Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes
Marica Meroni,
Paola Dongiovanni,
Miriam Longo,
Fabrizia Carli,
Guido Baselli,
Raffaela Rametta,
Serena Pelusi,
Sara Badiali,
Marco Maggioni,
Melania Gaggini,
Anna Ludovica Fracanzani,
Stefano Romeo,
Stefano Gatti,
Nicholas O. Davidson,
Amalia Gastaldelli,
Luca Valenti
Affiliations
Marica Meroni
General and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Ospedale Policlinico via F Sforza 35, 20122 Milano, Italy
Paola Dongiovanni
General and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy
Miriam Longo
General and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy
Fabrizia Carli
National Research Council (CNR), Institute of Clinical Physiology, Pisa, Italy
Guido Baselli
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Ospedale Policlinico via F Sforza 35, 20122 Milano, Italy
Raffaela Rametta
General and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy
Serena Pelusi
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Ospedale Policlinico via F Sforza 35, 20122 Milano, Italy; Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Italy
Sara Badiali
Department of Surgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy
Marco Maggioni
Department of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy
Melania Gaggini
National Research Council (CNR), Institute of Clinical Physiology, Pisa, Italy
Anna Ludovica Fracanzani
General and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Ospedale Policlinico via F Sforza 35, 20122 Milano, Italy
Stefano Romeo
Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden; Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden; Clinical Nutrition Department of Medical and Surgical Science, University Magna Graecia, Catanzaro, Italy
Stefano Gatti
Preclinical research center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy
Nicholas O. Davidson
Department of Medicine, Washington University School of Medicine, St. Louis, MO, Italy
Amalia Gastaldelli
National Research Council (CNR), Institute of Clinical Physiology, Pisa, Italy
Luca Valenti
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Ospedale Policlinico via F Sforza 35, 20122 Milano, Italy; Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Italy; Corresponding author at: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Ospedale Policlinico via F Sforza 35, 20122 Milano, Italy.
Background: Naturally occurring variation in Membrane-bound O-acyltransferase domain-containing 7 (MBOAT7), encoding for an enzyme involved in phosphatidylinositol acyl-chain remodelling, has been associated with fatty liver and hepatic disorders. Here, we examined the relationship between hepatic Mboat7 down-regulation and fat accumulation. Methods: Hepatic MBOAT7 expression was surveyed in 119 obese individuals and in experimental models. MBOAT7 was acutely silenced by antisense oligonucleotides in C57Bl/6 mice, and by CRISPR/Cas9 in HepG2 hepatocytes. Findings: In obese individuals, hepatic MBOAT7 mRNA decreased from normal liver to steatohepatitis, independently of diabetes, inflammation and MBOAT7 genotype. Hepatic MBOAT7 levels were reduced in murine models of fatty liver, and by hyper-insulinemia. In wild-type mice, Mboat7 was down-regulated by refeeding and insulin, concomitantly with insulin signalling activation. Acute hepatic Mboat7 silencing promoted hepatic steatosis in vivo and enhanced expression of fatty acid transporter Fatp1. MBOAT7 deletion in hepatocytes reduced the incorporation of arachidonic acid into phosphatidylinositol, consistently with decreased enzymatic activity, determining the accumulation of saturated triglycerides, enhanced lipogenesis and FATP1 expression, while FATP1 deletion rescued the phenotype. Interpretation: MBOAT7 down-regulation by hyper-insulinemia contributes to hepatic fat accumulation, impairing phosphatidylinositol remodelling and up-regulating FATP1. Funding: LV was supported by MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016–02,364,358, Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico; LV and AG received funding from the European Union Programme Horizon 2020 (No. 777,377) for the project LITMUS-“Liver Investigation: Testing Marker Utility in Steatohepatitis”. MM was supported by Fondazione Italiana per lo Studio del Fegato (AISF) ‘Mario Coppo’ fellowship. Keywords: LPIAT1, NAFLD, Nash, Nonalcoholic fatty liver disease, Steatohepatitis, Phospholipid, Phosphatidylinositol
