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Article ; Online: Splenectomy fails to attenuate immuno-hematologic changes after rodent vertical sleeve gastrectomy.

Himel, Alexandra R / Taylor, Erin B / Phillips, Charles L / Welch, Bradley A / Spann, Redin A / Bandyopadhyay, Sibali / Grayson, Bernadette E

Experimental biology and medicine (Maywood, N.J.)

2019 Volume 244, Issue 13, Page(s) 1125–1135

MeSH term(s)	Adiposity ; Animals ; Blood/metabolism ; Body Weight ; C-Reactive Protein/metabolism ; Cell Differentiation/genetics ; Chemokine CCL5/blood ; Female ; Gastrectomy/adverse effects ; Gene Expression Regulation ; Immune System/metabolism ; Organ Size ; Rats, Long-Evans ; Spleen/pathology ; Splenectomy ; T-Lymphocytes/cytology ; Thymus Gland/cytology
Chemical Substances	Chemokine CCL5 ; C-Reactive Protein (9007-41-4)
Keywords	covid19
Language	English
Publishing date	2019-06-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	4015-0
ISSN	1535-3699 ; 1525-1373 ; 0037-9727
ISSN (online)	1535-3699 ; 1525-1373
ISSN	0037-9727
DOI	10.1177/1535370219857991
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Article ; Online: Analysis of 1-Deoxysphingoid Bases and Their

Wan, Junliang / Li, Jian / Bandyopadhyay, Sibali / Kelly, Samuel L / Xiang, Yang / Zhang, Jin / Merrill, Alfred H / Duan, Jingjing

Journal of agricultural and food chemistry

2019 Volume 67, Issue 46, Page(s) 12953–12961

Abstract: Most common sphingolipids are comprised of "typical" sphingoid bases (sphinganine, sphingosine, and structurally related compounds) and are produced via the condensation of l-serine with a fatty acyl-CoA by serine palmitoyltransferase. Some organisms, ... ...

Abstract	Most common sphingolipids are comprised of "typical" sphingoid bases (sphinganine, sphingosine, and structurally related compounds) and are produced via the condensation of l-serine with a fatty acyl-CoA by serine palmitoyltransferase. Some organisms, including mammals, also produce "atypical" sphingoid bases that lack a 1-hydroxyl group as a result of the utilization of l-alanine or glycine instead of l-serine, resulting in the formation of 1-deoxy- or 1-desoxymethylsphingoid bases, respectively. Elevated production of "atypical" sphingolipids has been associated with human disease, but 1-deoxysphingoid bases have also been found to have potential as anticancer compounds, hence, the importance of knowing more about the occurrence of these compounds in food. Most of the "typical" and "atypical" sphingoid bases are found as the
MeSH term(s)	Acyl Coenzyme A/chemistry ; Acyl Coenzyme A/metabolism ; Serine/chemistry ; Serine/metabolism ; Spectrometry, Mass, Electrospray Ionization ; Sphingolipids/chemistry ; Sphingolipids/metabolism
Chemical Substances	1-deoxysphingolipid ; Acyl Coenzyme A ; Sphingolipids ; Serine (452VLY9402)
Language	English
Publishing date	2019-11-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	241619-0
ISSN	1520-5118 ; 0021-8561
ISSN (online)	1520-5118
ISSN	0021-8561
DOI	10.1021/acs.jafc.9b05708
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Article: Analysis of 1-Deoxysphingoid Bases and Their N-Acyl Metabolites and Exploration of Their Occurrence in Some Food Materials

Wan, Junliang / Li, Jian / Bandyopadhyay, Sibali / Kelly, Samuel L / Xiang, Yang / Zhang, Jin / Merrill, Alfred H / Duan, Jingjing

Journal of agricultural and food chemistry. 2019 Oct. 22, v. 67, no. 46

2019

Abstract: Most common sphingolipids are comprised of “typical” sphingoid bases (sphinganine, sphingosine, and structurally related compounds) and are produced via the condensation of l-serine with a fatty acyl-CoA by serine palmitoyltransferase. Some organisms, ... ...

