title: Cholesterol Biosynthesis and Trafficking in Cortisol-Producing Lesions of the Adrenal Cortex.
abstract: BACKGROUND
  Cortisol-producing adenomas (CPAs), primary pigmented nodular adrenocortical disease (PPNAD), and primary macronodular adrenocortical hyperplasia (PMAH) cause ACTH-independent Cushing syndrome (CS). Investigation of their pathogenesis has demonstrated their integral link to the cAMP-dependent protein kinase signaling pathway.
  
  
  OBJECTIVE
  The aim of this study was to identify differences in cholesterol biosynthesis among different CS-causing adrenocortical tumors. Because of the concomitant associations of cAMP levels with cholesterol and with steroid biosynthesis, we hypothesized that benign cortisol-producing tumors would display aberration of these pathways.
  
  
  METHODS
  Twenty-three patients with CPA, PPNAD, or PMAH who underwent adrenalectomy for CS were included in the study. Preoperative biochemical analyses were performed, and excised adrenal tissues were studied.
  
  
  METHODS
  Serum, urinary hormone levels, serum lipid profiles, and anthropometric data were obtained preoperatively. Adrenal tissues were analyzed for total protein, cholesterol, and neutral sterol content by mass spectrometry and expression of HMGCR, LDLR, ABCA1, DHCR24, and STAR genes.
  
  
  RESULTS
  There were differences in cholesterol content and markers of cholesterol biosynthesis and metabolism that distinguished CPAs from PMAH and PPNAD; cholesterol, lathosterol, and lathosterol/cholesterol ratio were significantly higher in CPAs. ABCA1 mRNA was lower among CPAs compared to tissues from bilateral adrenocortical hyperplasia (PMAH and PPNAD), and mRNA expression of LDL-R, DCHR24, and HMGCR tended to be higher in CPA tumor tissues.
  
  
  CONCLUSIONS
  CPAs displayed characteristics of "cholesterol-starved" tissues when compared to PPNAD and PMAH and appeared to have increased intrinsic cholesterol production and uptake from the periphery, as well as decreased cholesterol efflux. This has implications for a potential new way of treating these tumors.
authors.affiliation: Sections on Endocrinology and Genetics (E.L., A.H., C.T., A.A., A.S.K., C.A.S.) and Molecular Dysmorphology (C.A.W., F.D.P.), Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Edra
authors.initials: E
authors.lastname: London
authors.affiliation: Sections on Endocrinology and Genetics (E.L., A.H., C.T., A.A., A.S.K., C.A.S.) and Molecular Dysmorphology (C.A.W., F.D.P.), Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wassif
authors.affiliation: Sections on Endocrinology and Genetics (E.L., A.H., C.T., A.A., A.S.K., C.A.S.) and Molecular Dysmorphology (C.A.W., F.D.P.), Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Anelia
authors.initials: A
authors.lastname: Horvath
authors.affiliation: Sections on Endocrinology and Genetics (E.L., A.H., C.T., A.A., A.S.K., C.A.S.) and Molecular Dysmorphology (C.A.W., F.D.P.), Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Christina
authors.initials: C
authors.lastname: Tatsi
authors.affiliation: Sections on Endocrinology and Genetics (E.L., A.H., C.T., A.A., A.S.K., C.A.S.) and Molecular Dysmorphology (C.A.W., F.D.P.), Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Anna
authors.initials: A
authors.lastname: Angelousi
authors.affiliation: Sections on Endocrinology and Genetics (E.L., A.H., C.T., A.A., A.S.K., C.A.S.) and Molecular Dysmorphology (C.A.W., F.D.P.), Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Karageorgiadis
authors.affiliation: Sections on Endocrinology and Genetics (E.L., A.H., C.T., A.A., A.S.K., C.A.S.) and Molecular Dysmorphology (C.A.W., F.D.P.), Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
authors.affiliation: Sections on Endocrinology and Genetics (E.L., A.H., C.T., A.A., A.S.K., C.A.S.) and Molecular Dysmorphology (C.A.W., F.D.P.), Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000293:Adolescent; D000302:Adrenal Cortex / Q000378:metabolism* / Q000473:pathology; D000306:Adrenal Cortex Neoplasms / Q000378:metabolism* / Q000473:pathology; D018246:Adrenocortical Adenoma / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002784:Cholesterol / Q000096:biosynthesis*; D003480:Cushing Syndrome / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D050155:Lipogenesis / Q000502:physiology; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D002784:Cholesterol