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Cure E, Cumhur Cure M. Emerging risks of lipid-lowering therapy and low LDL levels: implications for eye, brain, and new-onset diabetes. Lipids Health Dis 2025; 24:185. [PMID: 40399888 PMCID: PMC12093843 DOI: 10.1186/s12944-025-02606-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Accepted: 05/10/2025] [Indexed: 05/23/2025] Open
Abstract
Atherosclerotic cardiovascular disease remains a major global health burden. Current guidelines emphasize aggressive lipid-lowering strategies, particularly those that reduce low-density lipoprotein cholesterol (LDL-C) levels. While effective in lowering cardiovascular risk, excessively low LDL-C may have unintended health consequences. LDL-C plays a critical physiological role in cellular structure and hormone synthesis. Emerging evidence links low LDL-C and high HDL-C with increased glaucoma risk. Statins, which are commonly used to lower LDL-C, may further increase this risk, raising concerns for patients with coronary artery disease. Low LDL-C has also been associated with gestational diabetes and intracranial hemorrhage, while statin therapy may contribute to new-onset diabetes mellitus. These findings highlight the need to reassess the "lower is better" paradigm. A patient-centered, risk-based approach to statin therapy is recommended. Large-scale randomized controlled trials are urgently needed to establish safe lipid thresholds and optimize therapeutic strategies.
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Affiliation(s)
- Erkan Cure
- Department of Internal Medicine, Istinye University, Gaziosmanpasa Medical Park Hospital, Gaziosmanpasa, Istanbul, 34250, Turkey.
| | - Medine Cumhur Cure
- Department of Biochemistry, Medilab Laboratory and Imaging Center, Sisli, Istanbul, Turkey
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2
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Bhasker A, Veleri S. Fundamental origins of neural tube defects with a basis in genetics and nutrition. Exp Brain Res 2025; 243:79. [PMID: 40025180 DOI: 10.1007/s00221-025-07016-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 01/30/2025] [Indexed: 03/04/2025]
Abstract
Neural tube defects (NTDs) are leading congenital malformations. Its global prevalence is one in 1000 pregnancies and it has high morbidity and mortality. It has multiple risk factors like genetic errors and environmental stressors like maternal malnutrition and in utero exposure to pollutants like chemicals. The genetic program determines neural tube development based on timely expression of many genes involved in developmental signaling pathways like BMP, PCP and SHH. BMP expression defines ectoderm. SOX represses BMP in ectoderm and convertes to the neuroectoderm. Subsequently, PCP molecules define the tissue patterning for convergent-extension, a critical step in neural tube genesis. Further, SHH sets spatial patterning of the neural tube. Nutrients are the essential major environmental input for embryogenesis. But it may also carry risk factors. Malnutrition, especially folate deficiency, during embryogenesis is a major cause for NTDs. Folate is integral in the One Carbon metabolic pathway. Its deficiency and error in the pathway are implicated in NTDs. Folate supplementation alone is insufficient to prevent NTDs. Thus, a comprehensive understanding of the various risk factors is necessary to strategize reduction of NTDs. We review the current knowledge of various risk factors, like genetic, metabolic, nutritional, and drugs causing NTDs and discuss the steps required to identify them in the early embryogenesis to avoid NTDs.
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Affiliation(s)
- Anjusha Bhasker
- Drug Safety Division, ICMR-National Institute of Nutrition, Department of Health Research, Ministry of Health & Family Welfare, Govt. of India, Hyderabad, 500007, India
| | - Shobi Veleri
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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3
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Popova EY, Kawasawa YI, Leung M, Barnstable CJ. Temporal changes in mouse hippocampus transcriptome after pilocarpine-induced seizures. Front Neurosci 2024; 18:1384805. [PMID: 39040630 PMCID: PMC11260795 DOI: 10.3389/fnins.2024.1384805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 06/07/2024] [Indexed: 07/24/2024] Open
Abstract
Introduction Status epilepticus (SE) is a seizure lasting more than 5 min that can have lethal consequences or lead to various neurological disorders, including epilepsy. Using a pilocarpine-induced SE model in mice we investigated temporal changes in the hippocampal transcriptome. Methods We performed mRNA-seq and microRNA-seq analyses at various times after drug treatment. Results At 1 h after the start of seizures, hippocampal cells upregulated transcription of immediate early genes and genes involved in the IGF-1, ERK/MAPK and RNA-PolII/transcription pathways. At 8 h, we observed changes in the expression of genes associated with oxidative stress, overall transcription downregulation, particularly for genes related to mitochondrial structure and function, initiation of a stress response through regulation of ribosome and translation/EIF2 signaling, and upregulation of an inflammatory response. During the middle of the latent period, 36 h, we identified upregulation of membrane components, cholesterol synthesis enzymes, channels, and extracellular matrix (ECM), as well as an increased inflammatory response. At the end of the latent period, 120 h, most changes in expression were in genes involved in ion transport, membrane channels, and synapses. Notably, we also elucidated the involvement of novel pathways, such as cholesterol biosynthesis pathways, iron/BMP/ferroptosis pathways, and circadian rhythms signaling in SE and epileptogenesis. Discussion These temporal changes in metabolic reactions indicate an immediate response to injury followed by recovery and regeneration. CREB was identified as the main upstream regulator. Overall, our data provide new insights into molecular functions and cellular processes involved at different stages of seizures and offer potential avenues for effective therapeutic strategies.
