Roy 2014 Abstract MiP2014
|Differential expression of mitochondrial transporter proteins leads to incomplete fatty acid oxidation and insulin resistance in palmitate-treated muscle cells.|
Mitochondrial dysfunction leads to reduced fatty acid oxidation, which is also found in obesity associated insulin resistance . Further, lipid deposition in skeletal muscle results in insulin resistance by a poorly defined mechanism called ‘lipotoxicity’. Uptake and oxidation of long chain fatty acids by mitochondria are reportedly impaired in skeletal muscles of obese diabetic individuals having insulin resistance . The resulting intramuscular fatty acids and their metabolite deposition lead to oxidative stress and activation of multiple stress-responsive signalling leading to insulin signalling defects . However, the molecular mechanisms of insulin resistance in insulin target tissues are yet to be understood well.
The impact of lipotoxicity on the genes regulating fatty acid oxidation in insulin resistant skeletal muscles was studied in our laboratory. Realtime-PCR based plate array has been used for this purpose, and we have identified many genes that are important for mitochondrial function and are significantly up- or down-regulated in rat skeletal muscle after high fat diet feeding. Importantly, several mitochondrial transporter proteins were included in this list of genes.
We report for the first time that high concentration of palmitic acid differentially expresses the carnitine palmitoyl transferase isoforms associated with fatty acid-transport and thus alters their ratio in muscle cells leading to incomplete fatty acid oxidation (Fig. 1). The carnitine palmitoyl transferase isoforms are a very important mitochondrial fatty acyl transporter that subsequently maintains the rate of fatty acid oxidation. Consequently, the accumulation of ceramides increases, which is a known factor for insulin resistance. PPARa agonist reinstated the ratio of carnitine palmitoyltransferase (CPT) isoforms in PA-treated muscle cells and thus normalized the rate of fatty acid oxidation (FAO) as well as the insulin-mediated glucose uptake. Taken together, palmitate-induced differential expression of mitochondrial CPT isoforms results in incomplete FAO, which promotes insulin resistance . Modulators of mitochondrial FAO may emerge as potentially useful agents to treat lipid-induced insulin resistance.
Labels: MiParea: nDNA;cell genetics, Exercise physiology;nutrition;life style Pathology: Diabetes
Organism: Rat Tissue;cell: Skeletal muscle
Regulation: Fatty acid
Event: C3, Oral MiP2014
1-Cell Biol Physiol Div, CSIR-Indian Inst Chem Biol; 2-Dep Endocr Metbolism, Inst Post Graduate Med Educ Res; Kolkata, India. - [email protected]
Figure 1. PA-mediated inhibition of FAO rate in muscle cells is shown in (a). Myotubes were incubated with or without PA in media containing trace amounts of radioalabelled [1-14C]-PA. Incubation of cells with 1 mM PA for 18 h reduced the FAO rate by about 40%. Excess PA restricts its own entry into mitochondria prior to FAO (b). Mitochondrial entry of radioactive metabolites in control and PA-treated muscle cells were measured after 18 h of incubation in presence of [1-14C]-PA. The cells were treated in presence or absence of 1 mM PA and radioactive count was measured from mitochondria and whole cell extract. (c) Time kinetics study of PA entry and its distribution in whole cells, mitochondria and cytosolic fractions. The cells incorporated more PA during 8 h of PA-treatment, but after that the, rate of PA uptake was reduced rapidly whereas control cell continues uptaking PA at a fairly constant rate (I). Mitochondrial fraction from control and PA-treated cells accumulate radioactive fatty acid derivatives almost at the same rate up to 12 h, then it decreases in PA-treated set, i.e. entry of PA in mitochondria is restricted after 12 h (II). The cytosolic fraction of PA-treated cells accumulate more radioactivity than that of control cytoplasm during 12-18 h of incubation. The statistical analysis was done as described in Materials and Methods. * represents (P<0.05).
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