Background and Aim:Pyruvate dehydrogenase kinase 4(PDK4)is a metabolism switch that regulates glucose oxidation and the tricarboxylic acid cycle(TCA cycle)in the mitochondria.Liver detoxifies xe-nobiotics and is constantly challenged by various injuries.This study aims at understanding how the loss of the metabolism regulator PDK4 contributes to liver injuries. Methods:Wild-type(WT)and Pdk4 knockout(Pdk4-/-)mice of different ages were examined for spon-taneous hepatic apoptosis.Juvenile or adult mice of two genotypes were insulted by diethylnitrosamine(DEN),arsenic,galactosamine(GalN)/lipopolysaccharide(LPS),anti-CD95(Jo2)antibody or carbon tet-rachloride(CCl4).Liver injury was monitored by blood biochemistry test.Apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)staining,poly(ADP-ribose)po-lymerase(PARP)cleavage,and caspase activity assay.Inflammatory response was determined by nuclear factor(NF)-κB activation and the activation of NF-κB target genes.Primary hepatocytes were isolated and cell viability was evaluated by MTS assay. Results:We showed that systematic Pdk4-/-in mice resulted in age-dependent spontaneous hepatic apoptosis.PDK4-deficiency increased the toxicity of DEN in juvenile mice,which correlated with a lethal consequence and massive hepatic apoptosis.Similarly,chronic arsenic administration induced more severe hepatic apoptosis in Pdk4-/mice compared to WT control mice.An aggravated hepatic NF-κB mediated-inflammatory response was observed in Pdk4-/-mice livers.In vitro,Pdk4-deficient primary hepatocytes were more vulnerable to DEN and arsenic challenges and displayed higher caspase activity than wild type cells.Notably,hepatic PDK4 mRNA level was remarkably reduced during acute liver failure induced by GalN/LPS or Jo2 antibody.The diminished PDK4 expression was also observed in CC14-induced acute liver injury. Conclusions:PDK4 may contribute to the protection from apoptotic injury in mouse liver.

Arsenic is a carcinogenic environmental factor found in food and drinking water around the world. The mechanisms in which arsenic alters homeostasis are not fully understood. Over the past few decades, light has been shed on varying mechanisms in which arsenic induces cancer. Such mechanisms include gut microbe perturbations, genotoxic effects, and epigenetic modification. Gut microbe perturbations have been shown to increase the level of pathogen-associated molecular patterns such as lipopolysaccharide (LPS) leading to uncontained inflammation. Increase in inflammation is the major factor in cirrhosis leading to hepatocellular carcinoma. Alterations in gut permeability and metabolites have also been observed as a fallout of arsenic induced gut microbe modification. The guts proximity and interaction through portal flow make the liver susceptible to gut perturbations and ensuing inflammatory responses. Genotoxic and epigenetic dysregulation induced by arsenic and its toxic metabolites present a more direct mechanism that works synergistically with gut microbe perturbations to induce the incidence of cancers. These pathways combined could be some of the main causes of arsenic-induced carcinogenesis.