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Affiliation(s)
- Evgenya Y. Popova
- Department of Neural and Behavioral Sciences, Penn State University College of Medicine, Hershey, PA, United States
- Penn State Hershey Eye Center, Hershey, PA, United States
| | - Yuka Imamura Kawasawa
- Department of Pharmacology, Penn State University College of Medicine, Hershey, PA, United States
- Center for Cancer Genomics and Precision Oncology, Wake Forest Baptist Comprehensive Cancer Center, Winston Salem, NC, United States
| | - Ming Leung
- Center for Cancer Genomics and Precision Oncology, Wake Forest Baptist Comprehensive Cancer Center, Winston Salem, NC, United States
| | - Colin J. Barnstable
- Department of Neural and Behavioral Sciences, Penn State University College of Medicine, Hershey, PA, United States
- Penn State Hershey Eye Center, Hershey, PA, United States
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Iwaya C, Suzuki A, Shim J, Kim A, Iwata J. Craniofacial bone anomalies related to cholesterol synthesis defects. Sci Rep 2024; 14:5371. [PMID: 38438535 PMCID: PMC10912708 DOI: 10.1038/s41598-024-55998-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 02/29/2024] [Indexed: 03/06/2024] Open
Abstract
DHCR7 and SC5D are enzymes crucial for cholesterol biosynthesis, and mutations in their genes are associated with developmental disorders, which are characterized by craniofacial deformities. We have recently reported that a loss of either Dhcr7 or Sc5d results in a failure in osteoblast differentiation. However, it remains unclear to what extent a loss of function in either DHCR7 or SC5D affects craniofacial skeletal formation. Here, using micro computed tomography (μCT), we found that the bone phenotype differs in Dhcr7-/- and Sc5d-/- mice in a location-specific fashion. For instance, in Sc5d-/- mice, although craniofacial bones were overall affected, some bone segments, such as the anterior part of the premaxilla, the anterior-posterior length of the frontal bone, and the main body of the mandible, did not present significant differences compared to WT controls. By contrast, in Dhcr7-/- mice, while craniofacial bones were not much affected, the frontal bone was larger in width and volume, and the maxilla and palatine bone were hypoplastic, compared to WT controls. Interestingly the mandible in Dhcr7-/- mice was mainly affected at the condylar region, not the body. Thus, these results help us understand which bones and how greatly they are affected by cholesterol metabolism aberrations in Dhcr7-/- and Sc5d-/- mice.
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Affiliation(s)
- Chihiro Iwaya
- Department of Diagnostic and Biomedical Sciences, The University of Texas Health Science Center at Houston (UTHealth), School of Dentistry, 1941 East Road, BBS 4208, Houston, TX, 77054, USA
- Center for Craniofacial Research, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX, 77054, USA
| | - Akiko Suzuki
- Department of Diagnostic and Biomedical Sciences, The University of Texas Health Science Center at Houston (UTHealth), School of Dentistry, 1941 East Road, BBS 4208, Houston, TX, 77054, USA
- Center for Craniofacial Research, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX, 77054, USA
- University of Missouri - Kansas City, School of Dentistry, Kansas City, MO, 64108, USA
| | - Junbo Shim
- Department of Diagnostic and Biomedical Sciences, The University of Texas Health Science Center at Houston (UTHealth), School of Dentistry, 1941 East Road, BBS 4208, Houston, TX, 77054, USA
- Center for Craniofacial Research, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX, 77054, USA
| | - Aemin Kim
- Department of Diagnostic and Biomedical Sciences, The University of Texas Health Science Center at Houston (UTHealth), School of Dentistry, 1941 East Road, BBS 4208, Houston, TX, 77054, USA
| | - Junichi Iwata
- Department of Diagnostic and Biomedical Sciences, The University of Texas Health Science Center at Houston (UTHealth), School of Dentistry, 1941 East Road, BBS 4208, Houston, TX, 77054, USA.
- Center for Craniofacial Research, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX, 77054, USA.
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA.
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Politiek FA, Turkenburg M, Koster J, Ofman R, Waterham HR. Identification of FDA-approved drugs that increase mevalonate kinase in hyper IgD syndrome. J Inherit Metab Dis 2024; 47:302-316. [PMID: 38131282 DOI: 10.1002/jimd.12698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/13/2023] [Accepted: 11/29/2023] [Indexed: 12/23/2023]
Abstract
Mevalonate kinase deficiency (MKD) is an autoinflammatory metabolic disorder caused by bi-allelic loss-of-function variants in the MVK gene, resulting in decreased activity of the encoded mevalonate kinase (MK). Clinical presentation ranges from the severe early-lethal mevalonic aciduria to the milder hyper-IgD syndrome (MKD-HIDS), and is in the majority of patients associated with recurrent inflammatory episodes with often unclear cause. Previous studies with MKD-HIDS patient cells indicated that increased temperature, as caused by fever during an inflammatory episode, lowers the residual MK activity, which causes a temporary shortage of non-sterol isoprenoids that promotes the further development of inflammation. Because an increase of the residual MK activity is expected to make MKD-HIDS patients less sensitive to developing inflammatory episodes, we established a cell-based screen that can be used to identify compounds and/or therapeutic targets that promote this increase. Using a reporter HeLa cell line that stably expresses the most common MKD-HIDS variant, MK-V377I, C-terminally tagged with bioluminescent NanoLuc luciferase (nLuc), we screened the Prestwick Chemical Library®, which includes 1280 FDA-approved compounds. Multiple compounds increased MK-V377I-nLuc bioluminescence, including steroids (i.e., glucocorticoids, estrogens, and progestogens), statins and antineoplastic drugs. The glucocorticoids increased MK-V377I-nLuc bioluminescence through glucocorticoid receptor signaling. Subsequent studies in MKD-HIDS patient cells showed that the potent glucocorticoid clobetasol propionate increases gene transcription of MVK and other genes regulated by the transcription factor sterol regulatory element-binding protein 2 (SREBP-2). Our results suggest that increasing the flux through the isoprenoid biosynthesis pathway by targeting the glucocorticoid receptor or SREBP-2 could be a potential therapeutic strategy in MKD-HIDS.
