scholarly journals Phosphatidylcholine: Greasing the Cholesterol Transport Machinery

2015 ◽  
Vol 8s1 ◽  
pp. LPI.S31746 ◽  
Author(s):  
Thomas A. Lagace
Keyword(s):  
Mammalian Cells ◽  
Cholesterol Metabolism ◽  
Membrane Lipids ◽  
Cholesterol Biosynthesis ◽  
Feedback Regulation ◽  
Membrane Lipid ◽  
Plasma Lipoproteins ◽  
Cholesterol Trafficking ◽  
Negative Feedback Regulation ◽  
Cholesterol Levels

Negative feedback regulation of cholesterol metabolism in mammalian cells ensures a proper balance of cholesterol with other membrane lipids, principal among these being the major phospholipid phosphatidylcholine (PC). Processes such as cholesterol biosynthesis and efflux, cholesteryl ester storage in lipid droplets, and uptake of plasma lipoproteins are tuned to the cholesterol/PC ratio. Cholesterol-loaded macrophages in atherosclerotic lesions display increased PC biosynthesis that buffers against elevated cholesterol levels and may also facilitate cholesterol trafficking to enhance cholesterol sensing and efflux. These same mechanisms could play a generic role in homeostatic responses to acute changes in membrane free cholesterol levels. Here, I discuss the established and emerging roles of PC metabolism in promoting intracellular cholesterol trafficking and membrane lipid homeostasis.

scholarly journals Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Vijay R. Varma ◽  
H. Büşra Lüleci ◽  
Anup M. Oommen ◽  
Sudhir Varma ◽  
Chad T. Blackshear ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Tissue ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
Transcriptomic Data ◽  
Brain Cholesterol ◽  
Cholesterol Levels

AbstractThe role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

Precholesterol Sterols Accumulate in Lipid Rafts of Patients with Smith-Lemli-Opitz Syndrome and X-Linked Dominant Chondrodysplasia Punctata

2008 ◽  
Vol 11 (2) ◽  
pp. 128-132 ◽  
Author(s):  
Dinesh Rakheja ◽  
Richard L. Boriack
Keyword(s):  
Lipid Rafts ◽  
Hedgehog Signaling ◽  
Cholesterol Biosynthesis ◽  
Membrane Lipid ◽  
Chondrodysplasia Punctata ◽  
Autopsy Material ◽  
Cholesterol Levels ◽  
Abnormal Accumulation ◽  
Hedgehog Proteins ◽  
Opitz Syndrome

Systemic fetal dysmorphogenesis in disorders of postsqualene cholesterol biosynthesis is thought to be caused by disruption of Hedgehog signaling. Because precholesterol sterols such as 7-dehydrocholesterol and lathosterol can replace cholesterol in the activation of Hedgehog proteins, it is currently believed that cholesterol deficiency-related Hedgehog signaling block occurs further downstream, probably at the level of Smoothened. Experimentally, such a block in Hedgehog signaling occurs at sterol levels of <40 μg/mg protein. Recently, we studied autopsy material from 2 infants with fatal cholesterol biosynthetic disorders (Smith-Lemli-Opitz syndrome and X-linked dominant chondrodysplasia punctata) in which the hepatic cholesterol levels were far greater. In this study, we demonstrate abnormal accumulation of sterol precursors of cholesterol in membrane lipid rafts (detergent resistance membranes) prepared from liver tissues of these 2 infants: 8-dehydrocholesterol and 7-dehydrocholesterol in lipid rafts of the infant with Smith-Lemli-Opitz syndrome and cholest-8(9)-ene-3β-ol in lipid rafts of the infant with X-linked dominant chondrodysplasia punctata. We suggest that such alterations in the lipid raft sterol environment may affect the biology of cells and the development of fetuses with cholesterol biosynthetic disorders.

scholarly journals Sterols lower energetic barriers of membrane bending and fission necessary for efficient clathrin mediated endocytosis

