title: Oxysterols in the orchestra of liver cell metabolism.
abstract: Non-alcoholic fatty liver disease (NAFLD) is a chronic hepatic disorder affecting up to 25% of the general population. Several intracellular events leading to NAFLD and progression to non-alcoholic steatohepatitis (NASH) have been identified, including lipid accumulation, mitochondrial dysfunction and oxidative stress. Emerging evidence has suggested the cooperation of both hepatic free fatty acids (FFAs) and cholesterol (FC) accumulation in NAFLD development. Oxysterols, oxidized derivatives of cholesterol were reported as activating ligands of Liver X Receptors. Interestingly, serum levels of agonist oxysterols such as 25-HC and 27-HC are significantly increased in NAFLD patients. By contrast, 22-s- HC is considered an antagonist ligand of LXRα. 22-s-Hc down-regulated expression of the FAS gene through an LXRE located in the promoter and abolished the effect of the synthetic LXRα agonist. In addition it has been reported that 22-s-HC attenuated hepatic steatogenesis in a mouse model of high-fat-induced fatty liver. Very recently, it has been demonstrated that the inhibition of LXRα by 22-s-HC dramatically represses steatosis and HIF-1 mediated activation of MCP-1 in ethanol-induced fatty liver injury in hepatocytes as well as in Kupferr cells. Our data demonstrated that High fat diet (HF) caused liver steatosis while an atherogenic diet (ATH) diet induced hepatocellular ballooning, but only the Ath+HF diet resulted in steatohepatitis with associated mitochondrial dysfunction and impaired mitochondriogenesis. We identified in the the oxysterol cholestane-3beta,5alpha,6beta-triol (Triol) the molecule able to impair mitochondrial respiration and mitochondriogenesis by down-regulation of PGC1-alpha, mTFA and NRF1 signal. It seems that the role of oxysterols in the pathogenesis of human diseases, particularly in fat induced injury, should take into account the possible disruption of the balance between activation and inhibition of LXR signalling. Development of LXRα that specifically control inflammation and hepatic lipogenesis may provide novel therapeutics that block the development and progression of NAFLD.
authors.affiliation: Centro Universitario per la Ricerca e la Cura delle Malattie Epatiche (C.U.R.E.), Institute of Internal Medicine, University of Foggia, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Serviddio
authors.affiliation: Centro Universitario per la Ricerca e la Cura delle Malattie Epatiche (C.U.R.E.), Institute of Internal Medicine, University of Foggia, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bellanti
authors.affiliation: Centro Universitario per la Ricerca e la Cura delle Malattie Epatiche (C.U.R.E.), Institute of Internal Medicine, University of Foggia, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Vendemiale