O-GlcNAc transferase acts as a critical nutritional node for the control of liver homeostasis.

Background & Aims: O-GlcNAcylation is a reversible post-translational modification controlled by the activity of two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). In the liver, O-GlcNAcylation has emerged as an important regulatory mechanism underlying normal liver physiology and metabolic disease. Methods: To address whether OGT acts as a critical hepatic nutritional node, mice with a constitutive hepatocyte-specific deletion of OGT (OGTLKO) were generated and challenged with different carbohydrate- and lipid-containing diets. Results: Analyses of 4-week-old OGTLKO mice revealed significant oxidative and endoplasmic reticulum stress, and DNA damage, together with inflammation and fibrosis, in the liver. Susceptibility to oxidative and endoplasmic reticulum stress-induced apoptosis was also elevated in OGTLKO hepatocytes. Although OGT expression was partially recovered in the liver of 8-week-old OGTLKO mice, hepatic injury and fibrosis were not rescued but rather worsened with time. Interestingly, weaning of OGTLKO mice on a ketogenic diet (low carbohydrate, high fat) fully prevented the hepatic alterations induced by OGT deletion, indicating that reduced carbohydrate intake protects an OGT-deficient liver. Conclusions: These findings pinpoint OGT as a key mediator of hepatocyte homeostasis and survival upon carbohydrate intake and validate OGTLKO mice as a valuable model for assessing therapeutical approaches of advanced liver fibrosis. Impact and Implications: Our study shows that hepatocyte-specific deletion of O-GlcNAc transferase (OGT) leads to severe liver injury, reinforcing the importance of O-GlcNAcylation and OGT for hepatocyte homeostasis and survival. Our study also validates the Ogt liver-deficient mouse as a valuable model for the study of advanced liver fibrosis. Importantly, as the severe hepatic fibrosis of Ogt liver-deficient mice could be fully prevented upon feeding on a ketogenic diet (i.e. very-low-carbohydrate, high-fat diet) this work underlines the potential interest of nutritional intervention as antifibrogenic strategies.

Membrane transporters in cell physiology, cancer metabolism and drug response.

By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic state of the cell. With more than 450 members, the Solute Carriers (SLCs) are the largest transporter super-family, clustering into families with different substrate specificities and regulatory properties. Cells of different types are, therefore, able to tailor their transporter expression signatures depending on their metabolic requirements, and the physiological importance of these proteins is illustrated by their mis-regulation in a number of disease states. In cancer, transporter expression is heterogeneous, and the SLC family has been shown to facilitate the accumulation of biomass, influence redox homeostasis, and also mediate metabolic crosstalk with other cell types within the tumour microenvironment. This Review explores the roles of membrane transporters in physiological and malignant settings, and how these roles can affect drug response, through either indirect modulation of sensitivity or the direct transport of small-molecule therapeutic compounds into cells.

Carbohydrate Sensing Through the Transcription Factor ChREBP.

Carbohydrate response element binding protein (ChREBP) is a carbohydrate-signaling transcription factor that in the past years has emerged as a central metabolic regulator. ChREBP expression is mostly abundant in active sites of de novo lipogenesis including liver and white and brown adipose tissues. ChREBP is also expressed in pancreatic islets, small intestine and to a lesser extent in the kidney and the brain. In response to glucose, ChREBP undergoes several post-translational modifications (PTMs) (phosphorylation, acetylation and/or O-GlcNAcylation) that will either modulate its cellular location, stability and/or its transcriptional activity. ChREBPß is a shorter isoform of ChREBP that was first described in adipose tissue and later found to be expressed in other sites including liver and pancreatic ß cells. ChREBPß lacks an important regulatory inhibitory domain, known as LID (low glucose inhibitory domain), in its N-terminal domain and is therefore reported as a highly active isoform. In this review, we recapitulate a recent progress concerning the mechanisms governing the activity of the ChREBP isoforms, including PTMs, partners/cofactors as well as novel metabolic pathways regulated by ChREBP in key metabolic tissues, by discussing phenotypes associated with tissue-specific deletion of ChREBP in knockout mice.