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

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.

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

npj Aging and Mechanisms of Disease ◽

10.1038/s41514-021-00064-9 ◽

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.

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Cholesterol Metabolic Reprogramming in Cancer and Its Pharmacological Modulation as Therapeutic Strategy

Frontiers in Oncology ◽

10.3389/fonc.2021.682911 ◽

2021 ◽

Vol 11 ◽

Author(s):

Isabella Giacomini ◽

Federico Gianfanti ◽

Maria Andrea Desbats ◽

Genny Orso ◽

Massimiliano Berretta ◽

...

Keyword(s):

De Novo ◽

Mevalonate Pathway ◽

Cholesterol Metabolism ◽

Tumor Development ◽

Cholesterol Homeostasis ◽

Metabolic Reprogramming ◽

Protein Prenylation ◽

Pharmacological Targets

Cholesterol is a ubiquitous sterol with many biological functions, which are crucial for proper cellular signaling and physiology. Indeed, cholesterol is essential in maintaining membrane physical properties, while its metabolism is involved in bile acid production and steroid hormone biosynthesis. Additionally, isoprenoids metabolites of the mevalonate pathway support protein-prenylation and dolichol, ubiquinone and the heme a biosynthesis. Cancer cells rely on cholesterol to satisfy their increased nutrient demands and to support their uncontrolled growth, thus promoting tumor development and progression. Indeed, transformed cells reprogram cholesterol metabolism either by increasing its uptake and de novo biosynthesis, or deregulating the efflux. Alternatively, tumor can efficiently accumulate cholesterol into lipid droplets and deeply modify the activity of key cholesterol homeostasis regulators. In light of these considerations, altered pathways of cholesterol metabolism might represent intriguing pharmacological targets for the development of exploitable strategies in the context of cancer therapy. Thus, this work aims to discuss the emerging evidence of in vitro and in vivo studies, as well as clinical trials, on the role of cholesterol pathways in the treatment of cancer, starting from already available cholesterol-lowering drugs (statins or fibrates), and moving towards novel potential pharmacological inhibitors or selective target modulators.

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Disruption of Dhcr7 and Insig1/2 in cholesterol metabolism causes defects in bone formation and homeostasis through primary cilium formation

Bone Research ◽

10.1038/s41413-019-0078-3 ◽

2020 ◽

Vol 8 (1) ◽

Cited By ~ 3

Author(s):

Akiko Suzuki ◽

Kenichi Ogata ◽

Hiroki Yoshioka ◽

Junbo Shim ◽

Christopher A. Wassif ◽

...

Keyword(s):

Bone Formation ◽

Primary Cilium ◽

Hedgehog Signaling ◽

Primary Cilia ◽

Cholesterol Metabolism ◽

Cholesterol Biosynthesis ◽

Cilium Formation ◽

Intracellular Cholesterol

AbstractHuman linkage studies suggest that craniofacial deformities result from either genetic mutations related to cholesterol metabolism or high-cholesterol maternal diets. However, little is known about the precise roles of intracellular cholesterol metabolism in the development of craniofacial bones, the majority of which are formed through intramembranous ossification. Here, we show that an altered cholesterol metabolic status results in abnormal osteogenesis through dysregulation of primary cilium formation during bone formation. We found that cholesterol metabolic aberrations, induced through disruption of either Dhcr7 (which encodes an enzyme involved in cholesterol synthesis) or Insig1 and Insig2 (which provide a negative feedback mechanism for cholesterol biosynthesis), result in osteoblast differentiation abnormalities. Notably, the primary cilia responsible for sensing extracellular cues were altered in number and length through dysregulated ciliary vesicle fusion in Dhcr7 and Insig1/2 mutant osteoblasts. As a consequence, WNT/β-catenin and hedgehog signaling activities were altered through dysregulated primary cilium formation. Strikingly, the normalization of defective cholesterol metabolism by simvastatin, a drug used in the treatment of cholesterol metabolic aberrations, rescued the abnormalities in both ciliogenesis and osteogenesis in vitro and in vivo. Thus, our results indicate that proper intracellular cholesterol status is crucial for primary cilium formation during skull formation and homeostasis.

