Antipsychotic Drugs Regulate Hedgehog Signaling by Modulation of 7-Dehydrocholesterol Reductase Levels

Lauth, Matthias; Rohnalter, Verena; Bergström, Åsa; Kooshesh, Mahsa; Svenningsson, Per; Toftgárd, Rune

doi:10.1124/mol.110.066431

Cited by 58 publications

(63 citation statements)

References 32 publications

(43 reference statements)

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“…Schizophrenic patients are on a wide variety of medications, including anticonvulsants and antipsychotic drugs [46,47]. Our findings showed no significant association between those taking antipsychotics and vitamin D level, in line with other studies that showed no effect of antipsychotics on vitamin D level [1,48,49].…”

Section: Discussionsupporting

confidence: 89%

“…It is hypothesized that anti psychotics would cause hypogonadism and might predispose the patient to a higher risk of osteoporosis [50] however, it is not known whether there are direct effects of this class of medications on vitamin D status [1]. Some anticonvulsant medications might increase the rate of vitamin D removal from the body via the liver [51] by enhancing the catabolism of vitamin D [47], thus, putting the patient at risk of low vitamin D levels.…”

Section: Discussionmentioning

confidence: 99%

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Vitamin D Levels in Lebanese Patients with Schizophrenia: A Case-Control Study

Azar¹

2017

Ann Nutr Disord & Ther

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Objectives: To compare the vitamin D status in schizophrenics to that of healthy controls; secondary objectives were to assess the correlation between severe vitamin D deficiency and the severity of schizophrenia symptoms and to evaluate the potential factors influencing this status. Methods:A case-control study, conducted between March and July 2016, recruited 100 patients with schizophrenia and 100 controls with no known psychiatric disorders and matched for age and sex.Results: Schizophrenic patients had a more severe vitamin D deficiency compared to healthy controls (9% vs. 3%). Vitamin D insufficiency was found in 28% of schizophrenic patients compared to 37% in healthy controls (p=0.053). BCRS and MRSS scales were significantly associated with a more severe vitamin D deficiency (p=0.006). We couldn't detect any association between the total PANSS score and its three subscales with vitamin D deficiency (p>0.05). Lebanon has a high prevalence of 25(OH)-D deficiency in adults and older adults [23,24] however, data regarding vitamin D levels in psychiatric patients is still lacking. Therefore, the primary objective of this study was to compare the vitamin D status in schizophrenics to that of healthy controls; secondary objectives were to assess the

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Vitamin D Levels in Lebanese Patients with Schizophrenia: A Case-Control Study

Azar¹

2017

Ann Nutr Disord & Ther

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“…This was not expected because in the adult tissues and cells, transcriptional regulation of Dhcr7 is in line with the cholesterol feedback loop and transcription factors of the sterol regulatory element binding transcription protein family. Dhcr7 mRNA is inducible under sterol starvation or when treated with cholesterol synthesis inhibitors in the liver (34) and brain (35). Proteomic studies confirmed the increased expression of cholesterol synthesis enzymes in brains of the Dhcr7 null mice (36).…”

Section: Discussionmentioning

confidence: 94%

Mouse Knockout of the Cholesterogenic Cytochrome P450 Lanosterol 14α-Demethylase (Cyp51) Resembles Antley-Bixler Syndrome

Keber

Motaln

Wagner

et al. 2011

Journal of Biological Chemistry

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Antley-Bixler syndrome (ABS) represents a group of heterogeneous disorders characterized by skeletal, cardiac, and urogenital abnormalities that have frequently been associated with mutations in fibroblast growth factor receptor 2 or cytochrome P450 reductase genes. In some ABS patients, reduced activity of the cholesterogenic cytochrome P450 CYP51A1, an ortholog of the mouse CYP51, and accumulation of lanosterol and 24,25-dihydrolanosterol has been reported, but the role of CYP51A1 in the ABS etiology has remained obscure. To test whether Cyp51 could be involved in generating an ABS-like phenotype, a mouse knock-out model was developed that exhibited several prenatal ABS-like features leading to lethality at embryonic day 15. Cyp51؊/؊ mice had no functional Cyp51 mRNA and no immunodetectable CYP51 protein. The two CYP51 enzyme substrates (lanosterol and 24,25-dihydrolanosterol) were markedly accumulated. Cholesterol precursors downstream of the CYP51 enzymatic step were not detected, indicating that the targeting in this study blocked de novo cholesterol synthesis. This was reflected in the up-regulation of 10 cholesterol synthesis genes, with the exception of 7-dehydrocholesterol reductase. Lethality was ascribed to heart failure due to hypoplasia, ventricle septum, and epicardial and vasculogenesis defects, suggesting that Cyp51 deficiency was involved in heart development and coronary vessel formation. As the most likely downstream molecular mechanisms, alterations were identified in the sonic hedgehog and retinoic acid signaling pathways. Cyp51 knock-out mice provide evidence that Cyp51 is essential for embryogenesis and present a potential animal model for studying ABS syndrome in humans.

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“…It is worth noting that newer HDAC6 inhibitors are able to penetrate the blood-brain barrier and can therefore be tested under more physiologic conditions in autochthonous medulloblastoma mouse models in the future (63). Interestingly, these newer HDAC6 inhibitors have been shown to possess antidepressive characteristics, a phenomenon that we have linked to Hh inhibition before (64).…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase 6 Represents a Novel Drug Target in the Oncogenic Hedgehog Signaling Pathway

Dhanyamraju

Holz

Finkernagel

et al. 2015

Molecular Cancer Therapeutics

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Uncontrolled Hedgehog (Hh) signaling is the cause of several malignancies, including the pediatric cancer medulloblastoma, a neuroectodermal tumor affecting the cerebellum. Despite the development of potent Hh pathway antagonists, medulloblastoma drug resistance is still an unresolved issue that requires the identification of novel drug targets. Following up on our observation that histone deacetylase 6 (HDAC6) expression was increased in Hh-driven medulloblastoma, we found that this enzyme is essential for full Hh pathway activation. Intriguingly, these stimulatory effects of HDAC6 are partly integrated downstream of primary cilia, a known HDAC6-regulated structure. In addition, HDAC6 is also required for the complete repression of basal Hh target gene expression. These contrasting effects are mediated by HDAC6 0 s impact on Gli2 mRNA and GLI3 protein expression. As a result of this complex interaction with Hh signaling, global transcriptome analysis revealed that HDAC6 regulates only a subset of Smoothened-and Gli-driven genes, including all well-established Hh targets such as Ptch1 or Gli1. Importantly, medulloblastoma cell survival was severely compromised by HDAC6 inhibition in vitro and pharmacologic HDAC6 blockade strongly reduced tumor growth in an in vivo allograft model. In summary, our data describe an important role for HDAC6 in regulating the mammalian Hh pathway and encourage further studies focusing on HDAC6 as a novel drug target in medulloblastoma.

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Antipsychotic Drugs Regulate Hedgehog Signaling by Modulation of 7-Dehydrocholesterol Reductase Levels

Cited by 58 publications

References 32 publications

Vitamin D Levels in Lebanese Patients with Schizophrenia: A Case-Control Study

Vitamin D Levels in Lebanese Patients with Schizophrenia: A Case-Control Study

Mouse Knockout of the Cholesterogenic Cytochrome P450 Lanosterol 14α-Demethylase (Cyp51) Resembles Antley-Bixler Syndrome

Histone Deacetylase 6 Represents a Novel Drug Target in the Oncogenic Hedgehog Signaling Pathway

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