Abstract	Most common sphingolipids are comprised of “typical” sphingoid bases (sphinganine, sphingosine, and structurally related compounds) and are produced via the condensation of l-serine with a fatty acyl-CoA by serine palmitoyltransferase. Some organisms, including mammals, also produce “atypical” sphingoid bases that lack a 1-hydroxyl group as a result of the utilization of l-alanine or glycine instead of l-serine, resulting in the formation of 1-deoxy- or 1-desoxymethylsphingoid bases, respectively. Elevated production of “atypical” sphingolipids has been associated with human disease, but 1-deoxysphingoid bases have also been found to have potential as anticancer compounds, hence, the importance of knowing more about the occurrence of these compounds in food. Most of the “typical” and “atypical” sphingoid bases are found as the N-acyl metabolites (e.g., ceramides and 1-deoxyceramides) in mammals, but this has not been uniformly assessed in previous studies nor determined in consumed food. Therefore, we developed a method for the quantitative analysis of “typical” and “atypical” sphingoid bases and their N-acyl derivatives by reverse-phase liquid chromatography coupled to electrospray ionization tandem mass spectrometry. On the basis of these analyses, there was considerable variability in the amounts and molecular subspecies of atypical sphingoid bases and their N-acyl metabolites found in different edible sources. These findings demonstrate that a broader assessment of the types of sphingolipids in foods is needed because some diets might contain sufficient amounts of atypical as well as typical sphingolipids that could have beneficial or possibly deleterious effects on human health.
Keywords	acyl coenzyme A ; alanine ; antineoplastic agents ; ceramides ; diet ; electrospray ionization mass spectrometry ; foods ; glycine (amino acid) ; human diseases ; human health ; mammals ; metabolites ; moieties ; quantitative analysis ; reversed-phase liquid chromatography ; serine ; serine C-palmitoyltransferase ; sphinganine
Language	English
Dates of publication	2019-1022
Size	p. 12953-12961.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	241619-0
ISSN	1520-5118 ; 0021-8561
ISSN (online)	1520-5118
ISSN	0021-8561
DOI	10.1021/acs.jafc.9b05708
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Article ; Online: Phosphatidylserine expressing platelet microparticle levels at hospital presentation are decreased in sepsis non-survivors and correlate with thrombocytopenia.

Puskarich, Michael A / Cornelius, Denise C / Bandyopadhyay, Sibali / McCalmon, Maggie / Tramel, Robert / Dale, Wood D / Jones, Alan E

Thrombosis research

2018 Volume 168, Page(s) 138–144

Abstract: Background: Sepsis induced platelet activation releases platelet microparticles (PMPs). PMPs express phosphatidylserine (PS) and can serve as a scaffold for the prothrombinase complex, thereby promoting coagulation. Studies of PMPs in intensive care ... ...