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OS6.2 Loss of CYP46A1 directs altered cholesterol homeostasis and opens therapeutic opportunities for glioblastoma

Neuro-Oncology ◽

10.1093/neuonc/noz126.040 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii12-iii12

Author(s):

M Han ◽

S Wang ◽

X Li ◽

J Wang ◽

R Bjerkvig

Keyword(s):

Tumour Growth ◽

Cholesterol Metabolism ◽

Ectopic Expression ◽

Xenograft Model ◽

Cholesterol Homeostasis ◽

Normal Brain ◽

Genomic Databases ◽

Orthotopic Xenograft Model

Abstract BACKGROUND Dysregulated cholesterol metabolism is a hallmark of many cancers, including glioblastoma (GBM), but its role in disease progression is not well understood. Here, we identified cholesterol 24-hydroxylase (CYP46A1), a brain-specific enzyme responsible for elimination of cholesterol through conversion of cholesterol to 24(S)-hydroxycholesterol (24OHC), as one of the most dramatically dysregulated cholesterol metabolism genes in GBM. MATERIAL AND METHODS Molecular and clinical data was obtained from publicly genomic databases. Immunohistochemistry was applied to assess protein levels of CYP46A1 in primary GBM samples. Lentiviral constructs expressing CYP46A1 were transduced into LN229, LN18 and primary GBM GSCs for functional assays carried out in vitro and in vivo in an orthotopic xenograft model. RNA-seq was performed to identify downstream targets of 24OHC. RESULTS CYP46A1 was significantly decreased in GBM samples compared to normal brain tissue. Reduced CYP46A1 expression was associated with increasing tumour grade and poor prognosis in GBM patients. Ectopic expression of CYP46A1 suppressed cell proliferation and in vivo tumour growth by increasing 24OHC levels. Treatment of GBM cells with 24OHC suppressed tumour growth through regulation of LXR and SREBP signalling. Efavirenz (EFV), an activator of CYP46A1 with BBB penetration, inhibited GBM growth in vivo. CONCLUSION Our findings demonstrate that CYP46A1 is a critical regulator of cellular cholesterol in GBM and that the CYP46A1/24OHC axis is a potential therapeutic target.

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Mathematical Models for Cholesterol Metabolism and Transport

Processes ◽

10.3390/pr10010155 ◽

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.

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Macrophage-derived cholesterol contributes to therapeutic resistance in prostate cancer

10.1101/2021.03.24.436480 ◽

2021 ◽

Author(s):

Asmaa El-Kenawi ◽

William Dominguez-Viqueira ◽

Min Liu ◽

Shivanshu Awasthi ◽

Aysenur Keske ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Nuclear Translocation ◽

Cholesterol Metabolism ◽

Therapeutic Potential ◽

Cholesterol Homeostasis ◽

Castration Resistant Prostate Cancer ◽

Macrophage Depletion

Tumor-associated macrophages are key immune cells associated with cancer progression. Here we sought to determine the role of macrophages in castration-resistant prostate cancer (CRPC) using a syngeneic model that reflected the mutational landscape of the disease. A transcriptomic analysis of CRPC tumors following macrophage depletion revealed lower molecular signatures for steroid and bile acid synthesis, indicating potential perturbation of cholesterol metabolism. Since cholesterol is the precursor of the five major classes of steroid hormones, we reasoned that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Indeed, macrophage depletion reduced the levels of androgens within prostate tumors and restricted androgen receptor (AR) nuclear localization in vitro and in vivo. Macrophages were cholesterol rich and had the ability to transfer cholesterol to tumor cells in vitro, and AR nuclear translocation was inhibited by activation of Liver X Receptor (LXR)-β, the master regulator of cholesterol homeostasis. Finally, combining macrophage depletion with androgen deprivation therapy increased survival, supporting the therapeutic potential of targeting macrophages in CRPC.

