@article{fd445832eac84deda8f1130524a8bcb9,
title = "Monoacylglycerol Acyltransferase 1 Knockdown Exacerbates Hepatic Ischemia/Reperfusion Injury in Mice With Hepatic Steatosis",
abstract = "Nonalcoholic fatty liver disease (NAFLD) is becoming the most common indication for liver transplantation. The growing prevalence of NAFLD not only increases the demand for liver transplantation, but it also limits the supply of available organs because steatosis predisposes grafts to ischemia/reperfusion injury (IRI) and many steatotic grafts are discarded. We have shown that monoacylglycerol acyltransferase (MGAT) 1, an enzyme that converts monoacylglycerol to diacylglycerol, is highly induced in animal models and patients with NAFLD and is an important mediator in NAFLD-related insulin resistance. Herein, we sought to determine whether Mogat1 (the gene encoding MGAT1) knockdown in mice with hepatic steatosis would reduce liver injury and improve liver regeneration following experimental IRI. Antisense oligonucleotides (ASO) were used to knockdown the expression of Mogat1 in a mouse model of NAFLD. Mice then underwent surgery to induce IRI. We found that Mogat1 knockdown reduced hepatic triacylglycerol accumulation, but it unexpectedly exacerbated liver injury and mortality following experimental ischemia/reperfusion surgery in mice on a high-fat diet. The increased liver injury was associated with robust effects on the hepatic transcriptome following IRI including enhanced expression of proinflammatory cytokines and chemokines and suppression of enzymes involved in intermediary metabolism. These transcriptional changes were accompanied by increased signs of oxidative stress and an impaired regenerative response. We have shown that Mogat1 knockdown in a mouse model of NAFLD exacerbates IRI and inflammation and prolongs injury resolution, suggesting that Mogat1 may be necessary for liver regeneration following IRI and that targeting this metabolic enzyme will not be an effective treatment to reduce steatosis-associated graft dysfunction or failure.",
author = "Liss, {Kim H.H.} and Ek, {Shelby E.} and Lutkewitte, {Andrew J.} and Pietka, {Terri A.} and Mai He and Priya Skaria and Eric Tycksen and Daniel Ferguson and Valerie Blanc and Graham, {Mark J.} and Hall, {Angela M.} and McGill, {Mitchell R.} and McCommis, {Kyle S.} and Finck, {Brian N.}",
note = "Funding Information: Work in the authors{\textquoteright} laboratory was supported by grants from the National Institutes of Health (NIH) by grant R56‐DK‐111735 and the American Diabetes Association by grant 1‐17‐IBS‐109 to Brian N. Finck and core laboratories of Washington University School of Medicine (Digestive Diseases Research Cores Center NIH grant P30‐DK‐052574 and the Nutrition Obesity Research Center grant P30‐DK‐056341). Kim H. H. Liss is supported by NIH grant K12‐HD‐076224‐06. Kyle S. McCommis is supported by NIH grant R00‐DK‐056341. Mitchell R. McGill is supported by a Pinnacle Research Award from the American Association for the Study of Liver Diseases Foundation. The Genome Technology Access Center in the McDonnell Genome Institute at Washington University School of Medicine is partially supported by National Cancer Institute Cancer Center Support grant P30 CA91842 to the Siteman Cancer Center and by Institute for Clinical and Translational Science Clinical and Translational Science Award grant UL1TR002345 from the National Center for Research Resources, a component of the NIH, and NIH Roadmap for Medical Research. The Metabolomics Facility at Washington University School of Medicine is supported by NIH grant P30‐DK‐056341. Funding Information: We thank the Genome?Technology Access Center in?the McDonnell Genome Institute at Washington University?School of Medicine for help?with genomic analysis. We thank the Metabolomics Facility at Washington University School of Medicine (NIH grant P30-DK-056341) for performing mass spectrometry studies. We thank the Digestive Diseases Research Cores Center in the Division of Gastroenterology at Washington University School of Medicine for immunohistochemical studies. We thank Ionis Pharmaceuticals, Inc (Richard Lee) for supplying the ASOs used in these studies. Funding Information: We thank the Genome Technology Access Center in the McDonnell Genome Institute at Washington University School of Medicine for help with genomic analysis. We thank the Metabolomics Facility at Washington University School of Medicine (NIH grant P30‐DK‐056341) for performing mass spectrometry studies. We thank the Digestive Diseases Research Cores Center in the Division of Gastroenterology at Washington University School of Medicine for immunohistochemical studies. We thank Ionis Pharmaceuticals, Inc (Richard Lee) for supplying the ASOs used in these studies. Publisher Copyright: Copyright {\textcopyright} 2020 by the American Association for the Study of Liver Diseases.",
year = "2021",
month = jan,
doi = "10.1002/lt.25886",
language = "English",
volume = "27",
pages = "116--133",
journal = "Liver Transplantation",
issn = "1527-6465",
number = "1",
}