Abstract	Background: Sepsis induced platelet activation releases platelet microparticles (PMPs). PMPs express phosphatidylserine (PS) and can serve as a scaffold for the prothrombinase complex, thereby promoting coagulation. Studies of PMPs in intensive care unit sepsis patients demonstrate mixed results, while the earliest changes and potential effects of clinical interventions remain understudied. We hypothesized PMPs would be associated with patient outcome and dysfunctional coagulation shortly after emergency department presentation with sepsis. Methods: Cohort study of patients from a single center enrolled in a previously published randomized control trial comparing two early resuscitation strategies. Adults presenting to the emergency department (ED) with suspected infection, ≥2 SIRS criteria, and either systolic blood pressure <90 mm Hg or lactate >4 mmol/L were eligible. Triple positive platelet microparticles (PMPs) expressing phosphatidylserine and integrin complexes alphaIIb (CD41) and beta3 (CD61) were quantitated using plasma from the time of enrollment. The primary outcome was in-hospital mortality. Secondary outcomes included platelet count, disseminated intravascular coagulation (DIC), and prothrombin time (PT). Results: 193 patients were enrolled and 184 had samples available. In-hospital mortality was 21%. 10 (5%) patients developed DIC. Median platelet count was 197 (IQR 135, 280) and PT was 13.2 (IQR 11.9, 16.8). Median triple positive PMP counts were 932 per μL (IQR 381, 1872). PMPs were significantly lower in non-survivors (575 vs 1128, p = 0.02) and non-significantly lower in DIC (387 vs 942, p = 0.17). PMPs demonstrated a positive linear association with platelet count (p < 0.001, R2 = 0.21). After adjusting for platelet count, PMPs were no longer significant predictors of mortality (p = 0.28). We observed no association between PMPs and PT. Conclusion: Similar to patients enrolled later in the intensive care unit, PS-expressing PMPs are lower in emergency department sepsis non-survivors. These changes primarily reflect the degree of thrombocytopenia, and an independent prognostic role was not observed. Future studies should control for platelet count in assessment of PMP prognosis in sepsis.
MeSH term(s)	Blood Platelets/drug effects ; Female ; Humans ; Male ; Middle Aged ; Phosphatidylserines/metabolism ; Sepsis/blood ; Thrombocytopenia/metabolism
Chemical Substances	Phosphatidylserines
Language	English
Publishing date	2018-06-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	121852-9
ISSN	1879-2472 ; 0049-3848
ISSN (online)	1879-2472
ISSN	0049-3848
DOI	10.1016/j.thromres.2018.06.017
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Article ; Online: Rodent vertical sleeve gastrectomy alters maternal immune health and fetoplacental development.

Spann, Redin A / Lawson, William J / Bidwell, Gene L / Zamarripa, C Austin / Maranon, Rodrigo O / Bandyopadhyay, Sibali / Taylor, Erin R / Reckelhoff, Jane F / Garrett, Michael R / Grayson, Bernadette E

Clinical science (London, England : 1979)

2018 Volume 132, Issue 2, Page(s) 295–312

Abstract: Bariatric surgery is increasingly employed to improve fertility and reduce obesity-related co-morbidities in obese women. Surgical weight loss not only improves the chance of conception but reduces the risk of pregnancy complications including pre- ... ...

Abstract	Bariatric surgery is increasingly employed to improve fertility and reduce obesity-related co-morbidities in obese women. Surgical weight loss not only improves the chance of conception but reduces the risk of pregnancy complications including pre-eclampsia, gestational diabetes, and macrosomia. However, bariatric procedures increase the incidence of intrauterine growth restriction (IUGR), fetal demise, thromboembolism, and other gestational disorders. Using our rodent model of vertical sleeve gastrectomy (VSG), we tested the hypothesis that VSG in diet-induced, obese dams would cause immune and placental structural abnormalities that may be responsible for fetal demise during pregnancy. VSG dams studied on gestational day (G) 19 had reduced circulating T-cell (CD3
MeSH term(s)	Animals ; Bariatric Surgery/adverse effects ; Bariatric Surgery/methods ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Diet, High-Fat/adverse effects ; Female ; Fetal Growth Retardation/etiology ; Fetal Growth Retardation/immunology ; Fetal Growth Retardation/pathology ; Gastrectomy/adverse effects ; Gastrectomy/methods ; Gene Expression ; Humans ; Interleukin-1beta/genetics ; Interleukin-1beta/metabolism ; Male ; Obesity/etiology ; Obesity/surgery ; Placenta/immunology ; Placenta/metabolism ; Pregnancy ; Pregnancy Complications/etiology ; Pregnancy Complications/immunology ; Pregnancy Complications/pathology ; Rats, Long-Evans
Chemical Substances	Interleukin-1beta
Language	English
Publishing date	2018-01-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	206835-7
ISSN	1470-8736 ; 0301-0538 ; 0009-0360 ; 0143-5221
ISSN (online)	1470-8736
ISSN	0301-0538 ; 0009-0360 ; 0143-5221
DOI	10.1042/CS20171416
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Article ; Online: Iron-sulfur cluster biosynthesis.

