Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle.
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-gamma 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.
Richardson
Dawn K
DK
Division of Diabetes, Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas 78229, USA.
Kashyap
Sangeeta
S
Bajaj
Mandeep
M
Cusi
Kenneth
K
Mandarino
Steven J
SJ
Finlayson
Jean
J
DeFronzo
Ralph A
RA
Jenkinson
Christopher P
CP
Mandarino
Lawrence J
LJ
D000328:Adult; D001706:Biopsy; D002467:Cell Nucleus / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007091:Image Processing, Computer-Assisted; D015151:Immunoblotting; D007249:Inflammation; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D015233:Models, Statistical; D018482:Muscle, Skeletal / Q000378:metabolism*; D009132:Muscles / Q000378:metabolism / Q000473:pathology; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism
D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D012333:RNA, Messenger; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D003094:Collagen