Early steps in steroidogenesis: intracellular cholesterol trafficking

Miller, Walter L.; Bose, Himangshu S.

doi:10.1194/jlr.r016675

Cited by 445 publications

(434 citation statements)

References 327 publications

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“…Free cholesterol is considered to be the main source for steroid hormone production in rodent testes (5). This is in contrast to rodent adrenal gland and ovary, where an important reservoir of cholesterol for steroidogenesis is present in cholesterol esters stored in the LDs.…”

Section: Discussionmentioning

confidence: 99%

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Plasma Membrane Origin of the Steroidogenic Pool of Cholesterol Used in Hormone-induced Acute Steroid Formation in Leydig Cells

Venugopal

Martinez–Arguelles

Chebbi

et al. 2016

Journal of Biological Chemistry

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Edited by George CarmanHormone-sensitive acute steroid biosynthesis requires trafficking of cholesterol from intracellular sources to the inner mitochondrial membrane. The precise location of the intracellular cholesterol and its transport mechanism are uncertain. Perfringolysin O, produced by Clostridium perfringens, binds cholesterol. Its fourth domain (D4) retains cholesterol-binding properties but not cytotoxicity. We transfected steroidogenic MA-10 cells of mouse Leydig cell tumors with the mCherry-D4 plasmid. Tagged D4 with fluorescent proteins enabled us to track cholesterol. The staining was primarily localized to the inner leaflet of the plasma membrane and was partially released upon treatment with dibutyryl-cAMP (Bt 2 cAMP), a cAMP analog. Inhibitors of cholesterol import into mitochondria blocked steroidogenesis and prevented release of D4 (and presumably cholesterol) from the plasma membrane. We conclude that the bulk of the steroidogenic pool of cholesterol, mobilized by Bt 2 cAMP for acute steroidogenesis, originates from the plasma membrane. Treatment of the cells with steroid metabolites, 22(R)-hydroxycholesterol and pregnenolone, also reduced D4 release from the plasma membrane, perhaps evidence for a feedback effect of elevated steroid formation on cholesterol release. Interestingly, D4 staining was localized to endosomes during Bt 2 cAMP stimulation suggesting that these organelles are on the route of cholesterol trafficking from the plasma membrane to mitochondria. Finally, D4 was expressed in primary rat Leydig cells with a lentivirus and was released from the plasma membrane following Bt 2 cAMP treatment. We conclude that the plasma membrane is the source of cholesterol for steroidogenesis in these cells as well as in MA-10 cells.

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Section: Discussionmentioning

confidence: 99%

“…Cholesterol trafficking has been implicated in a number of diseases, including cardiovascular and brain diseases, cancer, and several rare monogenic diseases (4,5).…”

mentioning

confidence: 99%

Plasma Membrane Origin of the Steroidogenic Pool of Cholesterol Used in Hormone-induced Acute Steroid Formation in Leydig Cells

Venugopal

Martinez–Arguelles

Chebbi

et al. 2016

Journal of Biological Chemistry

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“…Cholesterol is the raw material used for steroid hormone synthesis, and it is supplied to steroidogenic cells through two main supply routes: (1) incorporation from the blood and (2) de novo synthesis from acetyl-CoA through multiple enzymatic steps 40,41 . In fact, testicular Leydig cells synthesize a certain percentage of their intracellular cholesterol supplies 42 .…”

Section: Discussionmentioning

confidence: 99%

Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1

et al. 2014

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Genetic deficiencies in transcription factors can lead to the loss of certain types of cells and tissue. The steroidogenic tissue-specific nuclear receptor Ad4BP/SF-1 (NR5A1) is one such gene, because mice in which this gene is disrupted fail to develop the adrenal gland and gonads. However, the specific role of Ad4BP/SF-1 in these biological events remains unclear. Here we use chromatin immunoprecipitation sequencing to show that nearly all genes in the glycolytic pathway are regulated by Ad4BP/SF-1. Suppression of Ad4BP/SF-1 by small interfering RNA reduces production of the energy carriers ATP and nicotinamide adenine dinucleotide phosphate, as well as lowers expression of genes involved in glucose metabolism. Together, these observations may explain tissue dysgenesis as a result of Ad4BP/SF-1 gene disruption in vivo. Considering the function of estrogen-related receptor a, the present study raises the possibility that certain types of nuclear receptors regulate sets of genes involved in metabolic pathways to generate energy carriers.

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“…Because adult Leydig cells develop from the stem cells, this finding implies that the stem cells are modified functionally as well as numerically because of reduced fetal androgen exposure, and this ultimately translates in adulthood into compromised steroidogenesis. Based on results from the DBP rat model, a potential explanation is reduced expression of StAR, which contributes to regulating the import of cholesterol into the mitochondrion, the rate-limiting step for testosterone production (42)(43)(44). Expression of other genes involved in Leydig cell steroidogenesis was unaffected by in utero DBP exposure apart from 3β-hsd, which was also decreased, but this change might not be expected to significantly impact steroidogenesis, because it is not considered rate-limiting.…”

Section: -Hsd3mentioning

confidence: 99%

“…7). Because StAR is one of the factors involved in cholesterol transport into the mitochondrion (42), which is rate-limiting for steroidogenesis (43,44), this change was considered the most significant.…”

Section: Potential Mechanism For Fetal Programming Of Compensated Adultmentioning

confidence: 99%

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Kilcoyne

Smith

Atanassova

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

160

135

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Fetal growth plays a role in programming of adult cardiometabolic disorders, which in men, are associated with lowered testosterone levels. Fetal growth and fetal androgen exposure can also predetermine testosterone levels in men, although how is unknown, because the adult Leydig cells (ALCs) that produce testosterone do not differentiate until puberty. To explain this conundrum, we hypothesized that stem cells for ALCs must be present in the fetal testis and might be susceptible to programming by fetal androgen exposure during masculinization. To address this hypothesis, we used ALC ablation/regeneration to identify that, in rats, ALCs derive from stem/progenitor cells that express chicken ovalbumin upstream promoter transcription factor II. These stem cells are abundant in the fetal testis of humans and rodents, and lineage tracing in mice shows that they develop into ALCs. The stem cells also express androgen receptors (ARs). Reduction in fetal androgen action through AR KO in mice or dibutyl phthalate (DBP) -induced reduction in intratesticular testosterone in rats reduced ALC stem cell number by ∼40% at birth to adulthood and induced compensated ALC failure (low/normal testosterone and elevated luteinizing hormone). In DBP-exposed males, this failure was probably explained by reduced testicular steroidogenic acute regulatory protein expression, which is associated with increased histone methylation (H3K27me3) in the proximal promoter. Accordingly, ALCs and ALC stem cells immunoexpressed increased H3K27me3, a change that was also evident in ALC stem cells in fetal testes. These studies highlight how a key component of male reproductive development can fundamentally reprogram adult hormone production (through an epigenetic change), which might affect lifetime disease risk.adult Leydig stem/progenitor cells | compensated Leydig cell failure | GATA4 | ethane dimethane sulfonate

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Early steps in steroidogenesis: intracellular cholesterol trafficking

Cited by 445 publications

References 327 publications

Plasma Membrane Origin of the Steroidogenic Pool of Cholesterol Used in Hormone-induced Acute Steroid Formation in Leydig Cells

Plasma Membrane Origin of the Steroidogenic Pool of Cholesterol Used in Hormone-induced Acute Steroid Formation in Leydig Cells

Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

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