Bandyopadhyay, Sibali / Chandramouli, Kala / Johnson, Michael K

Biochemical Society transactions

2008 Volume 36, Issue Pt 6, Page(s) 1112–1119

Abstract: Iron-sulfur (Fe-S) clusters are present in more than 200 different types of enzymes or proteins and constitute one of the most ancient, ubiquitous and structurally diverse classes of biological prosthetic groups. Hence the process of Fe-S cluster ... ...

Abstract	Iron-sulfur (Fe-S) clusters are present in more than 200 different types of enzymes or proteins and constitute one of the most ancient, ubiquitous and structurally diverse classes of biological prosthetic groups. Hence the process of Fe-S cluster biosynthesis is essential to almost all forms of life and is remarkably conserved in prokaryotic and eukaryotic organisms. Three distinct types of Fe-S cluster assembly machinery have been established in bacteria, termed the NIF, ISC and SUF systems, and, in each case, the overall mechanism involves cysteine desulfurase-mediated assembly of transient clusters on scaffold proteins and subsequent transfer of pre-formed clusters to apo proteins. A molecular level understanding of the complex processes of Fe-S cluster assembly and transfer is now beginning to emerge from the combination of in vivo and in vitro approaches. The present review highlights recent developments in understanding the mechanism of Fe-S cluster assembly and transfer involving the ubiquitous U-type scaffold proteins and the potential roles of accessory proteins such as Nfu proteins and monothiol glutaredoxins in the assembly, storage or transfer of Fe-S clusters.
MeSH term(s)	Amino Acid Sequence ; Bacterial Proteins/chemistry ; Glutaredoxins/metabolism ; Iron-Sulfur Proteins/biosynthesis ; Iron-Sulfur Proteins/chemistry ; Molecular Sequence Data
Chemical Substances	Bacterial Proteins ; Glutaredoxins ; Iron-Sulfur Proteins
Language	English
Publishing date	2008-11-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST0361112
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Article ; Online: Ceramide sphingolipid signaling mediates Tumor Necrosis Factor (TNF)-dependent toxicity via caspase signaling in dopaminergic neurons

Martinez Terina N / Chen Xi / Bandyopadhyay Sibali / Merrill Alfred H / Tansey Malú G

Molecular Neurodegeneration, Vol 7, Iss 1, p

2012 Volume 45

Abstract: Abstract Background Dopaminergic (DA) neurons in the ventral midbrain selectively degenerate in Parkinson’s disease (PD) in part because their oxidative environment in the substantia nigra (SN) may render them vulnerable to neuroinflammatory stimuli. ... ...

Abstract	Abstract Background Dopaminergic (DA) neurons in the ventral midbrain selectively degenerate in Parkinson’s disease (PD) in part because their oxidative environment in the substantia nigra (SN) may render them vulnerable to neuroinflammatory stimuli. Chronic inhibition of soluble Tumor Necrosis Factor (TNF) with dominant-negative TNF inhibitors protects DA neurons in rat models of parkinsonism, yet the molecular mechanisms and pathway(s) that mediate TNF toxicity remain(s) to be clearly identified. Here we investigated the contribution of ceramide sphingolipid signaling in TNF-dependent toxicity. Results Ceramide dose-dependently reduced the viability of DA neuroblastoma cells and primary DA neurons and pharmacological inhibition of sphingomyelinases (SMases) with three different inhibitors during TNF treatment afforded significant neuroprotection by attenuating increased endoplasmic reticulum (ER) stress, loss of mitochondrial membrane potential, caspase-3 activation and decreases in Akt phosphorylation. Using lipidomics mass spectrometry we confirmed that TNF treatment not only promotes generation of ceramide, but also leads to accumulation of several atypical deoxy-sphingoid bases (DSBs). Exposure of DA neuroblastoma cells to atypical DSBs in the micromolar range reduced cell viability and inhibited neurite outgrowth and branching in primary DA neurons, suggesting that TNF-induced de novo synthesis of atypical DSBs may be a secondary mechanism involved in mediating its neurotoxicity in DA neurons. Conclusions We conclude that TNF/TNFR1-dependent activation of SMases generates ceramide and sphingolipid species that promote degeneration and caspase-dependent cell death of DA neurons. Ceramide and atypical DSBs may represent novel drug targets for development of neuroprotective strategies that can delay or attenuate the progressive loss of nigral DA neurons in patients with PD.
Keywords	Neuroinflammation ; TNF ; Ceramide ; Sphingolipids ; Neuronal apoptosis ; Neurodegeneration ; ER stress ; Caspase ; Akt ; Neurology. Diseases of the nervous system ; RC346-429 ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Neurology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	590
Language	English
Publishing date	2012-09-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Acid ceramidase (ASAH1) represses steroidogenic factor 1-dependent gene transcription in H295R human adrenocortical cells by binding to the receptor.

