Monoacylglycerol acyltransferase 1 knockdown exacerbates hepatic ischemia-reperfusion injury in mice with hepatic steatosis

2020-09-11

Background and aims: 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, it also limits the supply of available organs since steatosis predisposes grafts to ischemia-reperfusion (IR) injury and many steatotic grafts are discarded. We have shown that monoacylglycerol acyltransferase 1 (MGAT1), 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 (gene encoding MGAT1) knockdown in mice with hepatic steatosis would reduce liver injury and improve liver regeneration following experimental IR injury.

Approach and results: Antisense oligonucleotides (ASO) were used to knockdown expression of Mogat1 in a mouse model of NAFLD. Mice then underwent surgery to induce IR injury. We found that Mogat1 knockdown reduced hepatic triacylglycerol (TAG) accumulation, but unexpectedly exacerbated liver injury and mortality following experimental IR surgery in mice on a high fat diet. The increased liver injury was associated with robust effects on the hepatic transcriptome following IR injury 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.

Conclusions: We have shown that Mogat1 knockdown in a mouse model of NAFLD exacerbates IR injury and inflammation and prolongs injury resolution, suggesting that Mogat1 may be necessary for liver regeneration following IR injury and targeting this metabolic enzyme will not be an effective treatment to reduce steatosis-associated graft dysfunction or failure.

Authors: Kim H H Liss, Shelby E Ek, Andrew J Lutkewitte, Terri A Pietka, Mai He, Priya Skaria, Eric Tycksen, Daniel Ferguson, Valerie Blanc, Mark J Graham, Angela M Hall, Mitchell R McGill, Kyle S McCommis, Brian N Finck
; Full Source: Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2020 Sep 11. doi: 10.1002/lt.25886.