Oxysterol regulation of steroidogenic acute regulatory protein gene expression

Structural specificity and transcriptional and posttranscriptional actions

Lane K. Christenson, Jan M. McAllister, Kumiko O. Martin, Norman B. Javitt, Timothy Osborne, Jerome F. Strauss

Research output: Contribution to journalArticle

Abstract

Oxysterols exert a major influence over cellular cholesterol homeostasis. We examined the effects of oxysterols on the expression of steroidogenic acute regulatory protein (STAR), which increases the delivery of cholesterol to sterol-metabolizing P450s in the mitochondria. 22(R)- hydroxycholesterol (22(R)-OHC), 25-OHC, and 27-OHC each increased steroidogenic factor-1 (SF-1)-mediated StAR gene transactivation by -2-fold in CV-1 cells. In contrast, cholesterol, progesterone, and the 27-OHC metabolites, 27-OHC-5β-3-one and 7α,27-OHC, had no effect. Unlike our findings in CV-1 cells, SF-1-dependent StAR promoter activity was not augmented by 27-OHC in COS-1 cells, Y-1 cells, BeWo choriocarcinoma cells, Chinese hamster ovary (CHO) cells, and human granulosa cells. Studies examining the metabolism of 27-OHC indicated that CV-1 cells formed a single polar metabolite, 3β-OH-5-cholestenoic acid from radiolabeled 27-OHC. However, this metabolite inhibited StAR promoter activity in CV-1, COS-1 and CHO cells. Because 7α,27-OHC was unable to increase SF-1-dependent StAR promoter activity, we examined 27-OHC 7α-hydroxylase in COS-1 and CHO cells. COS-1 cells contained high 7α-hydroxylase activity, whereas the enzyme was undetectable in CHO cells. The hypothesis that oxysterols act in CV-1 cells to increase StAR promoter activity by reducing nuclear levels of sterol regulatory element binding protein was tested. This notion was refuted when it was discovered that sterol regulatory element binding protein-1a is a potent activator of the StAR promoter in CV-1, COS-1, and human granulosa cells. Human granulosa and theca cells, which express endogenous SF-1, contained more than 5-fold more StAR protein following addition of 27-OHC, whereas StAR mRNA levels remained unchanged. We conclude that 1) there are cell-specific effects of oxysterols on SF-1-dependent transactivation; 2) the ability to increase transactivation is limited to certain oxysterols; 3) there are cell-specific pathways of oxysterol metabolism; and 4) oxysterols elevate StAR protein levels through posttranscriptional actions.

Original languageEnglish (US)
Pages (from-to)30729-30735
Number of pages7
JournalJournal of Biological Chemistry
Volume273
Issue number46
DOIs
StatePublished - Nov 13 1998
Externally publishedYes

Fingerprint

Steroidogenic Factor 1
Regulator Genes
Gene expression
Gene Expression
Metabolites
Cholesterol
Mixed Function Oxygenases
Cricetulus
Metabolism
Granulosa Cells
Ovary
Sterol Regulatory Element Binding Proteins
Sterol Regulatory Element Binding Protein 1
Transcriptional Activation
Mitochondria
COS Cells
Sterols
Progesterone
steroidogenic acute regulatory protein
1,2-diamino-1,2-N,N'-carbonyl-1,2-dideoxyglucose hydrate

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Oxysterol regulation of steroidogenic acute regulatory protein gene expression : Structural specificity and transcriptional and posttranscriptional actions. / Christenson, Lane K.; McAllister, Jan M.; Martin, Kumiko O.; Javitt, Norman B.; Osborne, Timothy; Strauss, Jerome F.

In: Journal of Biological Chemistry, Vol. 273, No. 46, 13.11.1998, p. 30729-30735.