2021 ◽  
Author(s):  
Ruthellen H. Anderson ◽  
Kem A. Sochacki ◽  
Harika Vuppula ◽  
Brandon L. Scott ◽  
Elizabeth M. Bailey ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Inborn Errors ◽  
Pit Formation ◽  
Internalization Mechanism ◽  
Cellular Signal ◽  
Membrane Bending ◽  
Cellular Phenotypes ◽  
Transferrin Uptake

SUMMARYAs the principal internalization mechanism in mammalian cells, clathrin-mediated endocytosis (CME) is critical for cellular signal transduction, receptor recycling, and membrane homeostasis. Acute depletion of cholesterol disrupts CME, motivating analysis of CME dynamics in the context of disrupted cholesterol synthesis, sterol specificity, mechanisms involved, and relevance to disease pathology. Using genome-edited cell lines, we demonstrate that inhibition of post-squalene cholesterol biosynthesis as observed in inborn errors of cholesterol metabolism, results in striking immobilization of CME and impaired transferrin uptake. Imaging of membrane bending dynamics and CME pit ultrastructure revealed prolonged clathrin pit lifetimes and accumulation of shallow clathrin-coated structures that scaled with diminishing sterol abundance. Moreover, fibroblasts derived from Smith-Lemli-Opitz syndrome subjects displayed reduced CME function. We conclude that sterols lower the energetic costs of membrane bending during pit formation and vesicular scission during CME and suggest reduced CME contributes to cellular phenotypes observed within disorders of cholesterol metabolism.

scholarly journals Aberrant Cholesterol Metabolism in Ovarian Cancer: Identification of Novel Therapeutic Targets

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiangnan He ◽  
Michelle K.Y. Siu ◽  
Hextan Y. S. Ngan ◽  
Karen K. L. Chan
Keyword(s):  
Ovarian Cancer ◽  
Mammalian Cells ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Therapeutic Targets ◽  
Multiple Cancer ◽  
Cancer Types ◽  
Characteristic Features ◽  
Rate Limiting

Cholesterol is an essential substance in mammalian cells, and cholesterol metabolism plays crucial roles in multiple biological functions. Dysregulated cholesterol metabolism is a metabolic hallmark in several cancers, beyond the Warburg effect. Reprogrammed cholesterol metabolism has been reported to enhance tumorigenesis, metastasis and chemoresistance in multiple cancer types, including ovarian cancer. Ovarian cancer is one of the most aggressive malignancies worldwide. Alterations in metabolic pathways are characteristic features of ovarian cancer; however, the specific role of cholesterol metabolism remains to be established. In this report, we provide an overview of the key proteins involved in cholesterol metabolism in ovarian cancer, including the rate-limiting enzymes in cholesterol biosynthesis, and the proteins involved in cholesterol uptake, storage and trafficking. Also, we review the roles of cholesterol and its derivatives in ovarian cancer and the tumor microenvironment, and discuss promising related therapeutic targets for ovarian cancer.

scholarly journals Negative feedback regulation of calcineurin-dependent Prz1 transcription factor by the CaMKK-CaMK1 axis in fission yeast

2014 ◽  
Vol 42 (15) ◽  
pp. 9573-9587 ◽  
Author(s):  
Eugenia Cisneros-Barroso ◽  
Tula Yance-Chávez ◽  
Ayako Kito ◽  
Reiko Sugiura ◽  
Alba Gómez-Hierro ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Nuclear Export ◽  
Mammalian Cells ◽  
Calcium Signalling ◽  
Feedback Regulation ◽  
Negative Feedback Regulation ◽  
Cycle Arrest ◽  
Cell Cycle Inhibition ◽  
Active Transcription

