Deleterious Action of FA Metabolites on ATP Synthesis: The Link Between Lipotoxicity, Mitochondrial Dysfunction and Insulin Resistance. American journal of physiology. Endocrinology and metabolism [Am J Physiol Endocrinol Metab] Journal article | | Title | Deleterious Action of FA Metabolites on ATP Synthesis: The Link Between Lipotoxicity, Mitochondrial Dysfunction and Insulin Resistance. | | Author(s) | Abdul-Ghani MA, Muller FL, Liu Y, Chavez AO, Balas B, Zuo P, Chang Z, Tripathy D, Jani R, Molina-Carrion M, Monroy A, Folli F, Van Remmen H, Defronzo RA | | Institution | UTHSCSA. | | Source | Am J Physiol Endocrinol Metab 2008 Jul 1. | | Abstract | Introduction: Insulin resistance is a characteristic feature of type 2 diabetes and obesity. Insulin resistant individuals manifest multiple disturbances in 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. Research design and methods: We examined the effect of FFA metabolites (palmitoyl carnitine [PC], palmitoyl-CoA and oleoyl-CoA) on ATP synthesis in mitochondria isolated from mouse and human skeletal muscle.
Results: At concentrations ranging from 0.5-2 uM, these FFA metabolites stimulated ATP synthesis; however, above 5 uM there was a dose response inhibition of ATP synthesis. Further, 10 microM PC inhibits ATP synthesis from pyruvate. Elevated PC concentrations (>/=10 microM) inhibit electron transport chain activity and decrease the mitochondrial inner membrane potential.
Conclusion: 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. Key words: palmitoyl carnitine, palmitoyl-CoA, oleoyl-CoA, mitochondria. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 18593850 |
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