Regulation of cardiac fatty acids metabolism in transgenic mice overexpressing bovine GH.
Cardiac energy metabolism depends mainly on fatty acid (FA) oxidation; however, regulation of FA metabolism in acromegalic (Acro) heart is unknown. The aim of the study was to evaluate cardiac expression of key proteins of FA metabolism in young and elder transgenic mice overexpressing bovine GH Acro. Expression of proteins regulating FA entry into the cells, their uptake by mitochondria and beta-oxidation were evaluated by western blot, while FA content by Fourier transform infrared microspectrometry. Regulatory mechanisms of key steps of FA metabolism were also studied. The expression of plasma-membrane FA carriers (fatty acid-binding protein and fatty acid transport protein-1) and acylCoA synthetase was higher in young and lower in elder Acro than in corresponding controls; likewise, expression of cytoplasm to mitochondria-1 (CPT-1), the key enzyme of mitochondrial FA uptake, and that of medium-chain acyl-CoA dehydrogenase and long-chain acyl-CoA dehydrogenase, two regulatory beta-oxidation dehydrogenases, followed a similar pattern. FA content was lower in young and higher in elder Acro than in wild-type, suggesting an increased utilisation in young animals. GH regulated expression of key proteins of FA metabolism through changes in peroxisome proliferator-activated receptor alpha (PPARalpha) expression, which varied accordingly. GH effect was confirmed by treatment of Acro mice with a receptor antagonist, which abolished changes in key proteins of FA metabolism in young Acro. GH increased phosphorylation of AMP-activated protein kinase and anti-acetyl-CoA-carboxylase, two regulatory kinases, leading to lower CPT-1 inhibition by malonyl-CoA, and intervened in regulating PPARalpha expression through the ERK 1/2 pathway. In conclusion, chronic GH excess increased FA metabolism in the young age, whereas its action was overwhelmed in elder ages likely by GH-independent mechanisms, leading to reduced expression of key enzyme of FA metabolism.
Bogazzi
Fausto
F
Department of Endocrinology and Metabolism, University of Pisa, Ospedale Cisanello, Pisa, Italy. f.bogazzi@endoc.med.unipi.it
Raggi
Francesco
F
Ultimieri
Federica
F
Russo
Dania
D
D'Alessio
Aldo
A
Manariti
Antonella
A
Brogioni
Sandra
S
Manetti
Luca
L
Martino
Enio
E