Liver specific depletion of mitochondrial ATP transporter enhances uncoupled respiration and prevents fatty liver and obesity

Adenine nucleotide translocases (ANTs), also called ADP/ATP carriers (AACs), transport ADP and ATP through the mitochondrial inner membrane and play an essential role for mitochondrial energy supply in eukaryotes. In the liver mitochondria, Ant2 is predominantly expressed among the three murine Ant paralogs Ant1, 2 and 4 . When we conditionally disrupted the Ant2 gene in the liver using Alb‐Cre mice, ADP/ATP exchange capacity in the liver mitochondria was indeed inhibited over 96%. Surprisingly, the mice appeared normal though they had a noticeably leaner phenotype compared to WT mice. These null mice did not show signs of liver dysfunction for over 10 months suggesting mitochondrial ATP supply is largely dispensable for basal liver function and homeostasis. Upon closer examination of Ant2 depleted liver mitochondria, both outer and inner membranes were intact, and the membrane potential was maintained normally. Notably, mitochondrial mass was significantly increased in Ant2‐depleted hepatocytes, where basal respiration was upregulated due to an increase in uncoupled respiration. In addition, liver specific Ant2 knockout mice demonstrated low blood glucose, cholesterol, and insulin levels and improved glucose tolerance. These data indicate that the Ant2 depleted mitochondria in the liver become highly uncoupled and consequently energy‐inefficient, but remain intact yielding no apparent adverse effects to the organ or systemically to the body. Indeed, when mice subjected to high fat/fructose diet, the liver specific Ant2 knockout mice developed significantly less fatty liver changes and less obesity than controls. In addition, when wild type mice were subjected to a low dose of the general Ant inhibitor, carboxyatractyloside, during high fat/fructose diet regimens, the drug also partially mitigated fatty liver changes and obesity. Of interest, liver Ant2 expression in wild type mice is significantly decreased by high fat/fructose diet but increased by fasting. Further, In vitro treatment of a hepatic cell line with a high concentration of fatty acids demonstrated reduced human ANT2 expression. These indicate that there is a physiological mechanism to control Ant2 expression under high‐fat diet conditions which may help prevent obesity and fatty liver. Given the beneficial effects that we identified here with liver‐specific Ant depletion and systemic Ant inhibition combined with high fat diet, targeted manipulation of hepatic mitochondrial metabolism, particularly through inhibition of Ant2, could represent a novel strategy to prevent fatty liver and obesity. Support or Funding Information research grant from Otsuka Maryland Medicinal Laboratories