Lucki, Natasha C / Li, Donghui / Bandyopadhyay, Sibali / Wang, Elaine / Merrill, Alfred H / Sewer, Marion B

Molecular and cellular biology

2012 Volume 32, Issue 21, Page(s) 4419–4431

Abstract: Adrenocorticotropin (ACTH) signaling increases glucocorticoid production by promoting the interaction of transcription factors and coactivator proteins with the promoter of steroidogenic genes. The nuclear receptor steroidogenic factor 1 (SF-1) is ... ...

Abstract	Adrenocorticotropin (ACTH) signaling increases glucocorticoid production by promoting the interaction of transcription factors and coactivator proteins with the promoter of steroidogenic genes. The nuclear receptor steroidogenic factor 1 (SF-1) is essential for steroidogenic gene transcription. Sphingosine (SPH) is a ligand for SF-1. Moreover, suppression of expression of acid ceramidase (ASAH1), an enzyme that produces SPH, increases the transcription of multiple steroidogenic genes. Given that SF-1 is a nuclear protein, we sought to define the molecular mechanisms by which ASAH1 regulates SF-1 function. We show that ASAH1 is localized in the nuclei of H295R adrenocortical cells and that cyclic AMP (cAMP) signaling promotes nuclear sphingolipid metabolism in an ASAH1-dependent manner. ASAH1 suppresses SF-1 activity by directly interacting with the receptor. Chromatin immunoprecipitation (ChIP) assays revealed that ASAH1 is recruited to the promoter of various SF-1 target genes and that ASAH1 and SF-1 colocalize on the same promoter region of the CYP17A1 and steroidogenic acute regulatory protein (StAR) genes. Taken together, these results demonstrate that ASAH1 is a novel coregulatory protein that represses SF-1 function by directly binding to the receptor on SF-1 target gene promoters and identify a key role for nuclear lipid metabolism in regulating gene transcription.
MeSH term(s)	Acid Ceramidase/metabolism ; Adrenal Cortex/cytology ; Adrenal Cortex/enzymology ; Adrenal Cortex/metabolism ; Adrenocorticotropic Hormone/metabolism ; Animals ; Cell Line ; Cell Nucleus/metabolism ; Chromatin Immunoprecipitation ; Cyclic AMP/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Haplorhini ; Humans ; Lipid Metabolism ; Mice ; Phosphoproteins/genetics ; Promoter Regions, Genetic ; RNA Interference ; RNA, Small Interfering ; Regulatory Sequences, Nucleic Acid ; Signal Transduction/genetics ; Sphingolipids/metabolism ; Sphingosine/metabolism ; Steroid 17-alpha-Hydroxylase/genetics ; Steroidogenic Factor 1/genetics ; Steroidogenic Factor 1/metabolism ; Transcription, Genetic
Chemical Substances	DNA-Binding Proteins ; NR5A1 protein, human ; Phosphoproteins ; RNA, Small Interfering ; Sphingolipids ; Steroidogenic Factor 1 ; steroidogenic acute regulatory protein ; Adrenocorticotropic Hormone (9002-60-2) ; Cyclic AMP (E0399OZS9N) ; CYP17A1 protein, human (EC 1.14.14.19) ; Steroid 17-alpha-Hydroxylase (EC 1.14.14.19) ; ASAH1 protein, human (EC 3.5.1.23) ; Acid Ceramidase (EC 3.5.1.23) ; Sphingosine (NGZ37HRE42)
Language	English
Publishing date	2012-08-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.00378-12
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Article ; Online: Ceramide sphingolipid signaling mediates Tumor Necrosis Factor (TNF)-dependent toxicity via caspase signaling in dopaminergic neurons.

