Abstract
The main treatments for patients with nonalcoholic fatty liver disease (NAFLD) are currently based on lifestyle changes, including ponderal decrease and dietary management. However, a subgroup of patients with nonalcoholic steatohepatitis (NASH), who are unable to modify their lifestyle successfully, may benefit from pharmaceutical support. Several drugs targeting pathogenic mechanisms of NAFLD have been evaluated in clinical trials for the treatment of NASH. Farnesoid X receptor (FXR) is a nuclear key regulator controlling several processes of the hepatic metabolism. NAFLD has been proven to be associated with abnormal FXR activity. Obeticholic acid (OCA) is a first-in-class selective FXR agonist with anticholestatic and hepato-protective properties. Currently, OCA is registered for the treatment of primary biliary cholangitis. However, promising effects of OCA on NASH and its metabolic features have been reported in several studies.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is defined as the presence of fat in the liver either on imaging or on liver histology, and after the exclusion of secondary causes of fat accumulation in the liver [1,2]
The histopathological presentation of NAFLD covers a fairly large spectrum, including hepatic steatosis and nonalcoholic steatohepatitis (NASH), defined by liver steatosis associated with inflammation and ballooning of the liver cells, with or without fibrosis [3]
Intestinal bile salt activated Farnesoid X receptor (FXR) induces the expression of fibroblast growth factor 19 (FGF19, and its mouse homolog Fgf15), which is secreted into portal blood to down-regulate hepatic bile acids (BAs) synthesis via fibroblast growth factor receptor 4 (FGFR4) and B-Klotho signaling in the liver [31,32]
Summary
Nonalcoholic fatty liver disease (NAFLD) is defined as the presence of fat in the liver (hepatic steatosis) either on imaging or on liver histology, and after the exclusion of secondary causes of fat accumulation in the liver (e.g., significant alcohol consumption, certain medications, and other medical conditions) [1,2]. Several pathogenic hypotheses on NAFLD development have been discussed Both the “two-hit”, and the more recent “multi parallel hit” hypotheses suggest that many factors, such as diet, insulin resistance, hormones secreted by adipose tissue, gut microbiota, and genetics, influence fat accumulation in the hepatocytes, and expose the liver to oxidative stress, inflammation unbalance, cellular necrosis, and fibrosis [10,11]. The therapeutic targets of this new generation of drugs include some pathogenetic steps recently identified in the pathogenesis and the progression of this disease. These factors are insulin resistance, adi pokines/cytokines synthesis, oxidative stress, dysregulation of both lipid and carbohydrate metabolism, and fibrogenesis development [13,24]. Positively targeting FXR may represent a successful strategy for the pharmacological treatment of NASH [25,26]
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