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The prevalence of obesity and type II diabetes is growing globally at rates indicating that environment rather than genes is the principal driver. Exposures to high-fat diet and toxicants, as well as micronutrient deficiency, can impact our health and that of future generations. Only now are we beginning to identify mechanisms linking these exposures to parental and offspring health. One connection between environment and health is the epigenome. The epigenome refers to the biochemical content associated with DNA that impacts gene expression and chromatin organization. Uncovering how genomic information is organized and regulated through epigenetic processes to control gene expression and cell functions in the next generation is still in a nascent stage. 

Anne-Sophie Pepin, Christine Lafleur, Romain Lambrot, Vanessa Dumeaux, Sarah Kimmins

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Current Issue

ITCH E3 ubiquitin ligase downregulation compromises hepatic degradation of branched-chain amino acids

Rossella Menghini, Lesley Hoyles, Marina Cardellini, Viviana Casagrande, ... Massimo Federici

Objective

Metabolic syndrome, obesity, and steatosis are characterized by a range of dysregulations including defects in ubiquitin ligase tagging proteins for degradation. The identification of novel hepatic genes associated with fatty liver disease and metabolic dysregulation may be relevant to unravelling new mechanisms involved in liver disease progression

Methods

Through integrative analysis of liver transcriptomic and metabolomicobtained from obese subjects with steatosis, we identified itchy E ubiquitin protein ligase (ITCH) as a gene downregulated in human hepatic tissue in relation to steatosis grade. Wild-type or ITCH knockout mouse models of non-alcoholic fatty liver disease (NAFLD) and obesity-related hepatocellular carcinoma were analyzed to dissect the causal role of ITCH in steatosis

Results

We show that ITCH regulation of branched-chain amino acids (BCAAs) degradation enzymes is impaired in obese women with grade 3 compared with grade 0 steatosis, and that ITCH acts as a gatekeeper whose loss results in elevation of circulating BCAAs associated with hepatic steatosis. When ITCHexpression was specifically restored in the liver of ITCH knockout mice, ACADSB mRNA and protein are restored, and BCAA levels are normalized both in liver and plasma

Conclusions

Our data support a novel functional role for ITCH in the hepatic regulation of BCAA metabolism and suggest that targeting ITCH in a liver-specific manner might help delay the progression of metabolic hepatic diseases and insulin resistance.

Articles in Press

ITCH E3 ubiquitin ligase downregulation compromises hepatic degradation of branched-chain amino acids

Rossella Menghini, Lesley Hoyles, Marina Cardellini, Viviana Casagrande, ... Massimo Federici

Objective

Metabolic syndrome, obesity, and steatosis are characterized by a range of dysregulations including defects in ubiquitin ligase tagging proteins for degradation. The identification of novel hepatic genes associated with fatty liver disease and metabolic dysregulation may be relevant to unravelling new mechanisms involved in liver disease progression

Methods

Through integrative analysis of liver transcriptomic and metabolomicobtained from obese subjects with steatosis, we identified itchy E ubiquitin protein ligase (ITCH) as a gene downregulated in human hepatic tissue in relation to steatosis grade. Wild-type or ITCH knockout mouse models of non-alcoholic fatty liver disease (NAFLD) and obesity-related hepatocellular carcinoma were analyzed to dissect the causal role of ITCH in steatosis

Results

We show that ITCH regulation of branched-chain amino acids (BCAAs) degradation enzymes is impaired in obese women with grade 3 compared with grade 0 steatosis, and that ITCH acts as a gatekeeper whose loss results in elevation of circulating BCAAs associated with hepatic steatosis. When ITCHexpression was specifically restored in the liver of ITCH knockout mice, ACADSB mRNA and protein are restored, and BCAA levels are normalized both in liver and plasma

Conclusions

Our data support a novel functional role for ITCH in the hepatic regulation of BCAA metabolism and suggest that targeting ITCH in a liver-specific manner might help delay the progression of metabolic hepatic diseases and insulin resistance.

2021 impact factor: 7.422

The 60 Second Metabolist

In this section authors briefly report on their work recently published in Molecular Metabolism.

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