Martinez, Terina N / Chen, Xi / Bandyopadhyay, Sibali / Merrill, Alfred H / Tansey, Malú G

Molecular neurodegeneration

2012 Volume 7, Page(s) 45

Abstract: Background: Dopaminergic (DA) neurons in the ventral midbrain selectively degenerate in Parkinson's disease (PD) in part because their oxidative environment in the substantia nigra (SN) may render them vulnerable to neuroinflammatory stimuli. Chronic ... ...

Abstract	Background: Dopaminergic (DA) neurons in the ventral midbrain selectively degenerate in Parkinson's disease (PD) in part because their oxidative environment in the substantia nigra (SN) may render them vulnerable to neuroinflammatory stimuli. Chronic inhibition of soluble Tumor Necrosis Factor (TNF) with dominant-negative TNF inhibitors protects DA neurons in rat models of parkinsonism, yet the molecular mechanisms and pathway(s) that mediate TNF toxicity remain(s) to be clearly identified. Here we investigated the contribution of ceramide sphingolipid signaling in TNF-dependent toxicity. Results: Ceramide dose-dependently reduced the viability of DA neuroblastoma cells and primary DA neurons and pharmacological inhibition of sphingomyelinases (SMases) with three different inhibitors during TNF treatment afforded significant neuroprotection by attenuating increased endoplasmic reticulum (ER) stress, loss of mitochondrial membrane potential, caspase-3 activation and decreases in Akt phosphorylation. Using lipidomics mass spectrometry we confirmed that TNF treatment not only promotes generation of ceramide, but also leads to accumulation of several atypical deoxy-sphingoid bases (DSBs). Exposure of DA neuroblastoma cells to atypical DSBs in the micromolar range reduced cell viability and inhibited neurite outgrowth and branching in primary DA neurons, suggesting that TNF-induced de novo synthesis of atypical DSBs may be a secondary mechanism involved in mediating its neurotoxicity in DA neurons. Conclusions: We conclude that TNF/TNFR1-dependent activation of SMases generates ceramide and sphingolipid species that promote degeneration and caspase-dependent cell death of DA neurons. Ceramide and atypical DSBs may represent novel drug targets for development of neuroprotective strategies that can delay or attenuate the progressive loss of nigral DA neurons in patients with PD.
MeSH term(s)	Animals ; Caspases/metabolism ; Cell Death/physiology ; Cells, Cultured ; Ceramides/metabolism ; Dopaminergic Neurons/cytology ; Dopaminergic Neurons/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Signal Transduction/physiology ; Sphingolipids/metabolism ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Ceramides ; Sphingolipids ; Tumor Necrosis Factor-alpha ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2012-09-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2244557-2
ISSN	1750-1326 ; 1750-1326
ISSN (online)	1750-1326
ISSN	1750-1326
DOI	10.1186/1750-1326-7-45
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Article ; Online: Acid ceramidase (ASAH1) is a global regulator of steroidogenic capacity and adrenocortical gene expression.

Lucki, Natasha C / Bandyopadhyay, Sibali / Wang, Elaine / Merrill, Alfred H / Sewer, Marion B

Molecular endocrinology (Baltimore, Md.)