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Pro-Inflammatory Implications of 2-Hydroxypropyl-β-cyclodextrin Treatment

Frontiers in Immunology ◽

10.3389/fimmu.2021.716357 ◽

2021 ◽

Vol 12 ◽

Author(s):

Tom Houben ◽

Tulasi Yadati ◽

Robbin de Kruijf ◽

Marion J. J. Gijbels ◽

Joost J. F. P. Luiken ◽

...

Keyword(s):

Bone Marrow ◽

Cell Lines ◽

Cholesterol Metabolism ◽

Strong Increase ◽

Metabolic Inflammation ◽

Cholesterol Levels ◽

Short Term Exposure ◽

Inflammatory Profile

Lifestyle- and genetically induced disorders related to disturbances in cholesterol metabolism have shown the detrimental impact of excessive cholesterol levels on a plethora of pathological processes such as inflammation. In this context, two-hydroxypropyl-β-cyclodextrin (CD) is increasingly considered as a novel pharmacological compound to decrease cellular cholesterol levels due to its ability to increase cholesterol solubility. However, recent findings have reported contra-indicating events after the use of CD questioning the clinical applicability of this compound. Given its potential as a therapeutic compound in metabolic inflammatory diseases, in this study, we evaluated the inflammatory effects of CD administration in the context of cholesterol-induced metabolic inflammation in vivo and in vitro. The inflammatory and cholesterol-depleting effects of CD were first investigated in low-density lipoprotein receptor knockout (Ldlr-/) mice that were transplanted with Npc1nih or Npc1wt bone marrow and were fed either regular chow or a high-fat, high-cholesterol (HFC) diet for 12 weeks, thereby creating an extreme model of lysosomal cholesterol-induced metabolic inflammation. In the final three weeks, these mice received daily injections of either control (saline) or CD subcutaneously. Subsequently, the inflammatory properties of CD were investigated in vitro in two macrophage cell lines and in murine bone marrow-derived macrophages (BMDMs). While CD administration improved cholesterol mobilization outside lysosomes in BMDMs, an overall pro-inflammatory profile was observed after CD treatment, evidenced by increased hepatic inflammation in vivo and a strong increase in cytokine release and inflammatory gene expression in vitro in murine BMDMs and macrophages cell lines. Nevertheless, this CD-induced pro-inflammatory profile was time-dependent, as short term exposure to CD did not result in a pro-inflammatory response in BMDM. While CD exerts desired cholesterol-depleting effects, its inflammatory effect is dependent on the exposure time. As such, using CD in the clinic, especially in a metabolic inflammatory context, should be closely monitored as it may lead to undesired, pro-inflammatory side effects.

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Anti-Oxidant and Anti-Hypercholesterolemic Activities ofWasabia japonica

Evidence-based Complementary and Alternative Medicine ◽

10.1093/ecam/nen038 ◽

2010 ◽

Vol 7 (4) ◽

pp. 459-464 ◽

Cited By ~ 15

Author(s):

Young Sun Lee ◽

Jae Ha Yang ◽

Man Jong Bae ◽

Wang Keun Yoo ◽

Shen Ye ◽

...

Keyword(s):

