UCP3 expression in liver modulates gene expression and oxidative metabolism in response to fatty acids, and sensitizes mitochondria to permeability transition.
OBJECTIVE
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-gamma co-activator-1alpha). UCP3 also conferred to liver mitochondria an enhanced sensitivity to classical inducers of permeability transition, such as calcium and carboxyatractylate.


CONCLUSIONS
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.
Camara
Yolanda
Y
Departament de Bioquimica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain.
Mampel
Teresa
T
Armengol
Jordi
J
Villarroya
Francesc
F
Dejean
Laurent
L
D020155:3-Hydroxybutyric Acid / Q000097:blood; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects / Q000235:genetics; D004041:Dietary Fats / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D015870:Gene Expression / Q000187:drug effects*; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008933:Mitochondrial Swelling / Q000187:drug effects; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010101:Oxygen Consumption / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D013347:Subcellular Fractions / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D019076:Transgenes; D014280:Triglycerides / Q000097:blood; D000071247:Uncoupling Protein 3
D001786:Blood Glucose; D004041:Dietary Fats; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D007473:Ion Channels; D024101:Mitochondrial Proteins; D014280:Triglycerides; C000604392:UCP3 protein, human; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D020155:3-Hydroxybutyric Acid