2012 Volume 26, Issue 2, Page(s) 228–243

Abstract: In H295R human adrenocortical cells, ACTH rapidly activates ceramide (Cer) and sphingosine (SPH) turnover with a concomitant increase in SPH-1-phosphate secretion. These bioactive lipids modulate adrenocortical steroidogenesis, primarily by acting as ... ...

Abstract	In H295R human adrenocortical cells, ACTH rapidly activates ceramide (Cer) and sphingosine (SPH) turnover with a concomitant increase in SPH-1-phosphate secretion. These bioactive lipids modulate adrenocortical steroidogenesis, primarily by acting as second messengers in the protein kinase A/cAMP-dependent pathway. Acid ceramidase (ASAH1) directly regulates the intracellular balance of Cer, SPH, and SPH-1-phosphate by catalyzing the hydrolysis of Cer into SPH. ACTH/cAMP signaling stimulates ASAH1 transcription and activity, supporting a role for this enzyme in glucocorticoid production. Here, the role of ASAH1 in regulating steroidogenic capacity was examined using a tetracycline-inducible ASAH1 short hairpin RNA H295R human adrenocortical stable cell line. We show that ASAH1 suppression increases the transcription of multiple steroidogenic genes, including Cytochrome P450 monooxygenase (CYP)17A1, CYP11B1/2, CYP21A2, steroidogenic acute regulatory protein, hormone-sensitive lipase, 18-kDa translocator protein, and the melanocortin-2 receptor. Induced gene expression positively correlated with enhanced histone H3 acetylation at target promoters. Repression of ASAH1 expression also induced the expression of members of the nuclear receptor nuclear receptor subfamily 4 (NR4A) family while concomitantly suppressing the expression of dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1. ASAH1 knockdown altered the expression of genes involved in sphingolipid metabolism and changed the cellular amounts of distinct sphingolipid species. Finally, ASAH1 silencing increased basal and cAMP-dependent cortisol and dehydroepiandrosterone secretion, establishing ASAH1 as a pivotal regulator of steroidogenic capacity in the human adrenal cortex.
MeSH term(s)	Acetylation ; Acid Ceramidase/genetics ; Acid Ceramidase/metabolism ; Acid Ceramidase/physiology ; Adrenal Cortex/metabolism ; Adrenocorticotropic Hormone/pharmacology ; Biosynthetic Pathways/genetics ; Cell Line, Tumor ; Cell Proliferation ; Ceramides/metabolism ; Cyclic AMP/metabolism ; Cyclin B2/metabolism ; Dehydroepiandrosterone/metabolism ; Gene Expression Regulation ; Gene Knockdown Techniques ; Histones/metabolism ; Humans ; Hydrocortisone/metabolism ; Proliferating Cell Nuclear Antigen/metabolism ; Promoter Regions, Genetic ; RNA Interference ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism ; Signal Transduction ; Sphingolipids/genetics ; Sphingolipids/metabolism ; Steroid Hydroxylases/genetics ; Steroid Hydroxylases/metabolism ; Steroids/biosynthesis ; Transcription, Genetic ; beta Catenin/metabolism
Chemical Substances	Ceramides ; Cyclin B2 ; Histones ; Proliferating Cell Nuclear Antigen ; Receptors, Cytoplasmic and Nuclear ; Sphingolipids ; Steroids ; beta Catenin ; Dehydroepiandrosterone (459AG36T1B) ; Adrenocorticotropic Hormone (9002-60-2) ; Cyclic AMP (E0399OZS9N) ; Steroid Hydroxylases (EC 1.14.-) ; ASAH1 protein, human (EC 3.5.1.23) ; Acid Ceramidase (EC 3.5.1.23) ; Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	2012-01-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639167-9
ISSN	1944-9917 ; 0888-8809
ISSN (online)	1944-9917
ISSN	0888-8809
DOI	10.1210/me.2011-1150
Database	MEDical Literature Analysis and Retrieval System OnLINE

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