasis has been associated with NAFLD disease severity. Identification of nuclear receptors and G-protein-coupled receptors activated by different BAs not only significantly expanded the current understanding of NAFLD/NASH disease progression but also provided the opportunity to develop potential therapeutics for NAFLD/NASH. In this review, we will summarize the recent studies with a focus on BA-mediated signaling pathways in NAFLD/NASH. Furthermore, the therapeutic implications of targeting BA-mediated signaling pathways for NAFLD will also be discussed.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and is rapidly emerging as the leading cause of end-stage liver disease due to the global epidemic of obesity, type 2 diabetes, and metabolic syndrome [1]
It is well accepted that the disease progression from simple steatosis with little or no inflammation (nonalcoholic fatty liver (NAFL)) to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) is promoted by multiple factors and is closely associated with sex, age, and metabolic status [2,3,4,5,6,7,8]
Cholic acid (CA) and chenodeoxycholic acid (CDCA) are two primary Bile acids (BAs) found in humans, which are conjugated with glycine or taurine
Summary
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and is rapidly emerging as the leading cause of end-stage liver disease due to the global epidemic of obesity, type 2 diabetes, and metabolic syndrome [1]. Homeostasis, aberrant activation of the innate immune response, insulin resistance, and dysbiosis are major driving forces of the disease progression from NAFL to NASH, cirrhosis, and HCC [9,10,11,12]. Since the discovery of the first BA nuclear receptor, farnesoid receptor X (FXR), in 1999, BAs have been extensively studied for their role as critical signaling molecules and for their involvement in various physiological and pathological processes [16]. The gut microbiome is composed of a diverse range of microbes These microbes play critical roles in maintaining intestinal barrier function, modulating metabolic processes and immune responses [20]. One major function of gut microbes is the biotransformation of BAs. Dysbiosis disrupts intestinal barrier function and has detrimental effects on the liver [21,22,23]. We will discuss the therapeutic implications of targeting BA signaling pathways for NAFLD and NASH
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