Mechanisms of Action of Hormone-sensitive Lipase in Mouse Leydig Cells

Manna, Pulak R.; Cohen‐Tannoudji, Joëlle; Counis, Raymond; Garner, Charles W.; Huhtaniemi, Ilpo; Kraemer, Fredric B.; Stocco, Douglas M.

doi:10.1074/jbc.m112.417873

Cited by 77 publications

(57 citation statements)

References 63 publications

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“…Pregnenolone is synthetized in the mitochondria from cholesterol by cytochrome P450scc (15, 16). When high levels of steroid synthesis are needed (Fig.…”

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Pregnenolone Can Protect the Brain from Cannabis Intoxication

Vallée

Vitiello

Bellocchio

et al. 2014

Science

262

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Pregnenolone is considered the inactive precursor of all steroid hormones and its potential functional effects have been largely neglected. The administration of the main active principle of Cannabis sativa (marijuana) Δ9-tetrahydrocannabinol (THC) substantially increases the synthesis of pregnenolone in the brain via the activation of type-1 cannabinoid (CB1) receptor. Pregnenolone then, acting as a signaling specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals an unknown paracrine/autocrine loop protecting the brain from CB1 receptor over-activation that could open an unforeseen novel approach for the treatment of cannabis intoxication and addiction.

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“…Pregnenolone is synthetized in the mitochondria from cholesterol by cytochrome P450scc (15, 16). When high levels of steroid synthesis are needed (Fig.…”

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confidence: 99%

“…2A), new cholesterol is provided first by hydrolysis of cytoplasmic cholesterol esters by the hormone sensitive lipase (HSL) activated via phosphorylation of serine 660. Then, by cholesterol transport into the mitochondria by the steroidogenic acute regulatory protein (StAR) (15,16). …”

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confidence: 99%

Pregnenolone Can Protect the Brain from Cannabis Intoxication

Vallée

Vitiello

Bellocchio

et al. 2014

Science

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271

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“…steroidogenic acute regulatory protein (StAR) and several cytochrome P450 (CYP) family members necessary for steroid hormone biosynthesis. PKA also phosphorylates and likely activates StAR and stimulates cholesterol ester hydrolysis by phosphorylation of hormone sensitive lipase (HSL) [12, 13]. …”

Section: Introductionmentioning

confidence: 99%

Studying mechanisms of cAMP and cyclic nucleotide phosphodiesterase signaling in Leydig cell function with phosphoproteomics

Golkowski

Shimizu‐Albergine

Suh

et al. 2016

Cellular Signalling

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Many cellular processes are modulated by cyclic AMP and nucleotide phosphodiesterases (PDEs) regulate this second messenger by catalyzing its breakdown. The major unique function of testicular Leydig cells is to produce testosterone in response to luteinizing hormone (LH). Treatment of Leydig cells with PDE inhibitors increase cAMP levels and the activity of its downstream effector, cAMP-dependent protein kinase (PKA), leading to a series of kinase-dependent signaling and transcription events that ultimately increase testosterone release. We have recently shown that PDE4B, PDE8A and PDE8B are highly expressed in rodent Leydig and adrenocortical cells and that combined inhibition of PDE4 and PDE8 lead to dramatically increased steroid biosynthesis. Here we investigated and the effect of PDE4 and PDE8 inhibitions on the molecular mechanisms of cAMP in a mouse MA10 Leydig cell line model with SILAC mass spectrometry-based phosphoproteomics. We treated MA10 cells either with PDE family specific PDE4 inhibitor (Rolipram) and PDE8 family specific inhibitor (PF-04957325) alone or in combination and quantified the resulting phosphorylation changes at five different time points between 0 and 180 minutes. We identified 28,336 phosphosites from 4837 proteins and observed significant regulation of 749 sites in response to PDE4 and PDE8 inhibitor treatment. Of these, 132 phosphosites were consensus PKA sites. Our data strongly suggest that PDE4 and PDE8 inhibitors synergistically regulate phosphorylation of proteins required for many different cellular processes, including cell cycle progression, lipid and glucose metabolism, transcription, endocytosis and vesicle transport. Our data suggests cAMP, PDE4 and PDE8 coordinate regulation of steroidogenesis by acting on not one rate-limiting step but rather multiple pathways. Moreover, the pools of cAMP controlled by these PDEs also coordinate many other metabolic processes that must be regulated to assure timely and sufficient testosterone secretion in response to LH.

