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Obeticholic Acid: A New Era in the Treatment of Nonalcoholic Fatty Liver Disease.

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.

SUBMITTER: Abenavoli L

PROVIDER: S-EPMC6315965 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Obeticholic Acid: A New Era in the Treatment of Nonalcoholic Fatty Liver Disease.

Abenavoli Ludovico L Falalyeyeva Tetyana T Boccuto Luigi L Tsyryuk Olena O Kobyliak Nazarii N

Pharmaceuticals (Basel, Switzerland) 20181011 4

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 nucl ...[more]

PMID: 30314377

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Project description:IntroductionNonalcoholic fatty liver disease (NAFLD) is one of the most important causes of liver-related morbidity and mortality in children. Recently, we have reported the effects of docosahexaenoic acid (DHA), the major dietary long-chain polyunsaturated fatty acids, in children with NAFLD. DHA exerts a potent anti-inflammatory activity through the G protein-coupled receptor (GPR)120. Our aim was to investigate in pediatric NAFLD the mechanisms underlying the effects of DHA administration on histo-pathological aspects, GPR120 expression, hepatic progenitor cell activation and macrophage pool.Patients and methods20 children with untreated NAFLD were included. Children were treated with DHA for 18 months. Liver biopsies before and after the treatment were analyzed. Hepatic progenitor cell activation, macrophage pool and GPR120 expression were evaluated and correlated with clinical and histo-pathological parameters.ResultsGPR120 was expressed by hepatocytes, liver macrophages, and hepatic progenitor cells. After DHA treatment, the following modifications were present: i) the improvement of histo-pathological parameters such as NAFLD activity score, ballooning, and steatosis; ii) the reduction of hepatic progenitor cell activation in correlation with histo-pathological parameters; iii) the reduction of the number of inflammatory macrophages; iv) the increase of GPR120 expression in hepatocytes; v) the reduction of serine-311-phosphorylated nuclear factor kappa B (NF-κB) nuclear translocation in hepatocytes and macrophages in correlation with serum inflammatory cytokines.ConclusionsDHA could modulate hepatic progenitor cell activation, hepatocyte survival and macrophage polarization through the interaction with GPR120 and NF-κB repression. In this scenario, the modulation of GPR120 exploits a novel crucial role in the regulation of the cell-to-cell cross-talk that drives inflammatory response, hepatic progenitor cell activation and hepatocyte survival.

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Obeticholic Acid: A New Era in the Treatment of Nonalcoholic Fatty Liver Disease.

Publications

Obeticholic Acid: A New Era in the Treatment of Nonalcoholic Fatty Liver Disease.

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