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Affiliation(s)
- Frouwkje A Politiek
- Department of Laboratory Medicine, Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Marjolein Turkenburg
- Department of Laboratory Medicine, Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, the Netherlands
| | - Janet Koster
- Department of Laboratory Medicine, Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, the Netherlands
| | - Rob Ofman
- Department of Laboratory Medicine, Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, the Netherlands
| | - Hans R Waterham
- Department of Laboratory Medicine, Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
- Amsterdam Reproduction & Development, Amsterdam, the Netherlands
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Christensen JJ, Arnesen EK, Rundblad A, Telle-Hansen VH, Narverud I, Blomhoff R, Bogsrud MP, Retterstøl K, Ulven SM, Holven KB. Dietary fat quality, plasma atherogenic lipoproteins, and atherosclerotic cardiovascular disease: An overview of the rationale for dietary recommendations for fat intake. Atherosclerosis 2024; 389:117433. [PMID: 38219649 DOI: 10.1016/j.atherosclerosis.2023.117433] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 11/29/2023] [Accepted: 12/20/2023] [Indexed: 01/16/2024]
Abstract
The scientific evidence supporting the current dietary recommendations for fat quality keeps accumulating; however, a paradoxical distrust has taken root among many researchers, clinicians, and in parts of the general public. One explanation for this distrust may relate to an incomplete overview of the totality of the evidence for the link between fat quality as a dietary exposure, and health outcomes such as atherosclerotic cardiovascular disease (ASCVD). Therefore, the main aim of the present narrative review was to provide a comprehensive overview of the rationale for dietary recommendations for fat intake, limiting our discussion to ASCVD as outcome. Herein, we provide a core framework - a causal model - that can help us understand the evidence that has accumulated to date, and that can help us understand new evidence that may become available in the future. The causal model for fat quality and ASCVD is comprised of three key research questions (RQs), each of which determine which scientific methods are most appropriate to use, and thereby which lines of evidence that should feed into the causal model. First, we discuss the link between low-density lipoprotein (LDL) particles and ASCVD (RQ1); we draw especially on evidence from genetic studies, randomized controlled trials (RCTs), epidemiology, and mechanistic studies. Second, we explain the link between dietary fat quality and LDL particles (RQ2); we draw especially on metabolic ward studies, controlled trials (randomized and non-randomized), and mechanistic studies. Third, we explain the link between dietary fat quality, LDL particles, and ASCVD (RQ3); we draw especially on RCTs in animals and humans, epidemiology, population-based changes, and experiments of nature. Additionally, the distrust over dietary recommendations for fat quality may partly relate to an unclear understanding of the scientific method, especially as applied in nutrition research, including the process of developing dietary guidelines. We therefore also aimed to clarify this process. We discuss how we assess causality in nutrition research, and how we progress from scientific evidence to providing dietary recommendations.
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Affiliation(s)
- Jacob J Christensen
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
| | - Erik Kristoffer Arnesen
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Amanda Rundblad
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | | | - Ingunn Narverud
- Norwegian National Advisory Unit on Familial Hypercholesterolemia, Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway
| | - Rune Blomhoff
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Martin P Bogsrud
- Unit for Cardiac and Cardiovascular Genetics, Oslo University Hospital, Oslo, Norway
| | - Kjetil Retterstøl
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; The Lipid Clinic, Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway
| | - Stine M Ulven
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Kirsten B Holven
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Norwegian National Advisory Unit on Familial Hypercholesterolemia, Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway
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7
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Somers T, Siddiqi S, Morshuis WJ, Russel FGM, Schirris TJJ. Statins and Cardiomyocyte Metabolism, Friend or Foe? J Cardiovasc Dev Dis 2023; 10:417. [PMID: 37887864 PMCID: PMC10607220 DOI: 10.3390/jcdd10100417] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/23/2023] [Accepted: 09/30/2023] [Indexed: 10/28/2023] Open
Abstract
Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, and are the cornerstone of lipid-lowering treatment. They significantly reduce cardiovascular morbidity and mortality. However, musculoskeletal symptoms are observed in 7 to 29 percent of all users. The mechanism underlying these complaints has become increasingly clear, but less is known about the effect on cardiac muscle function. Here we discuss both adverse and beneficial effects of statins on the heart. Statins exert pleiotropic protective effects in the diseased heart that are independent of their cholesterol-lowering activity, including reduction in hypertrophy, fibrosis and infarct size. Adverse effects of statins seem to be associated with altered cardiomyocyte metabolism. In this review we explore the differences in the mechanism of action and potential side effects of statins in cardiac and skeletal muscle and how they present clinically. These insights may contribute to a more personalized treatment strategy.
