Fatty acids as a direct regulator of aldosterone hypersecretion

Abstract

Primary hyperaldosteronism is a major cause of secondary hypertension and carries additional cardiovascular risks beyond that of the elevated blood pressure. Primary hyperaldosteronism is more prevalent in obese people, and weight loss reduces aldosterone levels. It needs to be determined whether obesity related factors directly contribute to the pathogenesis of primary hyperaldosteronism. Here we show that the non-esterified fatty acids (NEFA) palmitic acid, and to a lesser extent, linoleic acid significantly stimulated aldosterone production and steroid enzyme induction in adrenocortical HAC15 cells of human origin. Palmitic acid, linoleic acid, and to a much lesser extent, oleic acid induced the expression of aldosterone synthase. Induction of the Steroidogenic Acute Regulatory Protein (StAR) was modest. Increased aldosterone secretion was independent of fatty acid beta-oxidation in the mitochondria but may involve free fatty acid receptor 1 (FFAR1/GPR40) and endoplasmic reticulum (ER) stress. Palmitic acid and linoleic acid induced the expression of C/EBP Homologous Protein (CHOP), a marker of ER stress, correlating with their ability to induce aldosterone synthase gene expression. Palmitic acid, but not linoleic acid decreased mitochondrial potentials and induced uncoupling protein 2 (UCP2). Palmitic acid enhanced, while docosahexaenoic acid (DHA) suppressed aldosterone response to angiotensin II (Ang-II). Our study provides evidence that NEFAs modulate aldosterone production, and further suggests that hyperaldosteronism shares similar pathogenesis with other obesity-related disorders such as metabolic syndrome.