Absence of Adiponutrin (PNPLA3) and Monoacylglycerol Lipase Synergistically Increases Weight Gain and Aggravates Steatohepatitis in Mice
Altered lipid metabolic pathways including hydrolysis of triglycerides are key players in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Whether adiponutrin (patatin-like phospholipase domain containing protein-3—PNPLA3) and monoacylglycerol lipase (MGL) synergistically contribute to...
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doaj-6d73bead7c4e4a43bc5852dcf7fe6cad2021-02-21T00:06:28ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01222126212610.3390/ijms22042126Absence of Adiponutrin (PNPLA3) and Monoacylglycerol Lipase Synergistically Increases Weight Gain and Aggravates Steatohepatitis in MiceMatteo Tardelli0Francesca V. Bruschi1Claudia D. Fuchs2Thierry Claudel3Nicole Auer4Victoria Kunczer5Onne A. H. O. Ronda6Henkjan J. Verkade7Tatjana Stojakovic8Hubert Scharnagl9Michael Trauner10Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, AustriaHans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, AustriaHans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, AustriaHans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, AustriaHans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, AustriaHans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, AustriaCenter for Liver, Digestive and Metabolic Diseases, Departments of Pediatrics, University Medical Center Groningen, 9712 Groningen, The NetherlandsCenter for Liver, Digestive and Metabolic Diseases, Departments of Pediatrics, University Medical Center Groningen, 9712 Groningen, The NetherlandsClinical Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Graz, 8036 Graz, AustriaClinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, AustriaHans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, AustriaAltered lipid metabolic pathways including hydrolysis of triglycerides are key players in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Whether adiponutrin (patatin-like phospholipase domain containing protein-3—PNPLA3) and monoacylglycerol lipase (MGL) synergistically contribute to disease progression remains unclear. We generated double knockout (<i>DKO</i>) mice lacking both <i>Mgl</i> and <i>Pnpla3</i>; <i>DKO</i> mice were compared to <i>Mgl<sup>−/−</sup></i> after a challenge by high-fat diet (HFD) for 12 weeks to induce steatosis. Serum biochemistry, liver transaminases as well as histology were analyzed. Fatty acid (FA) profiling was assessed in liver and adipose tissue by gas chromatography. Markers of inflammation and lipid metabolism were analyzed. Bone marrow derived macrophages (BMDMs) were isolated and treated with oleic acid. Combined deficiency of <i>Mgl</i> and <i>Pnpla3</i> resulted in weight gain on a chow diet; when challenged by HFD, <i>DKO</i> mice showed increased hepatic FA synthesis and diminished beta-oxidation compared to <i>Mgl<sup>−/−</sup>.</i><i>DKO</i> mice exhibited more pronounced hepatic steatosis with inflammation and recruitment of immune cells to the liver associated with accumulation of saturated FAs. Primary BMDMs isolated from the <i>DKO</i> mice showed increased inflammatory activities, which could be reversed by oleic acid supplementation. <i>Pnpla3</i> deficiency aggravates the effects of <i>Mgl</i> deletion on steatosis and inflammation in the liver under HFD challenge.https://www.mdpi.com/1422-0067/22/4/2126NAFLDMGLPNPLA3NASHinflammation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Matteo Tardelli Francesca V. Bruschi Claudia D. Fuchs Thierry Claudel Nicole Auer Victoria Kunczer Onne A. H. O. Ronda Henkjan J. Verkade Tatjana Stojakovic Hubert Scharnagl Michael Trauner |
spellingShingle |
Matteo Tardelli Francesca V. Bruschi Claudia D. Fuchs Thierry Claudel Nicole Auer Victoria Kunczer Onne A. H. O. Ronda Henkjan J. Verkade Tatjana Stojakovic Hubert Scharnagl Michael Trauner Absence of Adiponutrin (PNPLA3) and Monoacylglycerol Lipase Synergistically Increases Weight Gain and Aggravates Steatohepatitis in Mice International Journal of Molecular Sciences NAFLD MGL PNPLA3 NASH inflammation |
author_facet |
Matteo Tardelli Francesca V. Bruschi Claudia D. Fuchs Thierry Claudel Nicole Auer Victoria Kunczer Onne A. H. O. Ronda Henkjan J. Verkade Tatjana Stojakovic Hubert Scharnagl Michael Trauner |
author_sort |
Matteo Tardelli |
title |
Absence of Adiponutrin (PNPLA3) and Monoacylglycerol Lipase Synergistically Increases Weight Gain and Aggravates Steatohepatitis in Mice |
title_short |
Absence of Adiponutrin (PNPLA3) and Monoacylglycerol Lipase Synergistically Increases Weight Gain and Aggravates Steatohepatitis in Mice |
title_full |
Absence of Adiponutrin (PNPLA3) and Monoacylglycerol Lipase Synergistically Increases Weight Gain and Aggravates Steatohepatitis in Mice |
title_fullStr |
Absence of Adiponutrin (PNPLA3) and Monoacylglycerol Lipase Synergistically Increases Weight Gain and Aggravates Steatohepatitis in Mice |
title_full_unstemmed |
Absence of Adiponutrin (PNPLA3) and Monoacylglycerol Lipase Synergistically Increases Weight Gain and Aggravates Steatohepatitis in Mice |
title_sort |
absence of adiponutrin (pnpla3) and monoacylglycerol lipase synergistically increases weight gain and aggravates steatohepatitis in mice |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-02-01 |
description |
Altered lipid metabolic pathways including hydrolysis of triglycerides are key players in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Whether adiponutrin (patatin-like phospholipase domain containing protein-3—PNPLA3) and monoacylglycerol lipase (MGL) synergistically contribute to disease progression remains unclear. We generated double knockout (<i>DKO</i>) mice lacking both <i>Mgl</i> and <i>Pnpla3</i>; <i>DKO</i> mice were compared to <i>Mgl<sup>−/−</sup></i> after a challenge by high-fat diet (HFD) for 12 weeks to induce steatosis. Serum biochemistry, liver transaminases as well as histology were analyzed. Fatty acid (FA) profiling was assessed in liver and adipose tissue by gas chromatography. Markers of inflammation and lipid metabolism were analyzed. Bone marrow derived macrophages (BMDMs) were isolated and treated with oleic acid. Combined deficiency of <i>Mgl</i> and <i>Pnpla3</i> resulted in weight gain on a chow diet; when challenged by HFD, <i>DKO</i> mice showed increased hepatic FA synthesis and diminished beta-oxidation compared to <i>Mgl<sup>−/−</sup>.</i><i>DKO</i> mice exhibited more pronounced hepatic steatosis with inflammation and recruitment of immune cells to the liver associated with accumulation of saturated FAs. Primary BMDMs isolated from the <i>DKO</i> mice showed increased inflammatory activities, which could be reversed by oleic acid supplementation. <i>Pnpla3</i> deficiency aggravates the effects of <i>Mgl</i> deletion on steatosis and inflammation in the liver under HFD challenge. |
topic |
NAFLD MGL PNPLA3 NASH inflammation |
url |
https://www.mdpi.com/1422-0067/22/4/2126 |
work_keys_str_mv |
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