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Affiliation(s)
- Tim Somers
- Department of Cardiothoracic Surgery, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
- Division of Pharmacology and Toxicology, Department of Pharmacy, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
- Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
| | - Sailay Siddiqi
- Department of Cardiothoracic Surgery, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
- Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
| | - Wim J. Morshuis
- Department of Cardiothoracic Surgery, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
| | - Frans G. M. Russel
- Division of Pharmacology and Toxicology, Department of Pharmacy, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
- Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
| | - Tom J. J. Schirris
- Division of Pharmacology and Toxicology, Department of Pharmacy, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
- Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
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Shrivastava S, Paila YD, Chattopadhyay A. Role of Cholesterol and its Biosynthetic Precursors on Membrane Organization and Dynamics: A Fluorescence Approach. J Membr Biol 2023; 256:189-197. [PMID: 36781437 DOI: 10.1007/s00232-023-00278-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 01/23/2023] [Indexed: 02/15/2023]
Abstract
Cholesterol is the most representative sterol present in membranes of higher eukaryotes, and is the end product of a long and multistep biosynthetic pathway. Lathosterol and zymosterol are biosynthetic precursors of cholesterol in Kandutsch-Russell and Bloch pathways, respectively. Lathosterol differs with cholesterol merely in the position of the double bond in the sterol ring, whereas zymosterol differs with cholesterol in position and number of double bonds. In this work, we have monitored the effect of cholesterol and its biosynthetic precursors (lathosterol and zymosterol) on membrane organization and dynamics in fluid and gel phase membranes. Toward this goal, we have utilized two fluorescent membrane probes, DPH and its cationic derivative TMA-DPH. Our results using these probes show that cholesterol and its biosynthetic precursors (lathosterol and zymosterol) exhibit similar trend in maintaining membrane organization and dynamics (as reported by fluorescence anisotropy and apparent rotational correlation time), in fluid phase POPC membranes. Notably, although lathosterol and zymosterol show similar trend in maintaining membrane organization and dynamics, the corresponding change for cholesterol is different in gel phase DPPC membranes. These results demonstrate that the position and number of double bonds in sterols is an important determinant in maintaining membrane physical properties. Our results assume significance since accumulation of precursors of cholesterol have been reported to be associated with severe pathological conditions.
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Affiliation(s)
- Sandeep Shrivastava
- CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad, 500 007, India
| | - Yamuna Devi Paila
- CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad, 500 007, India.,Moderna Inc, Cambridge, MA, 02139, USA
| | - Amitabha Chattopadhyay
- CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad, 500 007, India. .,Academy of Scientific and Innovative Research, Ghaziabad, 201 002, India.
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9
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Human skeletal dysplasia causing L596P-mutant alters the conserved amino acid pattern at the lipid-water-Interface of TRPV4. BIOCHIMICA ET BIOPHYSICA ACTA. BIOMEMBRANES 2023; 1865:184085. [PMID: 36403799 DOI: 10.1016/j.bbamem.2022.184085] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 11/01/2022] [Accepted: 11/02/2022] [Indexed: 11/18/2022]
Abstract
TRPV4 is a polymodal and non-selective cation channel that is activated by multiple physical and chemical stimuli. >50 naturally occurring point-mutation of TRPV4 have been identified in human, most of which induce different diseases commonly termed as channelopathies. While, these mutations are either "gain-of-function" or "loss-of-function" in nature, the exact molecular and cellular mechanisms behind such diverse channelopathies are largely unknown. In this work, we analyze the evolutionary conservation of individual amino acids present in the lipid-water-interface (LWI) regions and the relationship of TRPV4 with membrane cholesterol. Our data suggests that the positive-negative charges and hydrophobic-hydrophilic amino acids form "specific patterns" in the LWI region which remain conserved throughout the vertebrate evolution and thus suggesting for the specific microenvironment where TRPV4 remain functional. Notably, Spondylometaphyseal Dysplasia, Kozlowski (SMDK) disease causing L596P mutation disrupts this pattern significantly at the LWI region. L596P mutant also sequesters Caveolin-1 differently, especially in partial cholesterol-depleted (~40 % reduction) conditions. L596P shows altered localization in membrane and enhanced Ca2+-influx properties in cell as well as in filopodia-like structures. We propose that conserved pattern of amino acids is an important parameter for proper localization and functions of TRPV4 in physiological conditions. These findings also offer a new paradigm to analyze the channelopathies caused by mutations in LWI regions of other channels as well.
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Sarkar P, Chattopadhyay A. Membrane Dipole Potential: An Emerging Approach to Explore Membrane Organization and Function. J Phys Chem B 2022; 126:4415-4430. [PMID: 35696090 DOI: 10.1021/acs.jpcb.2c02476] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Biological membranes are complex organized molecular assemblies of lipids and proteins that provide cells and membrane-bound intracellular organelles their individual identities by morphological compartmentalization. Membrane dipole potential originates from the electrostatic potential difference within the membrane due to the nonrandom arrangement (orientation) of amphiphile and solvent (water) dipoles at the membrane interface. In this Feature Article, we will focus on the measurement of dipole potential using electrochromic fluorescent probes and highlight interesting applications. In addition, we will focus on ratiometric fluorescence microscopic imaging technique to measure dipole potential in cellular membranes, a technique that can be used to address novel problems in cell biology which are otherwise difficult to address using available approaches. We envision that membrane dipole potential could turn out to be a convenient tool in exploring the complex interplay between membrane lipids and proteins and could provide novel insights in membrane organization and function.
