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Omega-6 highly unsaturated fatty acids in Leydig cells facilitate male sex hormone production.

ABSTRACT: Highly unsaturated fatty acids (HUFAs) are fatty acids with more than three double bonds in the molecule. Mammalian testes contain very high levels of omega-6 HUFAs compared with other tissues. However, the metabolic and biological significance of these HUFAs in the mammalian testis is poorly understood. Here we show that Leydig cells vigorously synthesize omega-6 HUFAs to facilitate male sex hormone production. In the testis, FADS2 (Fatty acid desaturase 2), the rate-limiting enzyme for HUFA biosynthesis, is highly expressed in Leydig cells. In this study, pharmacological and genetic inhibition of FADS2 drastically reduces the production of omega-6 HUFAs and male steroid hormones in Leydig cells; this reduction is significantly rescued by supplementation with omega-6 HUFAs. Mechanistically, hormone-sensitive lipase (HSL; also called LIPE), a lipase that supplies free cholesterol for steroid hormone production, preferentially hydrolyzes HUFA-containing cholesteryl esters as substrates. Taken together, our results demonstrate that Leydig cells highly express FADS2 to facilitate male steroid hormone production by accumulating omega-6 HUFA-containing cholesteryl esters, which serve as preferred substrates for HSL. These findings unveil a previously unrecognized importance of omega-6 HUFAs in the mammalian male reproductive system.

SUBMITTER: Ri K

PROVIDER: S-EPMC9492697 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Omega-6 highly unsaturated fatty acids in Leydig cells facilitate male sex hormone production.

Ri Keiken K Lee-Okada Hyeon-Cheol HC Yokomizo Takehiko T

Communications biology 20220921 1

Highly unsaturated fatty acids (HUFAs) are fatty acids with more than three double bonds in the molecule. Mammalian testes contain very high levels of omega-6 HUFAs compared with other tissues. However, the metabolic and biological significance of these HUFAs in the mammalian testis is poorly understood. Here we show that Leydig cells vigorously synthesize omega-6 HUFAs to facilitate male sex hormone production. In the testis, FADS2 (Fatty acid desaturase 2), the rate-limiting enzyme for HUFA bi ...[more]

PMID: 36131086

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Project description:BackgroundThe seAFOod randomized controlled trial tested colorectal polyp prevention by the omega-3 (ω-3) highly unsaturated fatty acid (HUFA) eicosapentaenoic acid (EPA) and aspirin. Variable dietary intake of omega-3 HUFAs (also including docosahexaenoic acid [DHA]) and differential EPA capsule compliance could confound analysis of trial outcomes.ObjectiveThe objective of this study was to investigate the relationship between total (diet and capsule) daily omega-3 HUFA intake, red blood cell (RBC), and rectal mucosa omega-3 HUFA concentrations, and colorectal polyp outcomes in a secondary analysis of the seAFOod trial.MethodsIndividual-participant dietary omega-3 HUFA intake (mg/d) was derived from food frequency questionnaires using the European Prospective Investigation into Cancer and Nutrition-Norfolk fatty acid nutrient database. Capsule EPA intake (mg/d) was adjusted for compliance (capsule counting). Fatty acids were analyzed by liquid chromatography-tandem mass spectrometry (as % of total fatty acids). HUFA oxidation was measured using the HUFA/saturated fatty acid (SAT) ratio. The colorectal polyp detection rate (PDR; % with ≥1 polyps) and polyp number per participant were analyzed according to the change in RBC EPA concentrations during the trial (ΔEPA), irrespective of treatment allocation.ResultsThere was a small degree of HUFA degradation over time in RBC samples stored at > -80oC at research sites (r = -0.36, P<0.001 for HUFA/SAT ratio over time), which did not affect analysis of omega-3 HUFA concentrations. Low baseline EPA concentration, as well as allocation to EPA and % compliance, were associated with a high ΔEPA. Individuals with a ΔEPA value >+0.5% points (ΔEPAhigh), irrespective of allocation to EPA or placebo, had a lower PDR than ΔEPAlow individuals (odds ratio: 0.63; 95% confidence interval [CI]: 0.40, 1.01) and reduced colorectal polyp number (incidence rate ratio: 0.74; 95% CI: 0.54, 1.02).ConclusionsAnalysis of the seAFOod trial according to the change in EPA concentration, instead of treatment allocation, revealed a protective effect of EPA treatment on colorectal polyp recurrence (ISRCTN05926847).

Project description:BackgroundOmega-3 fatty acids have various health benefits in combating against neurological problems, cancers, cardiac problems and hypertriglyceridemia. The main dietary omega-3 fatty acids are obtained from marine fish. Due to the pollution of marine environment, recently microalgae are considered as the promising source for the omega-3 fatty acid production. However, the demand and high production cost associated with microalgal biomass make it necessary to implement novel strategies in improving the biomass and omega-3 fatty acids from microalgae.ResultsFour plant hormones zeatin, indole acetic acid (IAA), gibberellic acid (GBA) and abscisic acid (ABA) were investigated for their effect on the production of biomass and lipid in isolated Chlorella sp. The cells showed an increase of the biomass and lipid content after treatments with the plant hormones where the highest stimulatory effect was observed in ABA-treated cells. On the other hand, IAA showed the highest stimulatory effect on the omega-3 fatty acids content, eicosapentaenoic acid (EPA) (23.25%) and docosahexaenoic acid (DHA) (26.06%). On the other hand, cells treated with ABA had highest lipid content suitable for the biodiesel applications. The determination of ROS markers, antioxidant enzymes, and fatty acid biosynthesis genes after plant hormones treatment helped elucidate the mechanism underlying the improvement in biomass, lipid content and omega-3 fatty acids. All four plant hormones upregulated the fatty acid biosynthesis genes, whereas IAA particularly increased omega-3-fatty acids as a result of the upregulation of omega-3 fatty acid desaturase.ConclusionsThe contents of omega-3 fatty acids, the clinically important compounds, were considerably improved in IAA-treated cells. The highest lipid content obtained from ABA-treated biomass can be used for biodiesel application according to its biodiesel properties. The EPA and DHA enriched ethyl esters are an approved form of omega-3 fatty acids by US Food and Drug Administration (FDA) which can be utilized as the therapeutic treatment for the severe hypertriglyceridemia.

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Omega-6 highly unsaturated fatty acids in Leydig cells facilitate male sex hormone production.

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Omega-6 highly unsaturated fatty acids in Leydig cells facilitate male sex hormone production.

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