Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783469497954336768 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6850774 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT helsleyrobertn obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT varadharajanvenkateshwari obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT brownamandal obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT gromovskyanthonyd obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT schugarrebeccac obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT ramachandiraniyappan obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT fungkevin obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT kabbanymohammadnasser obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT banerjeerakhee obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT neumannchasek obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT finneychelsea obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT pathakpreeti obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT orabidanny obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT osbornlucasj obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT masseywilliam obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT zhangrenliang obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT kadamanagha obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT sansburybriane obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT pancalvin obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT sacksjessica obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT leerichardg obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT crookerosannem obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT grahammarkj obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT lemieuxmadeleinee obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT gogoneavalentin obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT kirwanjohnp obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT allendedanielas obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT civelekmete obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT foxpaull obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT rudellawrencel obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT lusisaldonsj obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT spitematthew obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease AT brownjmark obesitylinkedsuppressionofmembraneboundoacyltransferase7mboat7drivesnonalcoholicfattyliverdisease |