Deficiency of pyruvate dehydrogenase kinase 4 sensitizes mouse liver to diethylnitrosamine and arsenic toxicity through inducing apoptosis

Jonathan Choiniere; Matthew Junda Lin; Li Wang; Jianguo Wu

doi:10.1016/j.livres.2018.05.001

Deficiency of pyruvate dehydrogenase kinase 4 sensitizes mouse liver to diethylnitrosamine and arsenic toxicity through inducing apoptosis

Liver Res. 2018 Jun;2(2):100-107. doi: 10.1016/j.livres.2018.05.001. Epub 2018 May 12.

Authors

Jonathan Choiniere¹, Matthew Junda Lin¹, Li Wang^{1

2

3

4}, Jianguo Wu¹

Affiliations

¹ Department of Physiology and Neurobiology, Institute for Systems Genomics, University of Connecticut, Storrs, CT, USA.
² Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA.
³ Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT, USA.
⁴ School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Abstract

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 xenobiotics 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 spontaneous 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 tetrachloride (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) polymerase (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 CCl4-induced acute liver injury.

Conclusions: PDK4 may contribute to the protection from apoptotic injury in mouse liver.

Keywords: Cell death; Hepatocytes; Liver injury; Pyruvate dehydrogenase kinase 4 (PDK4).

Abstract

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