title: The Role of Nuclear Receptors in the Pathophysiology, Natural Course, and Drug Treatment of NAFLD in Humans.
abstract: Nonalcoholic fatty liver disease (NAFLD) describes steatosis, nonalcoholic steatohepatitis with or without fibrosis, and hepatocellular carcinoma, namely the entire alcohol-like spectrum of liver disease though observed in the nonalcoholic, dysmetabolic, individual free of competing causes of liver disease. NAFLD, which is a major public health issue, exhibits intrahepatic triglyceride storage giving rise to lipotoxicity. Nuclear receptors (NRs) are transcriptional factors which, activated by ligands, are master regulators of metabolism and also have intricate connections with circadian control accounting for cyclical patterns in the metabolic fate of nutrients. Several transcription factors, such as peroxisome proliferator-activated receptors, liver X receptors, farnesoid X receptors, and their molecular cascades, finely regulate energetic fluxes and metabolic pathways. Dysregulation of such pathways is heavily implicated in those metabolic derangements characterizing insulin resistance and metabolic syndrome and in the histogenesis of progressive NAFLD forms. We review the role of selected NRs in NAFLD pathogenesis. Secondly, we analyze the role of NRs in the natural history of human NAFLD. Next, we discuss the results observed in humans following administration of drug agonists or antagonists of the NRs pathogenically involved in NAFLD. Finally, general principles of treatment and lines of research in human NAFLD are briefly examined.
authors.affiliation: Pavullo Hospital, Azienda USL Modena, Modena, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ballestri
authors.affiliation: NOCSAE, Outpatient Liver Clinic and Operating Unit Internal Medicine, Azienda USL Modena, Modena, Italy.|University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Nascimbeni
authors.affiliation: NOCSAE, Outpatient Liver Clinic and Operating Unit Internal Medicine, Azienda USL Modena, Modena, Italy.
authors.forename: Dante
authors.initials: D
authors.lastname: Romagnoli
authors.affiliation: University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Baldelli
authors.affiliation: NOCSAE, Outpatient Liver Clinic and Operating Unit Internal Medicine, Azienda USL Modena, Modena, Italy. a.lonardo@libero.it.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Lonardo
mesh_terms: D006801:Humans; D000071518:Liver X Receptors; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000503:physiopathology*; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000037:antagonists & inhibitors*
chemical_list: D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047492:Peroxisome Proliferator-Activated Receptors; D018160:Receptors, Cytoplasmic and Nuclear
keywords: Cirrhosis; Farnesoid X receptor; Fibrosis; Hepatocellular carcinoma; Liver X receptor; Natural history; Nonalcoholic steatohepatitis; Pathogenesis; Peroxisome proliferator-activated receptor; Steatosis