Cargando…

Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes

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 M...

Descripción completa

Detalles Bibliográficos
Autores principales: Meroni, Marica, Dongiovanni, Paola, Longo, Miriam, Carli, Fabrizia, Baselli, Guido, Rametta, Raffaela, Pelusi, Serena, Badiali, Sara, Maggioni, Marco, Gaggini, Melania, Fracanzani, Anna Ludovica, Romeo, Stefano, Gatti, Stefano, Davidson, Nicholas O., Gastaldelli, Amalia, Valenti, Luca
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026742/
https://www.ncbi.nlm.nih.gov/pubmed/32058943
http://dx.doi.org/10.1016/j.ebiom.2020.102658
_version_ 1783498744046551040
author Meroni, Marica
Dongiovanni, Paola
Longo, Miriam
Carli, Fabrizia
Baselli, Guido
Rametta, Raffaela
Pelusi, Serena
Badiali, Sara
Maggioni, Marco
Gaggini, Melania
Fracanzani, Anna Ludovica
Romeo, Stefano
Gatti, Stefano
Davidson, Nicholas O.
Gastaldelli, Amalia
Valenti, Luca
author_facet Meroni, Marica
Dongiovanni, Paola
Longo, Miriam
Carli, Fabrizia
Baselli, Guido
Rametta, Raffaela
Pelusi, Serena
Badiali, Sara
Maggioni, Marco
Gaggini, Melania
Fracanzani, Anna Ludovica
Romeo, Stefano
Gatti, Stefano
Davidson, Nicholas O.
Gastaldelli, Amalia
Valenti, Luca
author_sort Meroni, Marica
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7026742
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-70267422020-02-25 Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes Meroni, Marica Dongiovanni, Paola Longo, Miriam Carli, Fabrizia Baselli, Guido Rametta, Raffaela Pelusi, Serena Badiali, Sara Maggioni, Marco Gaggini, Melania Fracanzani, Anna Ludovica Romeo, Stefano Gatti, Stefano Davidson, Nicholas O. Gastaldelli, Amalia Valenti, Luca EBioMedicine Research paper 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. Elsevier 2020-02-12 /pmc/articles/PMC7026742/ /pubmed/32058943 http://dx.doi.org/10.1016/j.ebiom.2020.102658 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research paper
Meroni, Marica
Dongiovanni, Paola
Longo, Miriam
Carli, Fabrizia
Baselli, Guido
Rametta, Raffaela
Pelusi, Serena
Badiali, Sara
Maggioni, Marco
Gaggini, Melania
Fracanzani, Anna Ludovica
Romeo, Stefano
Gatti, Stefano
Davidson, Nicholas O.
Gastaldelli, Amalia
Valenti, Luca
Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes
title Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes
title_full Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes
title_fullStr Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes
title_full_unstemmed Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes
title_short Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes
title_sort mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes
topic Research paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026742/
https://www.ncbi.nlm.nih.gov/pubmed/32058943
http://dx.doi.org/10.1016/j.ebiom.2020.102658
work_keys_str_mv AT meronimarica mboat7downregulationbyhyperinsulinemiainducesfataccumulationinhepatocytes
AT dongiovannipaola mboat7downregulationbyhyperinsulinemiainducesfataccumulationinhepatocytes
AT longomiriam mboat7downregulationbyhyperinsulinemiainducesfataccumulationinhepatocytes
AT carlifabrizia mboat7downregulationbyhyperinsulinemiainducesfataccumulationinhepatocytes
AT baselliguido mboat7downregulationbyhyperinsulinemiainducesfataccumulationinhepatocytes
AT ramettaraffaela mboat7downregulationbyhyperinsulinemiainducesfataccumulationinhepatocytes
AT pelusiserena mboat7downregulationbyhyperinsulinemiainducesfataccumulationinhepatocytes
AT badialisara mboat7downregulationbyhyperinsulinemiainducesfataccumulationinhepatocytes
AT maggionimarco mboat7downregulationbyhyperinsulinemiainducesfataccumulationinhepatocytes
AT gagginimelania mboat7downregulationbyhyperinsulinemiainducesfataccumulationinhepatocytes
AT fracanzaniannaludovica mboat7downregulationbyhyperinsulinemiainducesfataccumulationinhepatocytes
AT romeostefano mboat7downregulationbyhyperinsulinemiainducesfataccumulationinhepatocytes
AT gattistefano mboat7downregulationbyhyperinsulinemiainducesfataccumulationinhepatocytes
AT davidsonnicholaso mboat7downregulationbyhyperinsulinemiainducesfataccumulationinhepatocytes
AT gastaldelliamalia mboat7downregulationbyhyperinsulinemiainducesfataccumulationinhepatocytes
AT valentiluca mboat7downregulationbyhyperinsulinemiainducesfataccumulationinhepatocytes