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J. Biol. Chem., Vol. 280, Issue 11, 10290-10297, March 18, 2005

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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, and Lawrence J. Mandarino¶||**

From the Division of Diabetes, Department of Medicine, and the Departments of ^¶Biochemistry and ^||Physiology, The University of Texas Health Science Center, San Antonio, Texas 78229

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- 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 mitochondrial 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.

Received for publication, August 5, 2004 , and in revised form, October 15, 2004.

^* These studies were supported in part by National Institutes of Health Grants DK47936 and DK66483 (to L. J. M.) and DK24092 (to R. A. D.), Veterans Administration Merit Awards (to R. A. D. and C. P. J.), the Veterans Affairs Medical Research Fund, and General Clinical Research Center Grant M01-RR-01346. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1 (a flow diagram of steps used in microarray data analysis) and supplemental Tables I and II (presenting information on the genes and gene sets analyzed).

These authors contributed equally to this work.

^** To whom correspondence should be addressed: Division of Diabetes MC 7886, Dept. of Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. Tel.: 210-567-4826; Fax: 210-567-6554; E-mail: mandarino{at}uthscsa.edu.

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