Research output: Contribution to journalArticle

Christenson, Lane K. ; McAllister, Jan M. ; Martin, Kumiko O. ; Javitt, Norman B. ; Osborne, Timothy ; Strauss, Jerome F. / Oxysterol regulation of steroidogenic acute regulatory protein gene expression : Structural specificity and transcriptional and posttranscriptional actions. In: Journal of Biological Chemistry. 1998 ; Vol. 273, No. 46. pp. 30729-30735.
@article{91bca571791144559b6ee0ddf928bc00,
title = "Oxysterol regulation of steroidogenic acute regulatory protein gene expression: Structural specificity and transcriptional and posttranscriptional actions",
abstract = "Oxysterols exert a major influence over cellular cholesterol homeostasis. We examined the effects of oxysterols on the expression of steroidogenic acute regulatory protein (STAR), which increases the delivery of cholesterol to sterol-metabolizing P450s in the mitochondria. 22(R)- hydroxycholesterol (22(R)-OHC), 25-OHC, and 27-OHC each increased steroidogenic factor-1 (SF-1)-mediated StAR gene transactivation by -2-fold in CV-1 cells. In contrast, cholesterol, progesterone, and the 27-OHC metabolites, 27-OHC-5β-3-one and 7α,27-OHC, had no effect. Unlike our findings in CV-1 cells, SF-1-dependent StAR promoter activity was not augmented by 27-OHC in COS-1 cells, Y-1 cells, BeWo choriocarcinoma cells, Chinese hamster ovary (CHO) cells, and human granulosa cells. Studies examining the metabolism of 27-OHC indicated that CV-1 cells formed a single polar metabolite, 3β-OH-5-cholestenoic acid from radiolabeled 27-OHC. However, this metabolite inhibited StAR promoter activity in CV-1, COS-1 and CHO cells. Because 7α,27-OHC was unable to increase SF-1-dependent StAR promoter activity, we examined 27-OHC 7α-hydroxylase in COS-1 and CHO cells. COS-1 cells contained high 7α-hydroxylase activity, whereas the enzyme was undetectable in CHO cells. The hypothesis that oxysterols act in CV-1 cells to increase StAR promoter activity by reducing nuclear levels of sterol regulatory element binding protein was tested. This notion was refuted when it was discovered that sterol regulatory element binding protein-1a is a potent activator of the StAR promoter in CV-1, COS-1, and human granulosa cells. Human granulosa and theca cells, which express endogenous SF-1, contained more than 5-fold more StAR protein following addition of 27-OHC, whereas StAR mRNA levels remained unchanged. We conclude that 1) there are cell-specific effects of oxysterols on SF-1-dependent transactivation; 2) the ability to increase transactivation is limited to certain oxysterols; 3) there are cell-specific pathways of oxysterol metabolism; and 4) oxysterols elevate StAR protein levels through posttranscriptional actions.",
author = "Christenson, {Lane K.} and McAllister, {Jan M.} and Martin, {Kumiko O.} and Javitt, {Norman B.} and Timothy Osborne and Strauss, {Jerome F.}",
year = "1998",
month = "11",
day = "13",
doi = "10.1074/jbc.273.46.30729",
language = "English (US)",
volume = "273",
pages = "30729--30735",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "46",

}

TY - JOUR

T1 - Oxysterol regulation of steroidogenic acute regulatory protein gene expression

T2 - Structural specificity and transcriptional and posttranscriptional actions

AU - Christenson, Lane K.

AU - McAllister, Jan M.

AU - Martin, Kumiko O.

AU - Javitt, Norman B.

AU - Osborne, Timothy

AU - Strauss, Jerome F.

