Monica Gomaraschi1, Anna Ludovica Fracanzani2, Paola Dongiovanni3, Chiara Pavanello4, Eleonora Giorgio4, Lorenzo Da Dalt5, Giuseppe Danilo Norata5, Laura Calabresi4, Dario Consonni6, Rosa Lombardi3, Adriana Branchi7, Silvia Fargion3. 1. Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy. Electronic address: monica.gomaraschi@unimi.it. 2. Department of Pathophysiology and Transplantation, Unit of Metabolic and Internal Medicine, University of Milan, Ca' Granda IRCCS Foundation, Maggiore Policlinico Hospital, Milan, Italy. Electronic address: anna.fracanzani@unimi.it. 3. Department of Pathophysiology and Transplantation, Unit of Metabolic and Internal Medicine, University of Milan, Ca' Granda IRCCS Foundation, Maggiore Policlinico Hospital, Milan, Italy. 4. Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy. 5. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy. 6. Epidemiology Unit, Ca' Granda Foundation IRCCS Maggiore Policlinico Hospital, University of Milan, Italy. 7. Department of Clinical Science and Community, University of Milan, Ca' Granda IRCCS Foundation, Maggiore Policlinico Hospital, Milan, Italy.
Abstract
AIMS: It has been hypothesized that the activity of lysosomal acid lipase (LAL), a key enzyme involved in lipid metabolism, is involved in the NAFLD phenotype. To clarify the role of LAL in NAFLD, we studied 164 consecutive patients with biopsy-proven NAFLD and fat-loaded HepG2 cells. METHODS: LAL activity was measured (i) on dried blood spots (DBS) from NAFLD patients and dyslipidemic subjects without fatty liver and (ii) on liver biopsies from NAFLD patients. LAL activity and expression were evaluated in HepG2 cells cultured in the presence of free fatty acids (FAs), with or without a PPAR-alpha agonist. RESULTS: LAL activity was significantly reduced in patients with NAFLD compared to dyslipidemic subjects. LAL activity measured in liver biopsies from NAFLD patients was highly correlated to that measured on DBS and was independent of LAL expression in the liver. In a fully adjusted model, LAL activity on DBS was associated only with platelets and, when normalized by platelet count, it did not differ according to fibrosis stage. In vitro, FA loading of HepG2 fully replicated the impairment of LAL activity observed in NALFD patients. In these cells, the activation of PPAR-alpha receptors prevented and corrected FA-induced LAL impairment, by stimulating FA oxidation and LAL expression. CONCLUSIONS: LAL activity is reduced in NAFLD patients, independently from disease progression. In vitro, impaired LAL activity induced by FA loading was rescued by PPAR-alpha activation. These data suggest that the pharmacological modulation of LAL should be explored in the management of NAFLD patients.
AIMS: It has been hypothesized that the activity of lysosomal acid lipase (LAL), a key enzyme involved in lipid metabolism, is involved in the NAFLD phenotype. To clarify the role of LAL in NAFLD, we studied 164 consecutive patients with biopsy-proven NAFLD and fat-loaded HepG2 cells. METHODS:LAL activity was measured (i) on dried blood spots (DBS) from NAFLD patients and dyslipidemic subjects without fatty liver and (ii) on liver biopsies from NAFLD patients. LAL activity and expression were evaluated in HepG2 cells cultured in the presence of free fatty acids (FAs), with or without a PPAR-alpha agonist. RESULTS:LAL activity was significantly reduced in patients with NAFLD compared to dyslipidemic subjects. LAL activity measured in liver biopsies from NAFLD patients was highly correlated to that measured on DBS and was independent of LAL expression in the liver. In a fully adjusted model, LAL activity on DBS was associated only with platelets and, when normalized by platelet count, it did not differ according to fibrosis stage. In vitro, FA loading of HepG2 fully replicated the impairment of LAL activity observed in NALFD patients. In these cells, the activation of PPAR-alpha receptors prevented and corrected FA-induced LAL impairment, by stimulating FA oxidation and LAL expression. CONCLUSIONS:LAL activity is reduced in NAFLD patients, independently from disease progression. In vitro, impaired LAL activity induced by FA loading was rescued by PPAR-alpha activation. These data suggest that the pharmacological modulation of LAL should be explored in the management of NAFLD patients.
Authors: Simone Carotti; Daniele Lettieri-Barbato; Katia Aquilano; Umberto Vespasiani-Gentilucci; Fiorella Piemonte; Sergio Ruggiero; Marco Rosina; Francesca Zalfa; Maria Zingariello; Francesca Arciprete; Francesco Valentini; Maria Francesconi; Jessica D'Amico; Antonio De Vincentis; Andrea Baiocchini; Giuseppe Perrone; Raffaele Antonelli-Incalzi; Sergio Morini; Antonio Picardi Journal: Cell Death Dis Date: 2021-11-18 Impact factor: 8.469