Mechanism of fatty acid inhibition of aldosterone synthesis by bovine adrenal glomerulosa cells.
Previous work from this laboratory has suggested that the adrenal glomerulosa is under tonic inhibition by fatty acids. The purpose of the present work was to define the mechanism by which fatty acids inhibit aldosterone synthesis. Experiments with isolated bovine adrenocortical cells showed the following. 1) Fatty acids inhibited angiotensin-II-stimulated and (Bu)2cAMP-stimulated aldosterone synthesis with similar potencies. 2) Inhibition of aldosterone synthesis was highly dependent on fatty acid chain length and degree of unsaturation as well as on configuration of double bonds. Oleic acid was the most potent inhibitor among fatty acids prominent in plasma. 3) Cortisol synthesis was less sensitive to oleic acid inhibition than was aldosterone synthesis. 4) Pregnenolone synthesis by angiotensin-II-stimulated adrenal glomerulosa cells was relatively insensitive to oleic acid. 5) For both glomerulosa and fasciculata cells, cortisol synthesis from 21-deoxycortisol, which requires the participation of P450(21), was relatively insensitive to fatty acids. Cortisol synthesis from corticosterone by fasciculata cells, which requires the participation of P450(17) alpha, was also insensitive to oleic acid. These are microsomal enzymes. 6) In glomerulosa cells, aldosterone synthesis from added corticosterone, which requires the 18-oxidase function of P450(11) beta, a mitochondrial enzyme, was potently inhibited by fatty acids; cortisol synthesis from 11-deoxycortisol by glomerulosa cells, which requires P450(11) beta, was less sensitive to inhibition, and cortisol synthesis from 11-deoxycortisol by fasciculata cells was even less sensitive. 7) Aldosterone synthesis from exogenous 18-hydroxycorticosterone was potently inhibited by oleic acid. Thus, fatty acids are potent inhibitors of the 18-oxidase function of the mitochondrial enzyme P450(11) beta, whereas nonmitochondrial steroidogenic enzymes and the 11-hydroxylase function of P450(11) beta are relatively insensitive to fatty acids. The special sensitivity of aldosterone synthesis to fatty acid inhibition appears to result from the unusual susceptibility of the 18-oxidase function of the mitochondrial steroidogenic enzyme P450(11) beta. This mechanism would allow differential regulation of aldosterone vs. cortisol production by unesterified fatty acids.
Hypertension Research Laboratory, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705.
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Elliott
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Goodfriend
D000418:Albumins / Q000494:pharmacology; D000450:Aldosterone / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D003345:Corticosterone / Q000378:metabolism; D005227:Fatty Acids / Q000494:pharmacology*; D006854:Hydrocortisone / Q000096:biosynthesis; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D019301:Oleic Acid; D009829:Oleic Acids / Q000494:pharmacology; D015384:Zona Glomerulosa / Q000166:cytology / Q000378:metabolism*
D000418:Albumins; D005227:Fatty Acids; D000451:Mineralocorticoid Receptor Antagonists; D009829:Oleic Acids; D000804:Angiotensin II; D019301:Oleic Acid; D000450:Aldosterone; D003345:Corticosterone; D006854:Hydrocortisone