An Oxidized Derivative of Linoleic Acid Stimulates Dehydroepiandrosterone Production by Human Adrenal Cells

Abstract

We previously reported that an oxidized derivative of linoleic acid stimulated steroidogenesis in rat adrenal cells. This derivative was also detected in human plasma, and was positively correlated with visceral adiposity and plasma DHEA-S. The present study sought to characterize the effects of this derivative, 12,13-epoxy-9-keto-(10-trans)-octadecenoic acid (EKODE), on steroid production by normal human adrenocortical cells obtained during clinically-indicated adrenalectomy. Cell suspensions were incubated in the presence of varying concentrations of EKODE and ACTH. EKODE (16 μM) significantly increased DHEA production by 28% under basal conditions and by 25% in the presence of a low concentration of ACTH (0.2 ng/ml). The effect on DHEA was absent at a higher ACTH concentration (2.0 ng/ml). EKODE decreased cortisol production by 16% (low ACTH) and 25% (high ACTH), but was without effect on cortisol under basal conditions. The results suggest that EKODE affects adrenal DHEA production in the human, possibly by modulating steroidogenic enzyme activity. We postulate that excess visceral fat delivers fatty acids to the liver, where oxidized derivatives are formed that modulate adrenal steroidogenesis. This may be an important phenomenon in the genesis of changes in adrenal function associated with syndromes of obesity, especially those that include androgen excess.

Key words

Adrenal cortex - steroidogenesis - androgens - fatty acids

References

• 1 Sarel I, Widmaier EP. Stimulation of steroidogenesis in cultured rat adrenocortical cells by unsaturated fatty acids.  Am J Physiol Regul Integr Comp Physiol. 1995;  268 R1484-R1490
• 2 Raff H, Bruder ED, Jankowski BM, Goodfriend TL. Neonatal hypoxic hyperlipidemia in the rat: effects on aldosterone and corticosterone synthesis in vitro.  Amer J Physiol Regul Integrat Comp Physiol. 2000;  278 R663-R668
• 3 Wang X, Walsh LP, Reinhart AJ, Stocco DM. The role of arachidonic acid in steroidogenesis and steroidogenic acute regulatory (StAR) gene and protein expression.  J Biol Chem. 2000;  275 20204-20209
• 4 Bruder ED, Ball DL, Goodfriend TL, Raff H. An oxidized metabolite of linoleic acid stimulates corticosterone production by rat adrenal cells.  Am J Physiol Regul Integr Comp Physiol. 2003;  284 R1631-R1635
• 5 Goodfriend TL, Ball DL, Gardner HW. An oxidized derivative of linoleic acid affects aldosterone secretion by adrenal cells in vitro.  Prostaglandins Leukot Essent Fatty Acids. 2002;  67 163-167
• 6 Goodfriend TL, Ball DL, Raff H, Bruder ED, Gardner HW, Spiteller G. Oxidized products of linoleic acid stimulate adrenal steroidogenesis.  Endocr Res. 2003;  28 325-330
• 7 Goodfriend TL, Ball DL, Egan BM, Campbell WB, Nithipatikom K. Epoxy-keto derivative of linoleic acid stimulates aldosterone secretion.  Hypertension. 2004;  43 358-363
• 8 Moghaddam MF, Motoba K, Borhan B, Pinot F, Hammock BD. Novel metabolic pathways for linoleic and arachidonic acid metabolism.  Biochim Biophys Acta. 1996;  1290 327-339
• 9 Moran JH, Nowak G, Grant DF. Analysis of the toxic effects of linoleic acid, 12, 13-cis-epoxyoctadecenoic acid and 12,13-dihydroxyoctadecenoic acid in rabbit renal cortical mitochondria.  Toxicol Appl Pharmacol. 2001;  172 150-161
• 10 Yamazaki T, Higuchi K, Kominami S, Takemori S. 15-Lipoxygenase metabolite(s) of arachidonic acid mediates adrenocorticotropin action in bovine adrenal steroidogenesis.  Endocrinology. 1996;  137 2670-2675
• 11 Payne AH, Hales DB. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones.  Endocr Rev. 2004;  25 947-970
• 12 Auchus RJ. Overview of dehydroepiandrosterone biosynthesis.  Semin Repro Med. 2004;  22 281-288
• 13 Rainey WE, Carr BR, Sasano H, Suzuki T, Mason JI. Dissecting human adrenal androgen production.  Trends Endocrinol Metab. 2002;  13 234-239
• 14 Pandey AV, Miller WL. Regulation of 17,20-lyase activity by cytochrome b₅ and by serine phosphorylation of P450c17.  J Biol Chem. 2005;  280 13265-13271
• 15 Sirianni R, Carr BR, Ando S, Rainey WE. Inhibition of Src tyrosine kinase stimulates adrenal androgen production.  J Mol Endocrinol. 2003;  30 287-299
• 16 Mai K, Bobbert T, Kullmann V, Andres J, Rochlitz AH, Osterhoff M, Weickert MO, Bahr V, Mohlig M, Pfeiffer AFH, Diederich S, Spranger J. Free fatty acids increase androgen precursors in vivo.  J Clin Endocrinol Metab. 2006;  91 1501-1507
• 17 Benthem L, Keizer K, Wiegman CH, de Boer SF, Strubbe JH, Steffens AB, Kuipers F, Scheurink AJ. Excess portal long-chain fatty acids induce syndrome X via HPA axis and sympathetic activation.  Am J Physiol Endocrinol Metab. 2000;  279 E1286-E1293
• 18 Draper AJ, Hammock BD. Identification of CYP2C9 as a human liver microsomal linoleic acid epoxygenase.  Arch Biochem Biophys. 2000;  376 199-205
• 19 Azziz R, Black V, Hines GA, Fox LM, Boots LR. Adrenal androgen excess in the polycystic ovary syndrome: sensitivity and responsivity of the hypothalamic-pituitary-adrenal axis.  J Clin Endocrinol Metab. 1998;  83 2317-2323
• 20 Moran C, Reyna R, Boots LS, Azziz R. Adrenocortical hyperresponsiveness to corticotropin in polycystic ovary syndrome patients with adrenal androgen excess.  Fert Steril. 2004;  81 126-131

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