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The histidine triad nucleotide‐binding protein 2 (HINT‐2) positively regulates hepatocellular energy metabolism

The histidine triad nucleotide‐binding protein 2 (HINT‐2) is a mitochondrial adenosine phosphor‐amidase expressed in hepatocytes. The phenotype of Hint2 knockout (Hint2−/−) mice includes progressive hepatic steatosis and lysine hyperacetylation of mitochondrial proteins, which are features of respiratory chain malfunctions. We postulated that the absence of HINT‐2 induces a defect in mitochondria bioenergetics. Isolated Hint2−/− hepatocytes produced less ATP and generated a lower mitochondrial membrane potential than did Hint2+/+ hepatocytes. In extracellular flux analyses with glucose, the basal, ATP‐linked, and maximum oxygen consumption rates (OCRs) were decreased in Hint2−/− hepatocytes and in HepG2 cells lacking HINT‐2. Conversely, in HINT‐2 overexpressing SNU‐449 and HepG2 cells, the basal, ATP‐linked, and maximum OCRs were increased. Similarly, with palmitate, basal and maximum OCRs were decreased in Hint2−/− hepatocytes, but they were increased in HINT‐2 overexpressing HepG2 cells. When assayed with radiolabeled substrate, palmitate oxidation was reduced by 25% in Hint2−/− mitochondria. In respirometry assays, complex I‐ and II‐driven, coupled and uncoupled respirations and complex IV KCN‐sensitive respiration were reduced in Hint2−/− mitochondria. Furthermore, HINT‐2 associated with cardiolipin and glucose‐regulated protein 75 kDa. Our study shows decreased electron transfer and oxidative phosphorylation capacity in the absence of HINT‐2. The bioenergetics deficit accumulated over time in hepatocytes lacking HINT‐2 likely leads to the secondary outcome of steatosis.—Rajasekaran, R., Felser, A., Nuoffer, J.‐M., Dufour, J.‐F., St‐Pierre, M. V. The histidine triad nucleotide‐binding protein 2 (HINT‐2) positively regulates hepatocellular energy metabolism. FASEB J. 32, 5143–5161 (2018). www.fasebj.org