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Affiliation(s)
- Parijat Sarkar
- CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India
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11
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Dutta A, Sarkar P, Shrivastava S, Chattopadhyay A. Effect of Hypoxia on the Function of the Human Serotonin 1A Receptor. ACS Chem Neurosci 2022; 13:1456-1466. [PMID: 35467841 DOI: 10.1021/acschemneuro.2c00181] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Cellular hypoxia causes numerous pathophysiological conditions associated with the disruption of oxygen homeostasis. Under oxygen-deficient conditions, cells adapt by controlling the cellular functions to facilitate the judicious use of available oxygen, such as cessation of cell growth and proliferation. In higher eukaryotes, the process of cholesterol biosynthesis is intimately coupled to the availability of oxygen, where the synthesis of one molecule of cholesterol requires 11 molecules of O2. Cholesterol is an essential component of higher eukaryotic membranes and is crucial for the physiological functions of several membrane proteins and receptors. The serotonin1A receptor, an important neurotransmitter G protein-coupled receptor associated with cognition and memory, has previously been shown to depend on cholesterol for its signaling and function. In this work, in order to explore the interdependence of oxygen levels, cholesterol biosynthesis, and the function of the serotonin1A receptor, we developed a cellular hypoxia model to explore the function of the human serotonin1A receptor heterologously expressed in Chinese hamster ovary cells. We observed cell cycle arrest at G1/S phase and the accumulation of lanosterol in cell membranes under hypoxic conditions, thereby validating our cellular model. Interestingly, we observed a significant reduction in ligand binding and disruption of downstream cAMP signaling of the serotonin1A receptor under hypoxic conditions. To the best of our knowledge, our results represent the first report linking the function of the serotonin1A receptor with hypoxia. From a broader perspective, these results contribute to our overall understanding of the molecular basis underlying neurological conditions often associated with hypoxia-induced brain dysfunction.
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Affiliation(s)
- Aritri Dutta
- CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India
| | - Parijat Sarkar
- CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India
| | - Sandeep Shrivastava
- CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India
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12
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The impact of TiO 2 nanoparticle exposure on transmembrane cholesterol transport and enhanced bacterial infectivity in HeLa cells. Acta Biomater 2021; 135:606-616. [PMID: 34400307 DOI: 10.1016/j.actbio.2021.08.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 08/06/2021] [Accepted: 08/10/2021] [Indexed: 02/04/2023]
Abstract
We have previously shown that exposure to TiO2 nanoparticles (NPs) reduces the resistance of HeLa cells to bacterial infection. Here we demonstrate that the increased infectivity is associated with enhanced asymmetry in the cholesterol distribution. We applied a live cell imaging method which uses tunable orthogonal cholesterol sensors to visualize and quantify in-situ cholesterol distribution between the two leaflets of the plasma membrane (PM). In the control culture, we found marked transbilayer asymmetry of cholesterol, with the concentration in the outer plasma membrane (OPM) being 13 ± 2-fold higher than that in the inner plasma membrane (IPM). Exposure of the culture to 0.1 mg/mL of rutile TiO2 NPs increased the asymmetry such that the concentration in the OPM was 51 ± 10 times higher, while the total cholesterol content increased only 21 ± 2%. This change in cholesterol gradient may explain the increase in bacterial infectivity in HeLa cells exposed to TiO2 NPs since many pathogens, including Staphylococcus aureus used in the present study, require cholesterol for proper membrane attachment and virulence. RT-PCR indicated that exposure to TiO2 was responsible for upregulation of the ABCA1 and ABCG1 mRNAs, which are responsible for the production of the cholesterol transporter proteins that facilitate cholesterol transport across cellular membranes. This was confirmed by the observation of an overall decrease in bacterial infection in ABCA1 knockout or methyl-β-cyclodextrin-treated HeLa cells, as regardless of TiO2 NP exposure. Hence rather than preventing bacterial infection, TiO2 nanoparticles upregulate genes associated with membrane cholesterol production and distribution, hence increasing infectivity. STATEMENT OF SIGNIFICANCE: A great deal of work has been done regarding the toxicology of the particles, especially focusing on detrimental outcomes associated with reactive oxygen species (ROS) production. In this paper we show unambiguously a very surprising result, namely the ability of these particles to enhance bacterial infection even at very small exposure levels, where none of the deleterious effects of ROS products can yet be detected. Using a new imaging technique, we are able to demonstrate, in operando, the effect of the particles on cholesterol generation and distribution in live HeLa cells. This paper also represents the first in a series where we explore other consequences of increased membrane cholesterol, due to particle exposure, which are known to have multiple other consequences on human tissue function and development.
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Politiek FA, Waterham HR. Compromised Protein Prenylation as Pathogenic Mechanism in Mevalonate Kinase Deficiency. Front Immunol 2021; 12:724991. [PMID: 34539662 PMCID: PMC8446354 DOI: 10.3389/fimmu.2021.724991] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 08/12/2021] [Indexed: 12/25/2022] Open
Abstract
Mevalonate kinase deficiency (MKD) is an autoinflammatory metabolic disorder characterized by life-long recurring episodes of fever and inflammation, often without clear cause. MKD is caused by bi-allelic pathogenic variants in the MVK gene, resulting in a decreased activity of the encoded enzyme mevalonate kinase (MK). MK is an essential enzyme in the isoprenoid biosynthesis pathway, which generates both non-sterol and sterol isoprenoids. The inflammatory symptoms of patients with MKD point to a major role for isoprenoids in the regulation of the innate immune system. In particular a temporary shortage of the non-sterol isoprenoid geranylgeranyl pyrophosphate (GGPP) is increasingly linked with inflammation in MKD. The shortage of GGPP compromises protein prenylation, which is thought to be one of the main causes leading to the inflammatory episodes in MKD. In this review, we discuss current views and the state of knowledge of the pathogenetic mechanisms in MKD, with particular focus on the role of compromised protein prenylation.
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Affiliation(s)
- Frouwkje A Politiek
- Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Hans R Waterham
- Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
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14
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Strong A, Ganetzky R, Rader DJ. Hepatic Manifestations of Mendelian Disorders of Cholesterol Biosynthesis and Cellular Metabolism. Clin Liver Dis (Hoboken) 2021; 18:266-273. [PMID: 34976370 PMCID: PMC8688899 DOI: 10.1002/cld.1154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/16/2021] [Accepted: 07/11/2021] [Indexed: 02/04/2023] Open
Abstract
Content available: Audio Recording.
