title: Troglitazone downregulates delta-6 desaturase gene expression in human skeletal muscle cell cultures.
abstract: 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.
authors.affiliation: Department of Endocrinology and Metabolism, University of Tübingen, Tübingen, Germany. hgwahl@klinikum-fulda.de
authors.forename: Hans Günther
authors.initials: HG
authors.lastname: Wahl
authors.forename: Christiana
authors.initials: C
authors.lastname: Kausch
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.forename: Kristian
authors.initials: K
authors.lastname: Rett
authors.forename: Michael
authors.initials: M
authors.lastname: Stumvoll
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
mesh_terms: 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
chemical_list: 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