title: Oxysterols induce mitochondrial impairment and hepatocellular toxicity in non-alcoholic fatty liver disease.
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 links both hepatic free fatty acids (FFAs) and cholesterol (FC) accumulation in NAFLD development; in particular oxysterols, the oxidative products of cholesterol, may contribute to liver injury. We performed a targeted lipidomic analysis of oxysterols in the liver of male Wistar rats fed a high-fat (HF), high-cholesterol (HC) or high-fat/high-cholesterol (HF/HC) diet. Both HF and HC diets caused liver steatosis, but the HF/HC diet resulted in steatohepatitis with associated mitochondrial dysfunction. Above all, the oxysterol cholestane-3beta,5alpha,6beta-triol (triol) was particularly increased in the liver of rats fed diets rich in cholesterol. To verify the molecular mechanism involved in mitochondrial dysfunction and hepatocellular toxicity, Huh7 and primary rat hepatocytes were exposed to palmitic acid (PA) and/or oleic acid (OA), with or without triol. This compound induced apoptosis in cells co-exposed to both PA and OA, and this was associated with impaired mitochondrial respiration as well as down-regulation of PGC1-alpha, mTFA and NRF1.In conclusion, our data show that hepatic free fatty acid or oxysterols accumulation per se induce low hepatocellular toxicity. On the contrary, hepatic accumulation of both fatty acids and toxic oxysterols such as triol are determinant in the impairment of mitochondrial function and biogenesis, contributing to liver pathology in NAFLD.
authors.affiliation: University of Foggia (C.U.R.E. University Centre for Liver Diseases Research and Treatment), Department of Medical and Surgical Sciences, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bellanti
authors.affiliation: University of Foggia (C.U.R.E. University Centre for Liver Diseases Research and Treatment), Department of Medical and Surgical Sciences, Italy.
authors.forename: Domenica
authors.initials: D
authors.lastname: Mitarotonda
authors.affiliation: University of Foggia (C.U.R.E. University Centre for Liver Diseases Research and Treatment), Department of Medical and Surgical Sciences, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Tamborra
authors.affiliation: University of Foggia (C.U.R.E. University Centre for Liver Diseases Research and Treatment), Department of Medical and Surgical Sciences, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Blonda
authors.affiliation: University of Foggia (C.U.R.E. University Centre for Liver Diseases Research and Treatment), Department of Medical and Surgical Sciences, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Iannelli
authors.affiliation: Istituto Zooprofilattico di Puglia e Basilicata (Sede di Foggia), Animal Breeding Department, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Petrella
authors.affiliation: Laboratorio Padre Pio (S.r.l.), Cerignola (FG), Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Sanginario
authors.affiliation: Sapienza University of Rome (Vascular Biology and Mass Spectrometry Laboratory), Department of Medico-Surgical Sciences and Biotechnology, Latina, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Iuliano
authors.affiliation: University of Foggia (C.U.R.E. University Centre for Liver Diseases Research and Treatment), Department of Medical and Surgical Sciences, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Vendemiale
authors.affiliation: University of Foggia (C.U.R.E. University Centre for Liver Diseases Research and Treatment), Department of Medical and Surgical Sciences, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Serviddio