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“…10,11 Earlier studies examining extra-adrenal aldosterone synthesis tested factors that upregulate aldosterone synthase, which catalyzes the later steps of aldosterone biosynthesis from cholesterol. We hypothesized that factors affecting steroidogenic acute regulatory protein (StAR), which transports cholesterol into the inner mitochondrial membrane and facilitates the first and rate-limiting step in aldosterone biosynthesis, 12 may generate aldosterone levels in PAECs that are sufficient to induce pulmonary remodeling and fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of Steroidogenic Acute Regulatory Protein by Hypoxia Stimulates Aldosterone Synthesis in Pulmonary Artery Endothelial Cells to Promote Pulmonary Vascular Fibrosis

et al. 2014

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Background The molecular mechanism(s) regulating hypoxia-induced vascular fibrosis are unresolved. Hyperaldosteronism correlates positively with vascular remodeling in pulmonary arterial hypertension (PAH), suggesting that aldosterone may contribute to the pulmonary vasculopathy of hypoxia. The hypoxia-sensitive transcription factors c-Fos/c-Jun regulate steroidogenic acute regulatory protein (StAR), which facilitates the rate-limiting step of aldosterone steroidogenesis. We hypothesized that c-Fos/c-Jun upregulation by hypoxia activates StAR-dependent aldosterone synthesis in human pulmonary artery endothelial cells (HPAECs) to promote vascular fibrosis in PAH. Methods and Results Patients with PAH, rats with Sugen/hypoxia-PAH, and mice exposed to chronic hypoxia expressed increased StAR in remodeled pulmonary arterioles, providing a basis for investigating hypoxia-StAR signaling in HPAECs. Hypoxia (2.0% FiO2) increased aldosterone levels selectively in HPAECs, which was confirmed by liquid chromatography-mass spectrometry. Increased aldosterone by hypoxia resulted from enhanced c-Fos/c-Jun binding to the proximal activator protein (AP-1) site of the StAR promoter in HPAECs, which increased StAR expression and activity. In HPAECs transfected with StAR-siRNA or treated with the AP-1 inhibitor, SR-11302, hypoxia failed to increase aldosterone, confirming that aldosterone biosynthesis required StAR activation by c-Fos/c-Jun. The functional consequences of aldosterone were confirmed by pharmacological inhibition of the mineralocorticoid receptor with spironolactone or eplerenone, which attenuated hypoxia-induced upregulation of the fibrogenic protein connective tissue growth factor and collagen III in vitro, and decreased pulmonary vascular fibrosis to improve pulmonary hypertension in Conclusions Our findings identify autonomous aldosterone synthesis in HPAECs due to hypoxia-mediated upregulation of StAR as a novel molecular mechanism that promotes pulmonary vascular remodeling and fibrosis.

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Mechanisms of Action of Hormone-sensitive Lipase in Mouse Leydig Cells

Cited by 77 publications

References 63 publications

Pregnenolone Can Protect the Brain from Cannabis Intoxication

Pregnenolone Can Protect the Brain from Cannabis Intoxication

Studying mechanisms of cAMP and cyclic nucleotide phosphodiesterase signaling in Leydig cell function with phosphoproteomics

Upregulation of Steroidogenic Acute Regulatory Protein by Hypoxia Stimulates Aldosterone Synthesis in Pulmonary Artery Endothelial Cells to Promote Pulmonary Vascular Fibrosis

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