Sterol O-acyltransferase 1 (SOAT1, ACAT) is a novel target of steroidogenic factor-1 (SF-1, NR5A1, Ad4BP) in the human adrenal.
BACKGROUND
Steroidogenic factor-1 (SF-1, NR5A1, Ad4BP) is a master regulator of adrenal development and steroidogenesis. Defects in several known targets of SF-1 can cause adrenal disorders in humans.


OBJECTIVE
We aimed to identify novel targets of SF-1 in the human adrenal. These factors could be important regulators of adrenal development and steroidogenesis and potential candidates for adrenal dysfunction.


METHODS
A gene discovery strategy was developed based on bidirectional manipulation of SF-1. Overexpression or knockdown of SF-1 in NCI-H295R human adrenocortical cells was used to identify a subset of positively-regulated SF-1 targets.


RESULTS
This approach identified well-established SF-1 target genes (STAR, CYP11A) and several novel genes (VSNL1, ZIM2, PEG3, SOAT1, and MTSS1). Given its role in cholesterol metabolism, sterol O-acyltransferase 1 (SOAT1, previously referred to as acyl-Coenzyme A:cholesterol acyltransferase 1, ACAT) was studied further and found to be expressed in the developing human fetal adrenal cortex. We hypothesized that impaired SOAT1 activity could result in adrenal insufficiency through reduced cholesteryl ester reserves or through toxic destruction of the adrenal cells during development. Therefore, mutational analysis of SOAT1 in a cohort of 43 patients with unexplained adrenal insufficiency was performed but failed to reveal significant coding sequence changes.


CONCLUSIONS
Our reverse discovery approach led to the identification of novel SF-1 targets and defined SOAT1 as an important factor in human adrenal steroidogenesis. SF-1-dependent up-regulation of SOAT1 may be important for maintaining readily-releasable cholesterol reserves needed for active steroidogenesis and during episodes of recurrent stress.
University College London Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom.
Bruno
B
Ferraz-de-Souza
Rebecca E
RE
Hudson-Davies
Lin
L
Lin
Rahul
R
Parnaik
Mike
M
Hubank
Mehul T
MT
Dattani
John C
JC
Achermann
D000311:Adrenal Glands / Q000196:embryology / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D016000:Cluster Analysis; D004622:Embryo, Mammalian; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D046228:Microarray Analysis; D008954:Models, Biological; D034741:RNA, Small Interfering / Q000494:pharmacology; D054339:Steroidogenic Factor 1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D013256:Steroids / Q000096:biosynthesis; D002785:Sterol O-Acyltransferase / Q000235:genetics* / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics / Q000502:physiology
C515057:NR5A1 protein, human; D034741:RNA, Small Interfering; D054339:Steroidogenic Factor 1; D013256:Steroids; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; C493492:sterol O-acyltransferase 1
N Engl J Med. 1996 Dec 19;335(25):1870-8
8948562
J Biol Chem. 1998 Jan 9;273(2):1064-9
9422770
Mol Cell Endocrinol. 2007 Feb;265-266:42-5
17208360
Nat Genet. 1999 Jun;22(2):125-6
10369247
J Clin Endocrinol Metab. 2008 Mar;93(3):696-702
18182448
Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):14041-6
8943057
J Lipid Res. 2000 Dec;41(12):1991-2001
11108732
J Biol Chem. 2000 Oct 13;275(41):31708-14
10913126
Endocr Rev. 1997 Jun;18(3):361-77
9183568
Methods. 2001 Dec;25(4):402-8
11846609
N Engl J Med. 2006 Mar 23;354(12):1253-63
16554527
Mol Endocrinol. 2010 Jul;24(7):1322-37
20203099
Am J Physiol Endocrinol Metab. 2009 Jul;297(1):E1-9
19141679
Bioinformatics. 2005 Jul 1;21(13):2933-42
15860560
Endocr Rev. 1982 Summer;3(3):299-329
6288367
J Clin Endocrinol Metab. 2009 Feb;94(2):678-83
18984668
J Clin Endocrinol Metab. 2006 Aug;91(8):3048-54
16684822
J Biol Chem. 1995 Mar 17;270(11):5772-8
7890706