PY - 1998/11/13

Y1 - 1998/11/13

N2 - Oxysterols exert a major influence over cellular cholesterol homeostasis. We examined the effects of oxysterols on the expression of steroidogenic acute regulatory protein (STAR), which increases the delivery of cholesterol to sterol-metabolizing P450s in the mitochondria. 22(R)- hydroxycholesterol (22(R)-OHC), 25-OHC, and 27-OHC each increased steroidogenic factor-1 (SF-1)-mediated StAR gene transactivation by -2-fold in CV-1 cells. In contrast, cholesterol, progesterone, and the 27-OHC metabolites, 27-OHC-5β-3-one and 7α,27-OHC, had no effect. Unlike our findings in CV-1 cells, SF-1-dependent StAR promoter activity was not augmented by 27-OHC in COS-1 cells, Y-1 cells, BeWo choriocarcinoma cells, Chinese hamster ovary (CHO) cells, and human granulosa cells. Studies examining the metabolism of 27-OHC indicated that CV-1 cells formed a single polar metabolite, 3β-OH-5-cholestenoic acid from radiolabeled 27-OHC. However, this metabolite inhibited StAR promoter activity in CV-1, COS-1 and CHO cells. Because 7α,27-OHC was unable to increase SF-1-dependent StAR promoter activity, we examined 27-OHC 7α-hydroxylase in COS-1 and CHO cells. COS-1 cells contained high 7α-hydroxylase activity, whereas the enzyme was undetectable in CHO cells. The hypothesis that oxysterols act in CV-1 cells to increase StAR promoter activity by reducing nuclear levels of sterol regulatory element binding protein was tested. This notion was refuted when it was discovered that sterol regulatory element binding protein-1a is a potent activator of the StAR promoter in CV-1, COS-1, and human granulosa cells. Human granulosa and theca cells, which express endogenous SF-1, contained more than 5-fold more StAR protein following addition of 27-OHC, whereas StAR mRNA levels remained unchanged. We conclude that 1) there are cell-specific effects of oxysterols on SF-1-dependent transactivation; 2) the ability to increase transactivation is limited to certain oxysterols; 3) there are cell-specific pathways of oxysterol metabolism; and 4) oxysterols elevate StAR protein levels through posttranscriptional actions.

AB - Oxysterols exert a major influence over cellular cholesterol homeostasis. We examined the effects of oxysterols on the expression of steroidogenic acute regulatory protein (STAR), which increases the delivery of cholesterol to sterol-metabolizing P450s in the mitochondria. 22(R)- hydroxycholesterol (22(R)-OHC), 25-OHC, and 27-OHC each increased steroidogenic factor-1 (SF-1)-mediated StAR gene transactivation by -2-fold in CV-1 cells. In contrast, cholesterol, progesterone, and the 27-OHC metabolites, 27-OHC-5β-3-one and 7α,27-OHC, had no effect. Unlike our findings in CV-1 cells, SF-1-dependent StAR promoter activity was not augmented by 27-OHC in COS-1 cells, Y-1 cells, BeWo choriocarcinoma cells, Chinese hamster ovary (CHO) cells, and human granulosa cells. Studies examining the metabolism of 27-OHC indicated that CV-1 cells formed a single polar metabolite, 3β-OH-5-cholestenoic acid from radiolabeled 27-OHC. However, this metabolite inhibited StAR promoter activity in CV-1, COS-1 and CHO cells. Because 7α,27-OHC was unable to increase SF-1-dependent StAR promoter activity, we examined 27-OHC 7α-hydroxylase in COS-1 and CHO cells. COS-1 cells contained high 7α-hydroxylase activity, whereas the enzyme was undetectable in CHO cells. The hypothesis that oxysterols act in CV-1 cells to increase StAR promoter activity by reducing nuclear levels of sterol regulatory element binding protein was tested. This notion was refuted when it was discovered that sterol regulatory element binding protein-1a is a potent activator of the StAR promoter in CV-1, COS-1, and human granulosa cells. Human granulosa and theca cells, which express endogenous SF-1, contained more than 5-fold more StAR protein following addition of 27-OHC, whereas StAR mRNA levels remained unchanged. We conclude that 1) there are cell-specific effects of oxysterols on SF-1-dependent transactivation; 2) the ability to increase transactivation is limited to certain oxysterols; 3) there are cell-specific pathways of oxysterol metabolism; and 4) oxysterols elevate StAR protein levels through posttranscriptional actions.

UR - http://www.scopus.com/inward/record.url?scp=0032515062&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032515062&partnerID=8YFLogxK

U2 - 10.1074/jbc.273.46.30729

DO - 10.1074/jbc.273.46.30729

M3 - Article

VL - 273

SP - 30729

EP - 30735

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 46

ER -