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Obesity-linked suppression of membrane-bound O-acyltransferase 7 (MBOAT7) drives non-alcoholic fatty liver disease

Recent studies have identified a genetic variant rs641738 near two genes encoding membrane bound O-acyltransferase domain-containing 7 (MBOAT7) and transmembrane channel-like 4 (TMC4) that associate with increased risk of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH...

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Autores principales: Helsley, Robert N, Varadharajan, Venkateshwari, Brown, Amanda L, Gromovsky, Anthony D, Schugar, Rebecca C, Ramachandiran, Iyappan, Fung, Kevin, Kabbany, Mohammad Nasser, Banerjee, Rakhee, Neumann, Chase K, Finney, Chelsea, Pathak, Preeti, Orabi, Danny, Osborn, Lucas J, Massey, William, Zhang, Renliang, Kadam, Anagha, Sansbury, Brian E, Pan, Calvin, Sacks, Jessica, Lee, Richard G, Crooke, Rosanne M, Graham, Mark J, Lemieux, Madeleine E, Gogonea, Valentin, Kirwan, John P, Allende, Daniela S, Civelek, Mete, Fox, Paul L, Rudel, Lawrence L, Lusis, Aldons J, Spite, Matthew, Brown, J Mark
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850774/
https://www.ncbi.nlm.nih.gov/pubmed/31621579
http://dx.doi.org/10.7554/eLife.49882
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author Helsley, Robert N
Varadharajan, Venkateshwari
Brown, Amanda L
Gromovsky, Anthony D
Schugar, Rebecca C
Ramachandiran, Iyappan
Fung, Kevin
Kabbany, Mohammad Nasser
Banerjee, Rakhee
Neumann, Chase K
Finney, Chelsea
Pathak, Preeti
Orabi, Danny
Osborn, Lucas J
Massey, William
Zhang, Renliang
Kadam, Anagha
Sansbury, Brian E
Pan, Calvin
Sacks, Jessica
Lee, Richard G
Crooke, Rosanne M
Graham, Mark J
Lemieux, Madeleine E
Gogonea, Valentin
Kirwan, John P
Allende, Daniela S
Civelek, Mete
Fox, Paul L
Rudel, Lawrence L
Lusis, Aldons J
Spite, Matthew
Brown, J Mark
author_facet Helsley, Robert N
Varadharajan, Venkateshwari
Brown, Amanda L
Gromovsky, Anthony D
Schugar, Rebecca C
Ramachandiran, Iyappan
Fung, Kevin
Kabbany, Mohammad Nasser
Banerjee, Rakhee
Neumann, Chase K
Finney, Chelsea
Pathak, Preeti
Orabi, Danny
Osborn, Lucas J
Massey, William
Zhang, Renliang
Kadam, Anagha
Sansbury, Brian E
Pan, Calvin
Sacks, Jessica
Lee, Richard G
Crooke, Rosanne M
Graham, Mark J
Lemieux, Madeleine E
Gogonea, Valentin
Kirwan, John P
Allende, Daniela S
Civelek, Mete
Fox, Paul L
Rudel, Lawrence L
Lusis, Aldons J
Spite, Matthew
Brown, J Mark
author_sort Helsley, Robert N
collection PubMed
description Recent studies have identified a genetic variant rs641738 near two genes encoding membrane bound O-acyltransferase domain-containing 7 (MBOAT7) and transmembrane channel-like 4 (TMC4) that associate with increased risk of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcohol-related cirrhosis, and liver fibrosis in those infected with viral hepatitis (Buch et al., 2015; Mancina et al., 2016; Luukkonen et al., 2016; Thabet et al., 2016; Viitasalo et al., 2016; Krawczyk et al., 2017; Thabet et al., 2017). Based on hepatic expression quantitative trait loci analysis, it has been suggested that MBOAT7 loss of function promotes liver disease progression (Buch et al., 2015; Mancina et al., 2016; Luukkonen et al., 2016; Thabet et al., 2016; Viitasalo et al., 2016; Krawczyk et al., 2017; Thabet et al., 2017), but this has never been formally tested. Here we show that Mboat7 loss, but not Tmc4, in mice is sufficient to promote the progression of NAFLD in the setting of high fat diet. Mboat7 loss of function is associated with accumulation of its substrate lysophosphatidylinositol (LPI) lipids, and direct administration of LPI promotes hepatic inflammatory and fibrotic transcriptional changes in an Mboat7-dependent manner. These studies reveal a novel role for MBOAT7-driven acylation of LPI lipids in suppressing the progression of NAFLD.