Abstract Calcium signals trigger the translocation of the Prz1 transcription factor from the cytoplasm to the nucleus. The process is regulated by the calcium-activated phosphatase calcineurin, which activates Prz1 thereby maintaining active transcription during calcium signalling. When calcium signalling ceases, Prz1 is inactivated by phosphorylation and exported to the cytoplasm. In budding yeast and mammalian cells, different kinases have been reported to counter calcineurin activity and regulate nuclear export. Here, we show that the Ca2+/calmodulin-dependent kinase Cmk1 is first phosphorylated and activated by the newly identified kinase CaMKK2 homologue, Ckk2, in response to Ca2+. Then, active Cmk1 binds, phosphorylates and inactivates Prz1 transcription activity whilst at the same time cmk1 expression is enhanced by Prz1 in response to Ca2+. Furthermore, Cdc25 phosphatase is also phosphorylated by Cmk1, inducing cell cycle arrest in response to an increase in Ca2+. Moreover, cmk1 deletion shows a high tolerance to chronic exposure to Ca2+, due to the lack of cell cycle inhibition and elevated Prz1 activity. This work reveals that Cmk1 kinase activated by the newly identified Ckk2 counteracts calcineurin function by negatively regulating Prz1 activity which in turn is involved in activating cmk1 gene transcription. These results are the first insights into Cmk1 and Ckk2 function in Schizosaccharomyces pombe.

scholarly journals Mathematical Models for Cholesterol Metabolism and Transport

Processes ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 155
Author(s):  
Fangyuan Zhang ◽  
Brittany Macshane ◽  
Ryan Searcy ◽  
Zuyi Huang
Keyword(s):  
Mathematical Models ◽  
Drug Targets ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
The Body ◽  
Cholesterol Homeostasis ◽  
Whole Body ◽  
Entire Body ◽  
High Cholesterol ◽  
Cholesterol Levels

Cholesterol is an essential component of eukaryotic cellular membranes. It is also an important precursor for making other molecules needed by the body. Cholesterol homeostasis plays an essential role in human health. Having high cholesterol can increase the chances of getting heart disease. As a result of the risks associated with high cholesterol, it is imperative that studies are conducted to determine the best course of action to reduce whole body cholesterol levels. Mathematical models can provide direction on this. By examining existing models, the suitable reactions or processes for drug targeting to lower whole-body cholesterol can be determined. This paper examines existing models in the literature that, in total, cover most of the processes involving cholesterol metabolism and transport, including: the absorption of cholesterol in the intestine; the cholesterol biosynthesis in the liver; the storage and transport of cholesterol between the intestine, the liver, blood vessels, and peripheral cells. The findings presented in these models will be discussed for potential combination to form a comprehensive model of cholesterol within the entire body, which is then taken as an in-silico patient for identifying drug targets, screening drugs, and designing intervention strategies to regulate cholesterol levels in the human body.

scholarly journals MYC Enhances Cholesterol Biosynthesis and Supports Cell Proliferation Through SQLE

2021 ◽  
Vol 9 ◽  
Author(s):  
Fan Yang ◽  
Junjie Kou ◽  
Zizhao Liu ◽  
Wei Li ◽  
Wenjing Du
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Cholesterol Synthesis ◽  
Cholesterol Metabolism ◽  
Cell Metabolism ◽  
Cholesterol Biosynthesis ◽  
Potential Therapeutic Target ◽  
Cholesterol Levels ◽  
Membrane Components ◽  
Rate Limiting

Oncogene c-Myc (referred in this report as MYC) promotes tumorigenesis in multiple human cancers. MYC regulates numerous cellular programs involved in cell growth and cell metabolism. Tumor cells exhibit obligatory dependence on cholesterol metabolism, which provides essential membrane components and metabolites to support cell growth. To date, how cholesterol biosynthesis is delicately regulated to promote tumorigenesis remains unclear. Here, we show that MYC enhances cholesterol biosynthesis and promotes cell proliferation. Through transcriptional upregulation of SQLE, a rate-limiting enzyme in cholesterol synthesis pathway, MYC increases cholesterol production and promotes tumor cell growth. SQLE overexpression restores the cellular cholesterol levels in MYC-knockdown cells. More importantly, in SQLE-depleted cells, enforced expression of MYC has no effect on cholesterol levels. Therefore, our findings reveal that SQLE is critical for MYC-mediated cholesterol synthesis, and further demonstrate that SQLE may be a potential therapeutic target in MYC-amplified cancers.

