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

Research output: Contribution to journalArticle

170 Citations (Scopus)

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
Externally publishedYes

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Mitochondrial Genes
Extracellular Matrix
Muscle
Skeletal Muscle
Nonesterified Fatty Acids
Genes
Lipids
Gene Expression
Connective Tissue Growth Factor
Plasmas
Microarray Analysis
Messenger RNA
Insulin Resistance
Insulin
Microarrays
Collagen
Peroxisome Proliferator-Activated Receptors
Association reactions
Emulsions
Biopsy

ASJC Scopus subject areas

  • Biochemistry

Cite this

Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle. / Richardson, Dawn K.; Kashyap, Sangeeta; Bajaj, Mandeep; Cusi, Kenneth; Mandarino, Steven J.; Finlayson, Jean; DeFronzo, Ralph A.; Jenkinson, Christopher P.; Mandarino, Lawrence J.

In: Journal of Biological Chemistry, Vol. 280, No. 11, 18.03.2005, p. 10290-10297.

Research output: Contribution to journalArticle

Richardson, DK, Kashyap, S, Bajaj, M, Cusi, K, Mandarino, SJ, Finlayson, J, DeFronzo, RA, Jenkinson, CP & Mandarino, LJ 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, vol. 280, no. 11, pp. 10290-10297. https://doi.org/10.1074/jbc.M408985200
Richardson, Dawn K. ; Kashyap, Sangeeta ; Bajaj, Mandeep ; Cusi, Kenneth ; Mandarino, Steven J. ; Finlayson, Jean ; DeFronzo, Ralph A. ; Jenkinson, Christopher P. ; Mandarino, Lawrence J. / Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 11. pp. 10290-10297.
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