Direct in vivo characterization of delta 5 desaturase activity in humans by deuterium labeling: Effect of insulin

doi:10.1016/0026-0495(89)90117-0

Metabolism

Volume 38, Issue 4, April 1989, Pages 315-321

https://doi.org/10.1016/0026-0495(89)90117-0 Get rights and content

Abstract

The conversion of dihomogamma linolenic acid (DHLA) into arachidonic acid (AA) was compared in normal subjects and diabetic patients before and after treatment with insulin. The kinetics of the incorporation of deuterium-labeled DHLA and its conversion product, deuterium-labeled AA, was determined in plasma triglycerides, plasma phospholipids, and platelet lipids of subjects after ingestion of 2 g of the labeled precursor. Analysis was performed by gas liquid chromatographymass spectrometry using multiple ion detection. In normal subjects, the deuterium-labeled DHLA concentration rose to 24 to 69 mg/L in plasma triglycerides four to nine hours after ingestion and to 20 to 34 mg/L in plasma phospholipids about four hours later. Deuterium-labeled AA appeared at 12 hours, rose to 2.4 to 3.8 mg/L between 48 and 72 hours in plasma phospholipids, but remained at the limit of detection in plasma triglycerides and was undetectable in platelet lipids. In diabetic patients both before and after insulin treatment, the deuterium-labeled DHLA concentration in plasma triglycerides and in plasma phospholipids followed the same pattern as in normal subjects. However, the deuterium-labeled arachidonic acid concentration was below 1 mg/L in plasma phospholipids before insulin. After insulin treatment the patients recovered normal DHLA metabolism because deuterium-labeled AA rose in phospholipids to a mean value of 3.5 mg/L, which is in the same range as that observed in normal subjects (3.2 mg/L). The present data provide direct evidence for the conversion of DHLA into AA in humans. The effect of insulin and the data from the literature of animal studies suggest insulin dependence of delta 5 desaturase in humans. AA concentrations of 2.5 mg/L in plasma phospholipids can be expected from the biologic conversion of 2 g of exogenous DHLA.

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This result suggests an association between lower D5D activity (and consequently, reduced levels of both ω-6 and AA) and the INF cluster. D5D activity has previously been investigated by other studies and seems to be downregulated by a diet high in saturated fat [37] and by insulin resistance [38]. Corroborated by our findings, prospective studies and investigations using a Mendelian randomization approach have shown that low estimated D5D activity and high estimated D6D activity, as well as genetic variability in their genes (FADS1 and FADS2, respectively), have a causal effect on the development of T2DM, insulin resistance, and higher plasma CRP concentration [23,39].
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Third, most of the T2D subjects received anti-diabetic drugs which could affect their plasma PUFA profiles. Among them, only insulin has been reported to modulate plasma PUFA profiles in diabetic patients [31–34,42]. We found in this study, that no significant difference in plasma PUFA profiles between the insulin user and non-user groups (data not shown), and that insulin use did not independently contribute to plasma AA/DGLA ratio in T2D subjects (Table 4).
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2010, Progress in Lipid Research
Non-alcoholic fatty liver disease (NAFLD) has a high occurrence in most countries. Recent studies estimate its prevalence to be near 30% in United States, Italian and Japanese general adult populations. NAFLD commonly presents along with obesity and insulin resistance (IR), pathologies that share with NAFLD metabolic and inflammatory components. These conditions, particularly NAFLD, are associated with alterations in the bioavailability of long-chain polyunsaturated fatty acids (LCPUFAs). In the human population, the bioavailability of LCPUFAs depends both on endogenous biosynthesis and diet amount of preformed LCPUFAs. However, the lower liver LCPUFAs product/precursor ratio namely (20:5n−3 + 22:6n−3)/18:3n−3, 20:4n−6/18:2n−6 present in common Western diets, makes critical an adequate pathway activity to ensure minimum bioavailability of LCPUFAs in most Western populations. The key step of this biosynthesis involves Δ5 and Δ6-desaturases, whose activities are altered in NAFLD. During the disease, the presence of molecular activators of these two enzymes does not correlate with the scarce LCPUFAS biosynthesis observed. The key to this apparent contradiction, or at least part of it, could be explained on the basis of the possible sensitivity of the desaturases to oxidative stress; a metabolic condition strongly linked to inflammatory pathologies such as NAFLD, obesity and IR and that, according to latest research, not only would be consequence but also possibly a cause of these diseases. The present review is focused on the relationship between NAFLD and the bioavailability of LCPUFAs, with special reference to the role that oxidative stress could play in the modulation of the liver fatty acid desaturase activity.
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Citation Excerpt :
As well, increased proportions of both AA and DHA in placental phospholipids51 and a preferential activation of lipid genes found in placenta of diabetic women,52 indicate a pronounced modification of fetus-placental pathways that could result in enhanced transplacental lipid fluxes in pregnancy with GDM. In both human and experimental diabetes, the activity of delta-6 and -5 desaturases required for AA and DHA synthesis are impaired,53–55 and in human diabetes the proportion of these fatty acids in membranes are decreased.56 In fact, it has been proposed that as a result of the impairment of AA and DHA synthesis in the mother, their levels are compromised in neonates of women who have type 1,57 type 258,59 and gestational58,59 diabetes.
The most common neonatal complication of gestational diabetes (GDM) is macrosomia. During early pregnancy an accumulation of maternal fat depots occurs followed by increased adipose tissue lipolysis and subsequent hyperlipidaemia, which mainly corresponds to increased triglycerides (TG) in all circulating lipoproteins. In GDM women, the enhanced insulin resistance and decreased oestrogens are responsible for the reported wide range of dyslipidaemic conditions. In GDM, decreased proportion of long chain polyunsaturated fatty acids in fetus plasma could result from decreased supply, impaired placental transfer or even altered intrauterine metabolism. A positive correlation between maternal TG and neonatal body weight or fat mass has been found in GDM. Augmented oxidative stress and altered adipokines have also been found, with an adverse outcome even in normoglycaemic conditions. Thus, although additional studies are required, overall these findings indicate that altered maternal lipid metabolism rather than hyperglycaemia constitutes a risk for macrosomia in GDM.

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^☆: Supported in part by the C.N.I.E.L. Grant No. 271/82 and Sopharga Laboratories, France.

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Direct in vivo characterization of delta 5 desaturase activity in humans by deuterium labeling: Effect of insulin☆

Abstract

Prostaglandins

Biochim Biophys Acta

Lancet

Lancet

Lancet

Lancet

Prostaglandins

Atherosclerosis

Atherosclerosis

J Lipid Res

J Nutr

Prog Lipid Res

J Biol Chem

Biochim Biophys Acta

J Biol Chem

The desaturation step in the animal biosynthesis of polyunsaturated fatty acids

Lipids