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O-GlcNAc transferase suppresses necroptosis and liver fibrosis.

ABSTRACT: Worldwide, over a billion people suffer from chronic liver diseases, which often lead to fibrosis and then cirrhosis. Treatments for fibrosis remain experimental, in part because no unifying mechanism has been identified that initiates liver fibrosis. Necroptosis has been implicated in multiple liver diseases. Here, we report that O-linked ?-N-acetylglucosamine (O-GlcNAc) modification protects against hepatocyte necroptosis and initiation of liver fibrosis. Decreased O-GlcNAc levels were seen in patients with alcoholic liver cirrhosis and in mice with ethanol-induced liver injury. Liver-specific O-GlcNAc transferase-KO (OGT-LKO) mice exhibited hepatomegaly and ballooning degeneration 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 is associated with 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.

SUBMITTER: Zhang B

PROVIDER: S-EPMC6948774 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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O-GlcNAc transferase suppresses necroptosis and liver fibrosis.

Zhang Bichen B Li Min-Dian MD Yin Ruonan R Liu Yuyang Y Yang Yunfan Y Mitchell-Richards Kisha A KA Nam Jin Hyun JH Li Rui R Wang Li L Iwakiri Yasuko Y Chung Dongjun D Robert Marie E ME Ehrlich Barbara E BE Bennett Anton M AM Yu Jun J Nathanson Michael H MH Yang Xiaoyong X

JCI insight 20191101 21

Worldwide, over a billion people suffer from chronic liver diseases, which often lead to fibrosis and then cirrhosis. Treatments for fibrosis remain experimental, in part because no unifying mechanism has been identified that initiates liver fibrosis. Necroptosis has been implicated in multiple liver diseases. 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 ...[more]

PMID: 31672932

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Project description:Background and aimsSerum levels of ?-glutamyl-transpeptidase(?-GT) were associated with liver disease severity and metabolic alterations, which in turn are able to affect hepatic damage. In patients with nonalcoholic fatty liver disease (NAFLD), genotype 1 chronic hepatitis C (G1CHC) and chronic hepatitis B (CHB), we assessed the link between liver fibrosis and ?-GT serum levels, and we evaluated if normal or high ?-GT serum levels affect the association between insulin resistance (IR) and severity of liver fibrosis.Methods843 consecutive patients with chronic liver disease (CLD)(193 NAFLD, 481 G1CHC, 169 CHB) were evaluated by liver biopsy (Kleiner and Scheuer scores) and clinical and metabolic measurements. IR was diagnosed if HOMA>3. A serum ?-GT concentration of >36 IU/L in females and >61 IU/L in males was considered the threshold value for identifying high levels of ?-GT.ResultsBy multivariate logistic regression analysis, abnormal ?-GT serum levels were independently linked to severe liver fibrosis in patients with NAFLD (OR2.711,CI1.120-6.564,p = 0.02), G1CHC (OR3.461,CI2.138-5.603,p<0.001) and CHB (OR2.778,CI1.042-7.414,p = 0.04), together with IR and liver necroinflammation, and with a negative predictive value>80%. Interestingly, among patients with high or normal ?-GT values, even if IR prevalence was significantly higher in patients with severe fibrosis compared to those without, IR remained significantly associated with severe fibrosis in patients with abnormal ?-GT values only (OR4.150,CI1.079-15.970,p = 0.03 for NAFLD; OR2.250,CI1.211-4.181,p = 0.01 for G1CHC; OR3.096,CI2.050-34.220,p = 0.01 for CHB).ConclusionsIn patients with CLD, IR is independently linked to liver fibrosis only in patients with abnormal ?-GT values, without differences according to liver disease etiology, and suggesting a role of ?-GT as a marker of metabolic-induced liver damage. These data could be useful for the clinical and pharmacologic management of patients with CLD.

Dataset Information

O-GlcNAc transferase suppresses necroptosis and liver fibrosis.

Publications

O-GlcNAc transferase suppresses necroptosis and liver fibrosis.

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