Decreased mitochondrial carnitine translocase in skeletal muscles impairs utilization of fatty acids in insulin-resistant patients.
Insulin resistance (IR) and its health consequences (diabetes, hypertension, cardiovascular disease, obesity etc.) affect between 25 and 35% of Westernized populations. Decreased fatty acid (FA) oxidation in skeletal muscle is implicated in obesity-related IR. Carnitine-acylcarnitine translocase (CACT) transports long-chain FAs both into mitochondria (as carnitine esters for energy-generating processes) and out of mitochondria. To determine whether CACT activity correlates with decreased FA oxidation we measured CACT concentrations in cellular and mitochondrial extracts from the skeletal muscle of 19 obese IR individuals and of 19 lean controls. We also evaluated carnitine transport in skeletal muscle mitochondria in both groups. Mitochondrial CACT was decreased at translational and transductional level, and carnitine-carnitine and acylcarnitine-carnitine exchange rates were significantly lower in IR subjects. Aberrant acylcarnitine flux into mitochondria was not correlated with decreased activity of other components of the mitochondrial carnitine system (i.e., carnitine palmitoyl transferase-I and II). Our data suggest that by restraining entry of FA-coenzyme A into mitochondria, low CACT levels increase cytosolic FA levels and their incorporation into glycerolipids. The low level of CACT in IR muscle may contribute to the elevated muscle concentrations of triglycerides, diacylglycerol, and FA-coenzyme A characteristic of IR muscle.
Peluso
Gianfranco
G
Institute of Protein Biochemistry and Enzymology, CNR, Naples, Italy. peluso@dafne.ibpe.na.cnr.it
Petillo
Orsolina
O
Margarucci
Sabrina
S
Mingrone
Gertrude
G
Greco
Aldo Virgilio
AV
Indiveri
Cesare
C
Palmieri
Ferdinando
F
Melone
Mariarosa Anna Beatrice
MA
Reda
Emilia
E
Calvani
Menotti
M
D015152:Blotting, Northern; D015153:Blotting, Western; D002333:Carnitine Acyltransferases / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism; D008297:Male; D008931:Mitochondria, Muscle / Q000201:enzymology*; D018482:Muscle, Skeletal / Q000201:enzymology*; D009765:Obesity / Q000201:enzymology / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D005227:Fatty Acids; D012333:RNA, Messenger; D002333:Carnitine Acyltransferases