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Insulin Resistance in the Hereditary Hypertriglyceridemic Rat Is Associated with an Impairment of Δ‐6 Desaturase Expression in Liver

Abstract: Our previous studies have shown that insulin resistance (IR) in the hereditary hypertriglyceridemic (hHTg) rat is accompanied by a specific fatty acid (FA) profile in insulin target tissues, possibly due to a defect in the desaturation pathway. Increased dietary intake of n‐3 polyunsaturated fatty acids (PUFAs) was shown to shape FA composition and to improve insulin sensitivity in this animal strain. Thus, the aim of this study is twofold: (1) to evaluate a defect in the FA desaturation by direct measurement of enzyme activity and gene expression for Δ‐6 desaturase (Δ‐6 D) in liver of hHTg rats and (2) to investigate the effect of dietary n‐3 PUFAs on hepatic Δ‐6 D in relation to tissue FA composition. Male Wistar or hHTg rats were fed ad libitum for 21 days either the basal or fish oil (FO)‐supplemented diets. Triglyceride (Tg) levels in serum and tissue lipid extracts were measured with the aid of a commercially available enzymatic set. Hepatic activity of the Δ‐6 D was determined radiometrically in a microsomal fraction using 1‐14C‐linoleic acid as a substrate. The Δ‐6 D mRNA levels were measured using the Northern blot technique. Tissue FA composition was determined by gas chromatography in the total phospholipid fraction after TLC separation. Increased levels of Tg in hHTg rat circulation were accompanied by raised accumulation of Tg in skeletal muscles. FO feeding lowered the concentration of Tg in serum and prevented their accumulation in skeletal muscles of hHTg rats. A pronounced decrease in the hepatic Δ‐6 D activity in hHTg rats (by about 80%) was not further diminished by FO feeding. On the other hand, the activity of Δ‐6 D in liver of control rats was reduced by about 40% after FO supplementation. These changes were paralleled by a decrease in the Δ‐6 D index as calculated from the liver phospholipid FA profile. In particular, an increase in the amount of 18:2 n‐6 and a decrease in arachidonic acid and PUFA n‐6 metabolites were found. The results indicate that a decrease of insulin action in hHTg rats is accompanied by an impairment of the hepatic Δ‐6 D activity already at the gene level, which is not further affected by n‐3 PUFA supplementation.