Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle

Dawn K. Richardson, Sangeeta Kashyap, Mandeep Bajaj, Kenneth Cusi, Steven J. Mandarino, Jean Finlayson, Ralph A. DeFronzo, Christopher P. Jenkinson, Lawrence J. Mandarino

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    178 Scopus citations

    Abstract

    The association between elevated plasma free fatty acid (FFA) concentrations and insulin resistance is well known. Although the cause and effect relationship between FFAs and insulin resistance is complex, plasma FFA is negatively correlated with the expression of peroxisome proliferator activated receptor-γ cofactor-1 (PGC-1) and nuclear encoded mitochondrial genes. To test whether this association is causal, we infused a triglyceride emulsion (or saline as control) into healthy subjects to increase plasma FFA for 48 h followed by muscle biopsies, microarray analysis, quantitative real time PCR, and immunoblots. Lipid infusion increased plasma FFA concentration from 0.48 ± 0.02 to 1.73 ± 0.43 mM and decreased insulin-stimulated glucose disposal from 8.82 ± 0.69 to 6.67 ± 0.66 mg/kg·min, both with p < 0.05. PGC·1 mRNA, along with mRNAs for a number of nuclear encoded mitocliondrial genes, were reduced by lipid infusion (p < 0.05). Microarray analysis also revealed that lipid infusion caused a significant overexpression of extracellular matrix genes and connective tissue growth factor. Quantitative reverse transcription PCR showed that the mRNA expression of collagens and multiple extracellular matrix genes was higher after the lipid infusion (p < 0.05). Immunoblot analysis revealed that lipid infusion also increased the expression of collagens and the connective tissue growth factor protein. These data suggest that an experimental increase in FFAs decreases the expression of PGC-1 and nuclear encoded mitochondrial genes and also increases the expression of extracellular matrix genes in a manner reminiscent of inflammation.

    Original languageEnglish (US)
    Pages (from-to)10290-10297
    Number of pages8
    JournalJournal of Biological Chemistry
    Volume280
    Issue number11
    DOIs
    StatePublished - Mar 18 2005

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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    Richardson, D. K., Kashyap, S., Bajaj, M., Cusi, K., Mandarino, S. J., Finlayson, J., DeFronzo, R. A., Jenkinson, C. P., & Mandarino, L. J. (2005). Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle. Journal of Biological Chemistry, 280(11), 10290-10297. https://doi.org/10.1074/jbc.M408985200