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Angiotensin II Activates Cholesterol Ester Hydrolase in Bovine Adrenal Glomerulosa Cells through Phosphorylation Mediated by p42/p44 Mitogen-Activated Protein Kinase

Division of Endocrinology, Diabetology, and Nutrition (N.C., B.P., A.M.C.), Department of Internal Medicine, Faculty of Medicine, CH-1211 Geneva, Switzerland; Jean Meyer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University (A.S.G.), Boston, Massachusetts 02111; and Veterans Affairs Palo Alto Health Care System and Stanford University (F.B.K.), Stanford, California 94305

Address all correspondence and requests for reprints to: Professor Alessandro Capponi, Division of Endocrinology, Diabetology and Nutrition, University Hospital, 24, Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. E-mail: alessandro.capponi{at}medecine.unige.ch.

In adrenal glomerulosa cells, the stimulation of aldosterone biosynthesis by angiotensin II (Ang II) occurs via activation of the Ca²⁺ messenger system, increased expression of the steroidogenic acute regulatory protein, and enhanced transfer of cholesterol to the inner mitochondrial membrane. We examined here whether Ang II affects the activity of cholesterol ester hydrolase (CEH), also named hormone-sensitive lipase, the enzyme recruiting cholesterol from intracellular pools, in bovine adrenal glomerulosa cells. In bovine adrenal tissue, CEH activity was detected with characteristics similar to those reported in other tissues (Michaelis constant = 46.3 ± 6.7 µM, n = 3; maximal velocity = 1 nmol/mg·min). This activity was significantly enhanced in isolated bovine glomerulosa cells challenged for 2 h with 10 nM Ang II (to 149 ± 11% of controls, n = 3). Similarly, 25 µM forskolin raised CEH activity to 151 ± 5% of controls (n = 3). This increase in activity of CEH was not due to an increase in the amount of enzyme protein but was associated with an increased phosphorylation of the enzyme to 337 ± 33% of controls (n = 9, P < 0.0001). Potassium ion (K⁺) and forskolin also stimulated [³²P]orthophosphate incorporation, although to a lesser extent (to 157 ± 18% and 186 ± 25% of controls, respectively). On SDS-PAGE, the majority of this radioactivity was associated with a species of 172 kDa, corresponding to a CEH dimer. Both Ang II-induced CEH phosphorylation and pregnenolone production were significantly reduced (to 47 ± 6% and 50 ± 8% of controls with Ang II alone, respectively) in the presence of PD098059, an inhibitor of p42/p44 MAPK. Indeed, Ang II challenge led to a rapid ³²P incorporation into p42/p44 MAPK. These results demonstrate that, in addition to its known effects on intramitochondrial cholesterol transfer, Ang II also promotes aldosterone biosynthesis by rapidly increasing cholesterol supply to the outer mitochondrial membrane.

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