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Affiliation(s)
- Alanna Strong
- Division of Human GeneticsChildren's Hospital of PhiladelphiaPhiladelphiaPA,The Center for Applied GenomicsChildren's Hospital of PhiladelphiaPhiladelphiaPA
| | - Rebecca Ganetzky
- Division of Human GeneticsChildren's Hospital of PhiladelphiaPhiladelphiaPA,Department of MedicinePerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA
| | - Daniel J. Rader
- Division of Human GeneticsChildren's Hospital of PhiladelphiaPhiladelphiaPA,Department of GeneticsPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA,Department of MedicinePerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA,Institute for Translational Medicine and TherapeuticsPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA
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15
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Bernardo A, De Nuccio C, Visentin S, Martire A, Minghetti L, Popoli P, Ferrante A. Myelin Defects in Niemann-Pick Type C Disease: Mechanisms and Possible Therapeutic Perspectives. Int J Mol Sci 2021; 22:ijms22168858. [PMID: 34445564 PMCID: PMC8396228 DOI: 10.3390/ijms22168858] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/11/2021] [Accepted: 08/16/2021] [Indexed: 12/25/2022] Open
Abstract
Niemann–Pick type C (NPC) disease is a wide-spectrum clinical condition classified as a neurovisceral disorder affecting mainly the liver and the brain. It is caused by mutations in one of two genes, NPC1 and NPC2, coding for proteins located in the lysosomes. NPC proteins are deputed to transport cholesterol within lysosomes or between late endosome/lysosome systems and other cellular compartments, such as the endoplasmic reticulum and plasma membrane. The first trait of NPC is the accumulation of unesterified cholesterol and other lipids, like sphingosine and glycosphingolipids, in the late endosomal and lysosomal compartments, which causes the blockade of autophagic flux and the impairment of mitochondrial functions. In the brain, the main consequences of NPC are cerebellar neurodegeneration, neuroinflammation, and myelin defects. This review will focus on myelin defects and the pivotal importance of cholesterol for myelination and will offer an overview of the molecular targets and the pharmacological strategies so far proposed, or an object of clinical trials for NPC. Finally, it will summarize recent data on a new and promising pharmacological perspective involving A2A adenosine receptor stimulation in genetic and pharmacological NPC dysmyelination models.
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Affiliation(s)
- Antonietta Bernardo
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy; (A.B.); (S.V.); (A.M.); (P.P.)
| | - Chiara De Nuccio
- Research Coordination and Support Service, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy; (C.D.N.); (L.M.)
| | - Sergio Visentin
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy; (A.B.); (S.V.); (A.M.); (P.P.)
| | - Alberto Martire
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy; (A.B.); (S.V.); (A.M.); (P.P.)
| | - Luisa Minghetti
- Research Coordination and Support Service, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy; (C.D.N.); (L.M.)
| | - Patrizia Popoli
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy; (A.B.); (S.V.); (A.M.); (P.P.)
| | - Antonella Ferrante
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy; (A.B.); (S.V.); (A.M.); (P.P.)
- Correspondence: ; Tel.: +39-06-49902050
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16
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Koczok K, Horváth L, Korade Z, Mezei ZA, Szabó GP, Porter NA, Kovács E, Mirnics K, Balogh I. Biochemical and Clinical Effects of Vitamin E Supplementation in Hungarian Smith-Lemli-Opitz Syndrome Patients. Biomolecules 2021; 11:biom11081228. [PMID: 34439893 PMCID: PMC8393612 DOI: 10.3390/biom11081228] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/02/2021] [Accepted: 08/12/2021] [Indexed: 11/16/2022] Open
Abstract
Smith-Lemli-Opitz syndrome (SLOS) is a severe monogenic disorder resulting in low cholesterol and high 7-dehydrocholesterol (7-DHC) levels. 7-DHC-derived oxysterols likely contribute to disease pathophysiology, and thus antioxidant treatment might be beneficial because of high oxidative stress. In a three-year prospective study, we investigated the effects of vitamin E supplementation in six SLOS patients already receiving dietary cholesterol treatment. Plasma vitamin A and E concentrations were determined by the high-performance liquid chromatography (HPLC) method. At baseline, plasma 7-DHC, 8-dehydrocholesterol (8-DHC) and cholesterol levels were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The clinical effect of the supplementation was assessed by performing structured parental interviews. At baseline, patients were characterized by low or low-normal plasma vitamin E concentrations (7.19-15.68 μmol/L), while vitamin A concentrations were found to be normal or high (1.26-2.68 μmol/L). Vitamin E supplementation resulted in correction or significant elevation of plasma vitamin E concentration in all patients. We observed reduced aggression, self-injury, irritability, hyperactivity, attention deficit, repetitive behavior, sleep disturbance, skin photosensitivity and/or eczema in 3/6 patients, with notable individual variability. Clinical response to therapy was associated with a low baseline 7-DHC + 8-DHC/cholesterol ratio (0.2-0.4). We suggest that determination of vitamin E status is important in SLOS patients. Supplementation of vitamin E should be considered and might be beneficial.
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Affiliation(s)
- Katalin Koczok
- Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (K.K.); (E.K.)
| | - László Horváth
- Department of Pharmaceutical Surveillance and Economics, Faculty of Pharmacy, University of Debrecen, 4032 Debrecen, Hungary;
| | - Zeljka Korade
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Zoltán András Mezei
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
| | - Gabriella P. Szabó
- Department of Pediatrics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
| | - Ned A. Porter
- Department of Chemistry, Vanderbilt University, Nashville, TN 37240, USA;
| | - Eszter Kovács
- Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (K.K.); (E.K.)
| | - Károly Mirnics
- Departments of Psychiatry, Biochemistry & Molecular Biology, Pharmacology & Experimental Neuroscience and Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE 68106, USA;
| | - István Balogh
- Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (K.K.); (E.K.)