scholarly journals TDP-43 mediates SREBF2-regulated gene expression required for oligodendrocyte myelination

2021 ◽  
Vol 220 (9) ◽  
Author(s):  
Wan Yun Ho ◽  
Jer-Cherng Chang ◽  
Kenneth Lim ◽  
Amaury Cazenave-Gassiot ◽  
Aivi T. Nguyen ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
Cholesterol Levels ◽  
The Central Nervous System ◽  
Cholesterol Supplementation ◽  
Regulated Gene Expression ◽  
Lateral Sclerosis

Cholesterol metabolism operates autonomously within the central nervous system (CNS), where the majority of cholesterol resides in myelin. We demonstrate that TDP-43, the pathological signature protein for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), influences cholesterol metabolism in oligodendrocytes. TDP-43 binds directly to mRNA of SREBF2, the master transcription regulator for cholesterol metabolism, and multiple mRNAs encoding proteins responsible for cholesterol biosynthesis and uptake, including HMGCR, HMGCS1, and LDLR. TDP-43 depletion leads to reduced SREBF2 and LDLR expression, and cholesterol levels in vitro and in vivo. TDP-43–mediated changes in cholesterol levels can be restored by reintroducing SREBF2 or LDLR. Additionally, cholesterol supplementation rescues demyelination caused by TDP-43 deletion. Furthermore, oligodendrocytes harboring TDP-43 pathology from FTD patients show reduced HMGCR and HMGCS1, and coaggregation of LDLR and TDP-43. Collectively, our results indicate that TDP-43 plays a role in cholesterol homeostasis in oligodendrocytes, and cholesterol dysmetabolism may be implicated in TDP-43 proteinopathies–related diseases.

scholarly journals Smad7 Antagonizes Transforming Growth Factor β Signaling in the Nucleus by Interfering with Functional Smad-DNA Complex Formation

2007 ◽  
Vol 27 (12) ◽  
pp. 4488-4499 ◽  
Author(s):  
Suping Zhang ◽  
Teng Fei ◽  
Lixia Zhang ◽  
Ran Zhang ◽  
Feng Chen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
Feedback Regulation ◽  
Transforming Growth Factor Β ◽  
Binding Activity ◽  
Type I ◽  
Negative Feedback Regulation ◽  
Dna Complex

ABSTRACT Smad7 plays an essential role in the negative-feedback regulation of transforming growth factor β (TGF-β) signaling by inhibiting TGF-β signaling at the receptor level. It can interfere with binding to type I receptors and thus activation of receptor-regulated Smads or recruit the E3 ubiquitin ligase Smurf to receptors and thus target them for degradation. Here, we report that Smad7 is predominantly localized in the nucleus of Hep3B cells. The targeted expression of Smad7 in the nucleus conferred superior inhibitory activity on TGF-β signaling, as determined by reporter assay in mammalian cells and by its effect on zebrafish embryogenesis. Furthermore, Smad7 repressed Smad3/4-, Smad2/4-, and Smad1/4-enhanced reporter gene expression, indicating that Smad7 can function independently of type I receptors. An oligonucleotide precipitation assay revealed that Smad7 can specifically bind to the Smad-responsive element via its MH2 domain, and DNA-binding activity was further confirmed in vivo with the promoter of PAI-1, a TGF-β target gene, by chromatin immunoprecipitation. Finally, we provide evidence that Smad7 disrupts the formation of the TGF-β-induced functional Smad-DNA complex. Our findings suggest that Smad7 inhibits TGF-β signaling in the nucleus by a novel mechanism.

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