Cholesterol Metabolism ◽

Normal Diet ◽

High Cholesterol Diet ◽

Inos Mrna ◽

No Production ◽

Sprague Dawley ◽

Cholesterol Levels ◽

Anti Oxidant

The effects ofWasabia japonica(WJ) were investigatedin vitroandin vivofor their anti-oxidant and anti-hypercholesterolemic activities. It was found that the aqueous extracts of WJ leaves (WJL) had strong scavenging activities towards 1,1-Diphenyl-2-picryhydrazyl (DPPH) and nitric oxide (NO) free radicals in cell free systems. WJL also inhibited NO production and the expressions of inducible NO synthase (iNOS) mRNA and enzyme protein, determined by Griess reactions, RT-PCR or Western blotting respectively in Lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages cells. The anti-hypercholesterolemic effects of WJ diet were investigated in hypercholesterolemia rats. Sprague-Dawley rats were divided into four groups and were fed with either normal diet (Group 1), or diet containing 1%(w/w) cholesterol (Groups 2, 3 and 4). After 4 weeks, Group 2 was changed to normal diet, Groups 3 and 4 were changed to the diet containing 5% WJ leaf and or 5% WJ root, respectively. 3 weeks after WJ diets, Serum HDL-cholesterol levels were significantly increased in WJ diet groups compared with the normal diet hypercholesterolemia rats. In contrast, the serum LDL-cholesterol levels and liver xanthine oxidase (XO) activity in WJ diet groups were significantly decreased. The results indicate that the WJ extracts have significant anti-oxidant activities, and the WJ diet exhibited anti-hypercholesterolemic action in high cholesterol diet rats, which was companied with modulations of cholesterol metabolism and decrease in liver XO activity.

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Effects of Bee Venom on Glutamate-Induced Toxicity in Neuronal and Glial Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/368196 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 10

Author(s):

Sang Min Lee ◽

Eun Jin Yang ◽

Sun-Mi Choi ◽

Seon Hwy Kim ◽

Myung Gi Baek ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Glutamate Release ◽

Bee Venom ◽

Microglial Cells ◽

Excitatory Neurotransmitter ◽

Kinase Activation ◽

The Central Nervous System ◽

Lateral Sclerosis

Bee venom (BV), which is extracted from honeybees, is used in traditional Korean medical therapy. Several groups have demonstrated the anti-inflammatory effects of BV in osteoarthritis bothin vivoandin vitro. Glutamate is the predominant excitatory neurotransmitter in the central nervous system (CNS). Changes in glutamate release and uptake due to alterations in the activity of glutamate transporters have been reported in many neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. To assess if BV can prevent glutamate-mediated neurotoxicity, we examined cell viability and signal transduction in glutamate-treated neuronal and microglial cells in the presence and absence of BV. We induced glutamatergic toxicity in neuronal cells and microglial cells and found that BV protected against cell death. Furthermore, BV significantly inhibited the cellular toxicity of glutamate, and pretreatment with BV altered MAP kinase activation (e.g., JNK, ERK, and p38) following exposure to glutamate. These findings suggest that treatment with BV may be helpful in reducing glutamatergic cell toxicity in neurodegenerative diseases.

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Certain aspects of cholesterol metabolism and hepatic protein synthesis in the rat

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1964.207.6.1287 ◽

1964 ◽

Vol 207 (6) ◽

pp. 1287-1294 ◽

Cited By ~ 6

Author(s):

Shiro Saito ◽

Louis Charles Fillios

Keyword(s):

Protein Synthesis ◽

Cholesterol Metabolism ◽

Dietary Treatment ◽

High Serum ◽

Liver Protein ◽

High Serum Cholesterol ◽

Cholesterol Levels ◽

Hepatic Protein Synthesis

Hepatic protein synthesis was studied in rats fed a hypercholesteremic diet, containing cholesterol and cholic acid, and high in fat. If such a diet was fed for periods of at least 4 weeks a lowered capacity of amino acid incorporation into liver protein in vivo and in vitro was observed. The animals selected were rats which had been previously characterized by such a dietary assay as being neither refractory nor susceptible to induction of high serum cholesterol levels. When "hypo-responders" (i.e., rats which are relatively refractory to hypercholesteremia) were compared to "hyper-responders" significant differences in protein synthesis in vivo were observed after only 2 weeks of dietary treatment; the capacity for incorporation of amino acids in the livers of hyper-responders was significantly lower than that in the hypo-responders. Several studies were also carried out in vitro including an attempt to determine which intracellular components of the liver may be affected; it appears that the defect(s) is primarily related to the endoplasmic reticulum. Thus, diet may act as the modus operandi for revealing any purported inherent defect(s).

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