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
- Correspondence: ; Tel.: +36-52-340-006
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17
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Yavuz U, Alaylıoğlu M, Şengül B, Karras SN, Gezen-Ak D, Dursun E. Protein disulfide isomerase A3 might be involved in the regulation of 24-dehydrocholesterol reductase via vitamin D equilibrium in primary cortical neurons. In Vitro Cell Dev Biol Anim 2021; 57:704-714. [PMID: 34338991 DOI: 10.1007/s11626-021-00602-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 06/11/2021] [Indexed: 11/28/2022]
Abstract
Vitamin D is a secosteroid hormone mediating its functions via vitamin D receptor (VDR) and an endoplasmic reticulum chaperone, protein disulfide isomerase A3 (PDIA3). From a physiological perspective, there is also a well-established association of cholesterol and vitamin D synthesis, since both share a common metabolic substrate, 7 dehydrocholesterol (7-DHC). Yet, the potential basic pathways, of the biological interplay of DHCR24 and vitamin D equilibrium, on neuronal level, are yet to be determined. In this study, we aimed to investigate the relation between vitamin D pathways and DHCR24 in primary cortical neuron cultures. The neocortex of Sprague-Dawley rat embryos (E16) was used for the preparation of primary cortical neuron cultures. DHCR24 mRNA and protein expression levels were determined by qRT-PCR, Western blotting, and immunofluorescent labeling in 1,25-dihydroxyvitamin D3-treated or VDR/PDIA3-silenced primary cortical neurons. The mRNA expression of DHCR24 was significantly decreased in the cortical neurons treated with 10-8M 1,25-dihydroxyvitamin D3 (p<0.001). In parallel with the mRNA results, DHCR24 protein expression in cortical neurons treated with 10-8M 1,25-dihydroxyvitamin D3 was also significantly lower than untreated neurons (p<0.05). These data were also confirmed with immunofluorescent labeling and fluorescence intensity measurements of DHCR24 (p<0.001). Finally, DHCR24 mRNA expression level was significantly increased in PDIA3 siRNA-treated neurons (p<0.05). Similar to the mRNA results, the DHCR24 protein expression of PDIA3 siRNA-treated neurons was also statistically higher than the other groups (p<0.05). Results of this mechanistic experimental basic study demonstrate that DHCR24 mRNA expression and protein concentrations attenuated in response to vitamin D treatment. Furthermore, we observed that PDIA3 might be involved in this modulatory effect. Our findings indicate a complex interaction of DHCR24 and vitamin D equilibrium, through the involvement of PDIA3 and vitamin D in the modulation of cholesterol metabolism in neuronal cells, requiring future studies on the field.
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Affiliation(s)
- Ulaş Yavuz
- Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Merve Alaylıoğlu
- Brain and Neurodegenerative Disorders Research Laboratory, Department of Medical Biology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Büşra Şengül
- Brain and Neurodegenerative Disorders Research Laboratory, Department of Medical Biology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | | | - Duygu Gezen-Ak
- Brain and Neurodegenerative Disorders Research Laboratory, Department of Medical Biology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.
| | - Erdinç Dursun
- Brain and Neurodegenerative Disorders Research Laboratory, Department of Medical Biology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.
- Department of Neuroscience, Institute of Neurological Sciences, Istanbul University-Cerrahpasa, Istanbul, Turkey.
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18
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Kothandapani A, Jefcoate CR, Jorgensen JS. Cholesterol Contributes to Male Sex Differentiation Through Its Developmental Role in Androgen Synthesis and Hedgehog Signaling. Endocrinology 2021; 162:6204698. [PMID: 33784378 PMCID: PMC8168945 DOI: 10.1210/endocr/bqab066] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Indexed: 12/17/2022]
Abstract
Two specialized functions of cholesterol during fetal development include serving as a precursor to androgen synthesis and supporting hedgehog (HH) signaling activity. Androgens are produced by the testes to facilitate masculinization of the fetus. Recent evidence shows that intricate interactions between the HH and androgen signaling pathways are required for optimal male sex differentiation and defects of either can cause birth anomalies indicative of 46,XY male variations of sex development (VSD). Further, perturbations in cholesterol synthesis can cause developmental defects, including VSD, that phenocopy those caused by disrupted androgen or HH signaling, highlighting the functional role of cholesterol in promoting male sex differentiation. In this review, we focus on the role of cholesterol in systemic androgen and local HH signaling events during fetal masculinization and their collective contributions to pediatric VSD.
