Troglitazone downregulates delta-6 desaturase gene expression in human skeletal muscle cell cultures.
Delta-6 Desaturase, one of the rate-limiting enzymes, catalyzes the conversion of linoleic acid (C18:2 omega6) into gamma-linolenic acid (C18:3 omega6), arachidonic acid (C20:4 omega6), and further metabolites. Recently, it has been shown that human Delta-6 desaturase is expressed not only in liver but in a variety of human tissues, including muscle. Skeletal muscle is a major site of insulin action, and insulin sensitivity may be related to the fatty acid composition of muscle lipids. We examined the effects of troglitazone on the regulation of Delta-6 desaturase gene expression in human muscle cell cultures obtained from muscle biopsies (n = 15). Delta-6 Desaturase mRNA and peroxisome proliferator-activated receptor gamma2 (PPARgamma2) mRNA were quantified by two-step RT-PCR, and the activity of the Delta-6 desaturase enzyme was estimated by gas chromatographic analysis of the omega 6-C18:3/C18:2 fatty acids ratio. In cells treated with 11.5 micromol troglitazone for 4 days, PPARgamma2 mRNA levels were significantly increased (301.0 +/- 51.5%, P < 0.05) and Delta-6 desaturase mRNA levels were significantly decreased (41.7 +/- 5.9%, P < 0.0005) compared with the untreated controls. In accordance with the decrease of Delta-6 desaturase mRNA, there was a significant decrease in the omega6-C18:3/C18:2 ratio down to 47.4 +/- 7.5% in cholesterol esters, 54.2 +/- 7.4% in phospholipids, 56.7 +/- 6.5% in nonesterified fatty acids, and 67.7 +/- 5.9% in triglycerides. The troglitazone-induced decrease in Delta-6 desaturase mRNA is associated with a change in the unsaturated fatty acid composition of the muscle cells. These results add new aspects to the known thiazolidinedione effects on lipid metabolism.
Wahl
Hans Günther
HG
Department of Endocrinology and Metabolism, University of Tübingen, Tübingen, Germany. hgwahl@klinikum-fulda.de
Kausch
Christiana
C
Machicao
Fausto
F
Rett
Kristian
K
Stumvoll
Michael
M
Häring
Hans-Ulrich
HU
D000328:Adult; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D044943:Fatty Acid Desaturases / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007700:Kinetics; D050602:Linoleoyl-CoA Desaturase; D008297:Male; D008745:Methylation; D018482:Muscle, Skeletal / Q000201:enzymology*; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D000077288:Troglitazone
D002788:Cholesterol Esters; D002839:Chromans; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D044943:Fatty Acid Desaturases; D050602:Linoleoyl-CoA Desaturase; D000077288:Troglitazone