Deleterious action of FA metabolites on ATP synthesis: possible link between lipotoxicity, mitochondrial dysfunction, and insulin resistance.
Insulin resistance is a characteristic feature of type 2 diabetes and obesity. Insulin-resistant individuals manifest multiple disturbances in free fatty acid (FFA) metabolism and have excessive lipid accumulation in insulin target tissues. Although much evidence supports a causal role for altered FFA metabolism in the development of insulin resistance, i.e., "lipotoxicity", the intracellular mechanisms by which elevated plasma FFA levels cause insulin resistance have yet to be completely elucidated. Recent studies have implicated a possible role for mitochondrial dysfunction in the pathogenesis of insulin resistance in skeletal muscle. We examined the effect of FFA metabolites [palmitoyl carnitine (PC), palmitoyl-coenzyme A (CoA), and oleoyl-CoA] on ATP synthesis in mitochondria isolated from mouse and human skeletal muscle. At concentrations ranging from 0.5 to 2 microM, these FFA metabolites stimulated ATP synthesis; however, above 5 microM, there was a dose-response inhibition of ATP synthesis. Furthermore, 10 microM PC inhibits ATP synthesis from pyruvate. Elevated PC concentrations (> or =10 microM) inhibit electron transport chain activity and decrease the mitochondrial inner membrane potential. These acquired mitochondrial defects, caused by a physiological increase in the concentration of FFA metabolites, provide a mechanistic link between lipotoxicity, mitochondrial dysfunction, and muscle insulin resistance.
Abdul-Ghani
Muhammad A
MA
Division of Diabetes, Univ. of Texas Health Science Center, San Antonio, TX 78229, USA. abdulghani@uthscsa.edu
Muller
Florian L
FL
Liu
Yuhong
Y
Chavez
Alberto O
AO
Balas
Bogdan
B
Zuo
Pengou
P
Chang
Zhi
Z
Tripathy
Devjit
D
Jani
Rucha
R
Molina-Carrion
Marjorie
M
Monroy
Adriana
A
Folli
Franco
F
Van Remmen
Holly
H
DeFronzo
Ralph A
RA
D000214:Acyl Coenzyme A / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000328:Adult; D000818:Animals; D054890:Fatty Acid Synthase, Type I / Q000378:metabolism; D054889:Fatty Acid Synthase, Type II / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism* / Q000633:toxicity*; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008055:Lipids / Q000633:toxicity*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000378:metabolism* / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D010172:Palmitoylcarnitine / Q000378:metabolism; D011773:Pyruvates / Q000378:metabolism; D013386:Succinates / Q000378:metabolism
D000214:Acyl Coenzyme A; D005227:Fatty Acids; D008055:Lipids; D011773:Pyruvates; D013386:Succinates; C017585:oleoyl-coenzyme A; D010171:Palmitoyl Coenzyme A; D010172:Palmitoylcarnitine; D000255:Adenosine Triphosphate; D054890:Fatty Acid Synthase, Type I; D054889:Fatty Acid Synthase, Type II