Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice

Robarts, Dakota R; McGreal, Steven R.; Umbaugh, David S.; Parkes, Wendena S; Kotulkar, Manasi; Abernathy, Sarah; Lee, Norman; Jaeschke, Hartmut; Gunewardena, Sumedha; Whelan, Stephen A.; Hanover, John A.; Zachara, Natasha E.; Slawson, Chad; Apte, Udayan

doi:10.1016/j.jcmgh.2022.01.014

Cited by 23 publications

(59 citation statements)

References 50 publications

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“…In the same study on the role of OGT in the regulation of liver regeneration [55], Robarts et al also evaluated the consequences of hepatocyte-specific OGA-KO on liver regeneration in OGA-floxed mice injected with Cre-expressing Adeno-Associated Virus (AAV8). As mentioned previously, the lack of O-GlcNAcylation in OGT-KO liver had profound effects on liver regeneration.…”

Section: Oga Knock-out In the Livermentioning

confidence: 99%

“…In contrast, excess O-GlcNAcylation induced by OGA-KO had no effect on liver regeneration after hepatectomy. As discussed by these authors [55], it is well known that when OGT or OGA expression is modified, a compensatory effect occurs, altering the expression of the reciprocal enzyme [92][93][94][95]. However, in liver OGT-KO mice, a compensatory decrease in OGA cannot restore O-GlcNAcylation levels, whereas in liver OGA-KO mice, a compensatory decrease in OGT expression will reduce global O-GlcNAcylation and thereby attenuate the consequences of OGA deletion.…”

Section: Oga Knock-out In the Livermentioning

confidence: 99%

“…OGA is also essential for embryonic development, and its deletion leads to neonatal mortality, indicating the importance of fine-tuned regulation of O-GlcNAc level on proteins [ 52 , 53 ]. As discussed below, some interesting studies have been performed on hemizygous animals with OGA haplo-insufficiency, but only few models with tissue specific OGA deletion have been developed to date [ 54 , 55 ].…”

Section: Introductionmentioning

confidence: 99%

“…These studies revealed an important role for OGT in the protection of the liver against fibrosis and cirrhosis. In addition, in a very recent study, Robarts et al examined the consequences of OGT deletion in hepatocytes on liver regeneration capacity after partial hepatectomy [ 55 ]. In this study, hepatocyte-specific OGT-KO was achieved by injecting OGT-floxed mice with a Cre-expressing Adeno-Associated Virus (AAV8).…”

Section: Introductionmentioning

confidence: 99%

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Protein O-GlcNAcylation and the regulation of energy homeostasis: lessons from knock-out mouse models

et al. 2022

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O-GlcNAcylation corresponds to the addition of N-Acetylglucosamine (GlcNAc) on serine or threonine residues of cytosolic, nuclear and mitochondrial proteins. This reversible modification is catalysed by a unique couple of enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). OGT uses UDP-GlcNAc produced in the hexosamine biosynthesis pathway, to modify proteins. UDP-GlcNAc is at the cross-roads of several cellular metabolisms, including glucose, amino acids and fatty acids. Therefore, OGT is considered as a metabolic sensor that post-translationally modifies proteins according to nutrient availability. O-GlcNAcylation can modulate protein–protein interactions and regulate protein enzymatic activities, stability or subcellular localization. In addition, it can compete with phosphorylation on the same serine or threonine residues, or regulate positively or negatively the phosphorylation of adjacent residues. As such, O-GlcNAcylation is a major actor in the regulation of cell signaling and has been implicated in numerous physiological and pathological processes. A large body of evidence have indicated that increased O-GlcNAcylation participates in the deleterious effects of glucose (glucotoxicity) in metabolic diseases. However, recent studies using mice models with OGT or OGA knock-out in different tissues have shown that O-GlcNAcylation protects against various cellular stresses, and indicate that both increase and decrease in O-GlcNAcylation have deleterious effects on the regulation of energy homeostasis.

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Section: Oga Knock-out In the Livermentioning

confidence: 99%

Section: Oga Knock-out In the Livermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Protein O-GlcNAcylation and the regulation of energy homeostasis: lessons from knock-out mouse models

et al. 2022

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“…Elevated O-GlcNAcylation is not entirely detrimental to the liver. The termination of defective liver regeneration leads to reduced hepatocyte redifferentiation, severe necroinflammation, early fibrotic changes, and the formation of dysplastic nodules leading to the development of hepatocellular carcinoma (HCC) [ 45 ]. HNF4a O-GlcNAcylation in hepatocytes plays a key role in the termination of liver regeneration and prevention of hepatic dysplasia [ 45 ].…”

Section: Role Of O-glcnac In Normal Liver Tissuementioning

confidence: 99%

O-GlycNacylation Remission Retards the Progression of Non-Alcoholic Fatty Liver Disease

Zhou

et al. 2022

Cells

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Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease spectrum associated with insulin resistance (IR), from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). O-GlcNAcylation is a posttranslational modification, regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Abnormal O-GlcNAcylation plays a key role in IR, fat deposition, inflammatory injury, fibrosis, and tumorigenesis. However, the specific mechanisms and clinical treatments of O-GlcNAcylation and NAFLD are yet to be elucidated. The modification contributes to understanding the pathogenesis and development of NAFLD, thus clarifying the protective effect of O-GlcNAcylation inhibition on liver injury. In this review, the crucial role of O-GlcNAcylation in NAFLD (from NAFL to HCC) is discussed, and the effect of therapeutics on O-GlcNAcylation and its potential mechanisms on NAFLD have been highlighted. These inferences present novel insights into the pathogenesis and treatments of NAFLD.

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Defining cardiac fibrosis complexity and regulation towards therapeutic development

Claridge

Drack

Pinto

et al. 2023

Clinical and Translational Dis

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Cardiac fibrosis is insidious, accelerating cardiovascular diseases, heart failure, and death. With a notable lack of effective therapies, advances in both understanding and targeted treatment of fibrosis are urgently needed. Remodelling of the extracellular matrix alters the biomechanical and biochemical cardiac structure and function, disrupting cell-matrix interactions and exacerbating pathogenesis to ultimately impair cardiac function. Attempts at clinical fibrotic reduction have been fruitless, constrained by an understanding which severely underestimates its dynamic complexity and regulation. Integration of single-cell sequencing and quantitative proteomics has provided new insights into cardiac fibrosis, including reparative or maladaptive processes, spatiotemporal changes and fibroblast heterogeneity. Further studies have revealed microenvironmental and intercellular signalling mechanisms (including soluble mediators and extracellular vesicles), and intracellular regulators including posttranslational/epigenetic modifications, RNA binding proteins, and non-coding RNAs. This understanding of novel disease processes and molecular targets has supported the development of innovative therapeutic strategies. Indeed, targeted modulation of cellular heterogeneity, microenvironmental signalling, and intracellular regulation offer promising pre-clinical therapeutic leads. Clinical development will require further advances in our mechanistic understanding of cardiac fibrosis and dissection of the molecular basis for fibrotic remodelling.This review provides an overview of the complexities of cardiac fibrosis, emerging regulatory mechanisms and therapeutic strategies, and highlights knowledge gaps and opportunities for further investigation towards therapeutic/clinical translation.

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Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice

Cited by 23 publications

References 50 publications

Protein O-GlcNAcylation and the regulation of energy homeostasis: lessons from knock-out mouse models

Protein O-GlcNAcylation and the regulation of energy homeostasis: lessons from knock-out mouse models

O-GlycNacylation Remission Retards the Progression of Non-Alcoholic Fatty Liver Disease

Defining cardiac fibrosis complexity and regulation towards therapeutic development

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