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.

Dynamic changes in the mouse hepatic lipidome following warm ischemia reperfusion injury

“…Specifically, we noted significant TG accumulation in non-steatotic liver following IRI. This is in line with previous findings of transient steatosis following IRI (11) and partial hepatectomy (30). Of note, we did not see a similar increase in TG in steatotic liver.…”

“…However, the mechanisms that lead to increased susceptibility of steatotic livers to IRI is not well understood and there are currently no pharmacological interventions to prevent or treat IRI. Studies in non-steatotic liver have indicated that IRI is associated with alterations in lipid metabolism (8)(9)(10)(11)(12)(13)(14). Lipids play important physiological functions as an energy source, as signaling intermediates, and as building blocks for plasma membranes (15,16).…”

Multiple antisense oligonucleotides targeted against monoacylglycerol acyltransferase 1 (Mogat1) improve glucose metabolism independently of Mogat1

“…Immediately following dissection, livers were fixed in 10% buffered formalin for 48 h. Liver tissue was rinsed and stored in 70% EtOH until paraffin embedding, sectioning, and staining with hematoxylin-eosin (H&E) in the Anatomic and Molecular Pathology Core Labs at Washington University School of Medicine. H&E sections were used to determine NAFLD activity score by a blinded independent clinical pathologist [ 24 ].…”

N-Acetylcysteine alleviates high fat diet-induced hepatic steatosis and liver injuryviaregulating the intestinal microecology in mice

“…Knockdown of the expression of Mogat1 in mice with hepatic steatosis reduced liver injury and improved liver regeneration. 54 It also has been…”