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spelling pubmed-68507742019-11-14 Obesity-linked suppression of membrane-bound O-acyltransferase 7 (MBOAT7) drives non-alcoholic fatty liver disease Helsley, Robert N Varadharajan, Venkateshwari Brown, Amanda L Gromovsky, Anthony D Schugar, Rebecca C Ramachandiran, Iyappan Fung, Kevin Kabbany, Mohammad Nasser Banerjee, Rakhee Neumann, Chase K Finney, Chelsea Pathak, Preeti Orabi, Danny Osborn, Lucas J Massey, William Zhang, Renliang Kadam, Anagha Sansbury, Brian E Pan, Calvin Sacks, Jessica Lee, Richard G Crooke, Rosanne M Graham, Mark J Lemieux, Madeleine E Gogonea, Valentin Kirwan, John P Allende, Daniela S Civelek, Mete Fox, Paul L Rudel, Lawrence L Lusis, Aldons J Spite, Matthew Brown, J Mark eLife Human Biology and Medicine Recent studies have identified a genetic variant rs641738 near two genes encoding membrane bound O-acyltransferase domain-containing 7 (MBOAT7) and transmembrane channel-like 4 (TMC4) that associate with increased risk of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcohol-related cirrhosis, and liver fibrosis in those infected with viral hepatitis (Buch et al., 2015; Mancina et al., 2016; Luukkonen et al., 2016; Thabet et al., 2016; Viitasalo et al., 2016; Krawczyk et al., 2017; Thabet et al., 2017). Based on hepatic expression quantitative trait loci analysis, it has been suggested that MBOAT7 loss of function promotes liver disease progression (Buch et al., 2015; Mancina et al., 2016; Luukkonen et al., 2016; Thabet et al., 2016; Viitasalo et al., 2016; Krawczyk et al., 2017; Thabet et al., 2017), but this has never been formally tested. Here we show that Mboat7 loss, but not Tmc4, in mice is sufficient to promote the progression of NAFLD in the setting of high fat diet. Mboat7 loss of function is associated with accumulation of its substrate lysophosphatidylinositol (LPI) lipids, and direct administration of LPI promotes hepatic inflammatory and fibrotic transcriptional changes in an Mboat7-dependent manner. These studies reveal a novel role for MBOAT7-driven acylation of LPI lipids in suppressing the progression of NAFLD. eLife Sciences Publications, Ltd 2019-10-17 /pmc/articles/PMC6850774/ /pubmed/31621579 http://dx.doi.org/10.7554/eLife.49882 Text en © 2019, Helsley et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Human Biology and Medicine
Helsley, Robert N
Varadharajan, Venkateshwari
Brown, Amanda L
Gromovsky, Anthony D
Schugar, Rebecca C
Ramachandiran, Iyappan
Fung, Kevin
Kabbany, Mohammad Nasser
Banerjee, Rakhee
Neumann, Chase K
Finney, Chelsea
Pathak, Preeti
Orabi, Danny
Osborn, Lucas J
Massey, William
Zhang, Renliang
Kadam, Anagha
Sansbury, Brian E
Pan, Calvin
Sacks, Jessica
Lee, Richard G
Crooke, Rosanne M
Graham, Mark J
Lemieux, Madeleine E
Gogonea, Valentin
Kirwan, John P
Allende, Daniela S
Civelek, Mete
Fox, Paul L
Rudel, Lawrence L
Lusis, Aldons J
Spite, Matthew
Brown, J Mark
Obesity-linked suppression of membrane-bound O-acyltransferase 7 (MBOAT7) drives non-alcoholic fatty liver disease
title Obesity-linked suppression of membrane-bound O-acyltransferase 7 (MBOAT7) drives non-alcoholic fatty liver disease
title_full Obesity-linked suppression of membrane-bound O-acyltransferase 7 (MBOAT7) drives non-alcoholic fatty liver disease
title_fullStr Obesity-linked suppression of membrane-bound O-acyltransferase 7 (MBOAT7) drives non-alcoholic fatty liver disease
title_full_unstemmed Obesity-linked suppression of membrane-bound O-acyltransferase 7 (MBOAT7) drives non-alcoholic fatty liver disease
title_short Obesity-linked suppression of membrane-bound O-acyltransferase 7 (MBOAT7) drives non-alcoholic fatty liver disease
title_sort obesity-linked suppression of membrane-bound o-acyltransferase 7 (mboat7) drives non-alcoholic fatty liver disease
topic Human Biology and Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850774/
https://www.ncbi.nlm.nih.gov/pubmed/31621579
http://dx.doi.org/10.7554/eLife.49882
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