O-GlcNAc transferase suppresses necroptosis and liver fibrosis

Abstract

Over a billion people suffer from chronic liver diseases worldwide, which often leads to fibrosis and then cirrhosis. Treatments for fibrosis remain experimental, in part because no unifying mechanism has been identified that initiates liver fibrosis. Here we report that O-linked β-N-acetylglucosamine (O-GlcNAc) modification protects against hepatocyte necroptosis and initiation of liver fibrosis. Decreased O-GlcNAc levels were seen in patients with liver cirrhosis and in mice with ethanol-induced liver injury. Liver-specific O-GlcNAc transferase (OGT) knockout (OGT-LKO) mice exhibited ballooning degeneration and elevated circulating alanine aminotransferase levels at an early age and progressed to liver fibrosis and portal inflammation by 10 weeks of age. OGT-deficient hepatocytes underwent excessive necroptosis and exhibited elevated protein expression levels of receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), which are key mediators of necroptosis. Furthermore, glycosylation of RIPK3 by OGT reduced RIPK3 protein stability. Taken together, these findings identify OGT as a key suppressor of hepatocyte necroptosis and OGT-LKO mice may serve as an effective spontaneous genetic model of liver fibrosis.

Regulation of Liver Regeneration by hepatocyte O-GlcNAcylation in mice

“…These data are consistent with previous studies by Zhang et al demonstrated that OGT deletion, in the liver using a CRE governed by the albumin promoter, resulted in significant necroptosis and fibrosis (7). They further showed that RIP3K undergoes O-GlcNAcylation which reduces the stability of the protein (7). Our studies showed that delayed cell death in OGT-KO mice after PHX is both necroptosis as well as apoptosis (Fig.…”

“…These data indicate that loss of O-GlcNAcylation may make hepatocytes more vulnerable to cell death. These data are consistent with previous studies by Zhang et al demonstrated that OGT deletion, in the liver using a CRE governed by the albumin promoter, resulted in significant necroptosis and fibrosis (7). They further showed that RIP3K undergoes O-GlcNAcylation which reduces the stability of the protein (7).…”

“…In some cases, the residues that undergo O-GlcNAcylation on the target protein can also become phosphorylated providing the cell an additional mechanism of regulating downstream signaling (4). O-GlcNAcylation homeostasis is critical for healthy cells and aberrant O-GlcNAcylation has been linked to various diseases, including cancer, nonalcoholic fatty liver disease (NAFLD) and alcoholic steatohepatitis (ASH) (5)(6)(7). O-GlcNAcylation plays a major role in a myriad of cellular processes, including cell proliferation (8)(9)(10).…”

Methylation-directed glycosylation of chromatin factors represses retrotransposon promoters

“…Other direct evidence for a role of protein O-glycosylation in the silencing of retrotransposon comes from studies of a liverspecific deletion of Ogt in mice (32). We reanalyzed the RNAseq data from this study for transposon reactivation.…”

Pleiotropic actions of IP6K1 mediate hepatic metabolic dysfunction to promote nonalcoholic fatty liver disease and steatohepatitis

“…Polyphenolic compounds silibinin and curcumin reduce NAFLD/NASH and protein O -GlcNAcylation in mouse models [ 56 , 57 ]. In contrast, decreased protein O -GlcNAcylation in human cirrhotic livers and the protective effects of hepatocyte-OGT on alcohol-induced cirrhosis in mice have also been demonstrated [ 58 ]. Overall, both activation and disruption of protein O -GlcNAcylation have been shown to stimulate HSC activation [ [59] , [60] , [61] ].…”