Hepatic transcriptional signature of alcohol on genes involved in canonical retinoid metabolism

unknown.The alteration of Mg 2+ levels in ALD and the key role of Mg 2+ transporters in enabling the flux of Mg 2+ across cell membranes, have prompted us to investigate the role of cyclin M4 in ALD.In this context, the inhibition of CNNM4 by RNA interference emerge as a new therapeutic approach for ALD.Method: The expression of CNNM4 was studied in ALD patients, in primary hepatocytes under ethanol exposure and in mice under chronic and binge ethanol feeding (the NIAAA model).Primary hepatocytes were treated with a GalNAc siRNA targeting Cnnm4 to evaluate the effect of silencing Cnnm4 in hepatocytes exposed to 50 mM EtOH for 12 h, 24 h and 36 h.NIAAA model mice were divided into 2 groups after day 5 of the diet and treated with a control molecule or GalNAc siRNA that specifically silences Cnnm4 in hepatocytes.Results: The expression of Cnnm4 was upregulated in the liver of patients with ALD and correlated with the stages of the disease: early AH, non-severe AH, severe AH, compensated HCV-related cirrhosis, AH explants and cirrhosis hepatitis C virus.Hepatic CNNM4 levels were overexpressed in the NIAAA model.Silencing Cnnm4 exhibited a reduction in transaminases.Importantly, the absence of cnnm4 resulted in a significant decrease in mitochondrial ROS and ER stress in hepatocytes.High-throughput proteomic analysis performed in liver tissue from NIAAA models revealed a significant representation of the following processes in the absence of CNNM4; oxidationreduction, lipid metabolism, cellular response to oxidative stress, endoplasmic reticulum stress or protein folding families.The machinery for repairing damaged proteins, represented by the enzyme protein-L-isoaspartate (D-aspartate) O-methyltransferase