UCP3 Expression in Liver Modulates Gene Expression and Oxidative Metabolism in Response to Fatty Acids, and Sensitizes Mitochondria to Permeability Transition

Abstract

Background/Aims: Uncoupling protein-3 (UCP3) is expressed in liver only under conditions of high fatty acid catabolism. However, the specific role of UCP3 in liver mitochondria and overall hepatic function is still poorly known. Methods: A model of “in vivo” induction of UCP3 expression in mouse liver mitochondria via a tail-vein injection of a recombinant adenoviral vector was developed. The effects on liver mitochondrial bioenergetics and permeability transition, liver gene expression, and systemic metabolism were then determined. Results: UCP3 expression in liver did not cause basal, non-specific, uncoupling but led to a stimulation of palmitate-induced state 4 respiration. UCP3 expression in liver also caused an increase in the expression of certain genes involved in lipid catabolism and metabolic response to starvation (e.g. medium chain acyl-CoA-dehydrogenase or peroxisome proliferator-activated receptor-γ co-activator-1α). UCP3 also conferred to liver mitochondria an enhanced sensitivity to classical inducers of permeability transition, such as calcium and carboxyatractylate. Conclusion: UCP3 expression in liver exerts direct actions on mitochondrial activity, favoring fatty acid-induced uncoupling and sensitizing mitochondria to permeability transition, as well as causing retrograde signaling to nuclear gene expression consistent with favoring lipid catabolism and oxidative metabolism.