Premium
Monoacylglycerol Acyltransferase 1 Knockdown Exacerbates Hepatic Ischemia/Reperfusion Injury in Mice With Hepatic Steatosis
Author(s) -
Liss Kim H. H.,
Ek Shelby E.,
Lutkewitte Andrew J.,
Pietka Terri A.,
He Mai,
Skaria Priya,
Tycksen Eric,
Ferguson Daniel,
Blanc Valerie,
Graham Mark J.,
Hall Angela M.,
McGill Mitchell R.,
McCommis Kyle S.,
Finck Brian N.
Publication year - 2021
Publication title -
liver transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.814
H-Index - 150
eISSN - 1527-6473
pISSN - 1527-6465
DOI - 10.1002/lt.25886
Subject(s) - steatosis , monoacylglycerol lipase , medicine , gene knockdown , nonalcoholic fatty liver disease , liver transplantation , reperfusion injury , proinflammatory cytokine , fatty liver , endocrinology , liver injury , steatohepatitis , transplantation , ischemia , inflammation , biology , endocannabinoid system , disease , apoptosis , biochemistry , receptor
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 M o gat1 in a mouse model of NAFLD. Mice then underwent surgery to induce IRI. We found that M ogat1 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 M ogat1 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.