Troglitazone Downregulates Δ-6 Desaturase Gene Expression in Human Skeletal Muscle Cell Cultures
- Hans Günther Wahl,
- Christiana Kausch,
- Fausto Machicao,
- Kristian Rett,
- Michael Stumvoll and
- Hans-Ulrich Häring
Δ-6 Desaturase, one of the rate-limiting enzymes, catalyzes the conversion of linoleic acid (C18:2 ω6) into γ-linolenic acid (C18:3 ω6), arachidonic acid (C20:4 ω6), and further metabolites. Recently, it has been shown that human Δ-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 Δ-6 desaturase gene expression in human muscle cell cultures obtained from muscle biopsies (n = 15). Δ-6 Desaturase mRNA and peroxisome proliferator–activated receptor γ2 (PPARγ2) mRNA were quantified by two-step RT-PCR, and the activity of the Δ-6 desaturase enzyme was estimated by gas chromatographic analysis of the ω 6-C18:3/C18:2 fatty acids ratio. In cells treated with 11.5 μmol troglitazone for 4 days, PPARγ2 mRNA levels were significantly increased (301.0 ± 51.5%, P < 0.05) and Δ-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 Δ-6 desaturase mRNA, there was a significant decrease in the ω6-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 Δ-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.
Address correspondence and reprint requests to Dr. Hans Günther Wahl, Klinikum Fulda, Institut für Laboratoriumsmedizin, 36043 Fulda, Germany. E-mail:.
Received for publication 13 March 2001 and accepted in revised form 27 December 2001.
EFA, essential fatty acid; MCR, metabolic clearance rate; PPARγ, peroxisome proliferator-activated receptor γ; PUFA, polyunsaturated fatty acid; TZD, thiazolidinedione.