We have for many years been interested in the biochemistry, function and physiological roles of enzymes that are involved in steroid hormone biosynthesis and inactivation. Aldosterone is the principal endogenous mineralocorticoid in humans and regulates salt and water homeostasis. Cortisol, the major glucocorticoid, has high affinity for the mineralocorticoid receptor; however, 11alpha-hydroxysteroid dehydrogenase type 2 converts cortisol to the inactive steroid cortisone in aldosterone target cells of the kidney, thus limiting the mineralocorticoid action of cortisol. Deoxycorticosterone (DOC) binds to the mineralocorticocoid receptor with high affinity and circulates at concentrations comparable to aldosterone. Severe DOC excess as is seen in 17alpha- and 11alpha-hydroxylase deficiencies causes hypertension, and moderate DOC overproduction in late pregnancy is associated with hypertension. We recently demonstrated that DOC is inactivated by the 20-ketosteroid reductase activity of the human AKR1C3 enzyme. Immunohistochemical analyses demonstrated that AKR1C3 is expressed in the mineralocorticoid-responsive epithelial cells of the renal cortical and medullary collecting ducts, as well as the colon. Our findings suggest that AKR1C3 protects the mineralocorticoid receptor from activation by DOC in mineralocorticoid target cells of the kidney and colon, analogous to cortisol inactivation by 11a-hydroxysteroid dehydrogenase type 2. Our research effort is directed at gaining insight into the physiological role of the AKR1C3 enzyme in diseases such as gestational hypertension, a common affliction of pregnant women in the United States.
We are also interested in the mechanism by which plant carotenoids are being converted to vitamin A in man. The intestinal symmetrically cleaving enzyme carotenoid monooxygenase (CMO1) catalyzes the first step in this pathway, and thus, is crucial for the utilization of provtamin A carotenoids as a dietary source of vitamin A. Recently, a second enzyme that catalyzes asymmetric cleavage of carotenoids was discovered, termed CMO2. We have developed molecular genetic and biochemical tools to study the two human carotene monooxygenase genes and proteins. Our goal is to understand at the molecular level how the two carotene monooxygenases influence carotenoid and vitamin A homeostases.
RESEARCH INTERESTS
Biochemistry and endocrinology of enzymes in carotenoid and steroid hormone metabolism.
SIGNIFICANT PUBLICATIONS
Lindqvist, A., Andersson, S., "Biochemical properties of purified recombinant human beta-carotene 15,15’-monooxygenase." J. Biol. Chem., 277:23942-23948, 2002
Lindqvist A, Andersson S, "Cell type-specific expression of beta-carotene 15,15’-monooxygenase in human tissues." J Histochem Cytochem, 52:491-499, 2004
Lindqvist A, He Y-G, Andersson S, "Cell type-specific expression of beta-carotene 9’-10’-monooxygenase in human tissues." J Histochem Cytochem, 53:1403-1412, 2005
Sharma KK, Lindqvist A, Zhou XJ, Auchus RJ, Penning TM, Andersson S, "Deoxycorticosterone inactivation by AKR1C3 in human mineralocorticoid target tissues." Molecular and Cellular Endocrinology, 248:79-86, 2006
Annika Lindqvist, John Sharvill, Denis E. Sharvill and Stefan Andersson, "Loss-of-function mutation in carotenoid 15,15’-monooxygenase identified in a patient with hypercarotenemia and hypovitaminosis A" Journal of Nutrition, In press
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