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Affiliation(s)
- Anbarasi Kothandapani
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA
- Correspondence: Anbarasi Kothandapani, PhD, Department of Comparative Biosciences, University of Wisconsin-Madison, 2015 Linden Dr, Madison, WI 53705, USA. E-mail:
| | - Colin R Jefcoate
- Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705, USA
| | - Joan S Jorgensen
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA
- Correspondence: Joan S. Jorgensen, DVM, PhD, Department of Comparative Biosciences, University of Wisconsin-Madison, 2015 Linden Dr, Madison, WI 53705, USA. E-mail:
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19
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mTOR Driven Gene Transcription Is Required for Cholesterol Production in Neurons of the Developing Cerebral Cortex. Int J Mol Sci 2021; 22:ijms22116034. [PMID: 34204880 PMCID: PMC8199781 DOI: 10.3390/ijms22116034] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/15/2021] [Accepted: 05/28/2021] [Indexed: 12/13/2022] Open
Abstract
Dysregulated mammalian target of rapamycin (mTOR) activity is associated with various neurodevelopmental disorders ranging from idiopathic autism spectrum disorders (ASD) to syndromes caused by single gene defects. This suggests that maintaining mTOR activity levels in a physiological range is essential for brain development and functioning. Upon activation, mTOR regulates a variety of cellular processes such as cell growth, autophagy, and metabolism. On a molecular level, however, the consequences of mTOR activation in the brain are not well understood. Low levels of cholesterol are associated with a wide variety of neurodevelopmental disorders. We here describe numerous genes of the sterol/cholesterol biosynthesis pathway to be transcriptionally regulated by mTOR complex 1 (mTORC1) signaling in vitro in primary neurons and in vivo in the developing cerebral cortex of the mouse. We find that these genes are shared targets of the transcription factors SREBP, SP1, and NF-Y. Prenatal as well as postnatal mTORC1 inhibition downregulated expression of these genes which directly translated into reduced cholesterol levels, pointing towards a substantial metabolic function of the mTORC1 signaling cascade. Altogether, our results indicate that mTORC1 is an essential transcriptional regulator of the expression of sterol/cholesterol biosynthesis genes in the developing brain. Altered expression of these genes may be an important factor contributing to the pathogenesis of neurodevelopmental disorders associated with dysregulated mTOR signaling.
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20
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Christensen JJ, Telle-Hansen VH, Ulven SM, Kovanen PT, Jauhiainen M, Öörni K, Holven KB. The homeoviscous adaptation to dietary lipids (HADL) hypothesis is probably incorrect. Am J Clin Nutr 2021; 113:1711-1712. [PMID: 34060599 PMCID: PMC8168348 DOI: 10.1093/ajcn/nqab110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
| | - Vibeke H Telle-Hansen
- Department of Nutrition, Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway
| | - Stine M Ulven
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Petri T Kovanen
- Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland
| | - Matti Jauhiainen
- Minerva Foundation Institute for Medical Research, Biomedicum, Helsinki, Finland
| | - Katariina Öörni
- Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland,Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Kirsten B Holven
- From the Norwegian National Advisory Unit on Familial Hypercholesterolemia, Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway,Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
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21
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Structural Stringency and Optimal Nature of Cholesterol Requirement in the Function of the Serotonin1A Receptor. J Membr Biol 2020; 253:445-457. [DOI: 10.1007/s00232-020-00138-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 09/04/2020] [Indexed: 12/11/2022]
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22
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Shrivastava S, Paila YD, Kombrabail M, Krishnamoorthy G, Chattopadhyay A. Role of Cholesterol and Its Immediate Biosynthetic Precursors in Membrane Dynamics and Heterogeneity: Implications for Health and Disease. J Phys Chem B 2020; 124:6312-6320. [DOI: 10.1021/acs.jpcb.0c04338] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Sandeep Shrivastava
- CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India
| | - Yamuna Devi Paila
- CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India
| | - Mamata Kombrabail
- Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Mumbai 400 005, India
| | - G. Krishnamoorthy
- Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Mumbai 400 005, India
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23
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Jing X, Behmer ST. Insect Sterol Nutrition: Physiological Mechanisms, Ecology, and Applications. ANNUAL REVIEW OF ENTOMOLOGY 2020; 65:251-271. [PMID: 31600456 DOI: 10.1146/annurev-ento-011019-025017] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Insects, like all eukaryotes, require sterols for structural and metabolic purposes. However, insects, like all arthropods, cannot make sterols. Cholesterol is the dominant tissue sterol for most insects; insect herbivores produce cholesterol by metabolizing phytosterols, but not always with high efficiency. Many insects grow on a mixed-sterol diet, but this ability varies depending on the types and ratio of dietary sterols. Dietary sterol uptake, transport, and metabolism are regulated by several proteins and processes that are relatively conserved across eukaryotes. Sterol requirements also impact insect ecology and behavior. There is potential to exploit insect sterol requirements to (a) control insect pests in agricultural systems and (b) better understand sterol biology, including in humans. We suggest that future studies focus on the genetic mechanism of sterol metabolism and reverse transportation, characterizing sterol distribution and function at the cellular level, the role of bacterial symbionts in sterol metabolism, and interrupting sterol trafficking for pest control.
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Affiliation(s)
- Xiangfeng Jing
- State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi 712100, China;
- Key Laboratory of Integrated Pest Management on Crops in Northwestern Loess Plateau, Ministry of Agriculture, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Spencer T Behmer
- Department of Entomology, Texas A&M University, College Station, Texas 77843, USA;
- Ecology & Evolutionary Biology Graduate Program, Texas A&M University, College Station, Texas 77843, USA
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24
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Gelzo M, Di Taranto MD, Sica C, Boscia A, Papagni F, Fortunato G, Corso G, Dello Russo A. Age-related changes of cholestanol and lathosterol plasma concentrations: an explorative study. Lipids Health Dis 2019; 18:235. [PMID: 31888647 DOI: 10.1186/s12944‐019‐1176‐3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 12/23/2019] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Cerebrotendinous xanthomatosis (CTX) and Lathosterolosis represent two treatable inherited disorders of cholesterol metabolism that are characterized by the accumulation of cholestanol and lathosterol, respectively. The age of the patients suspected of having these disorders is highly variable due to the very different phenotypes. The early diagnosis of these disorders is important because specific therapeutic treatment could prevent the disease progression. The biochemical diagnosis of these defects is generally performed analyzing the sterol profile. Since age-related levels of these sterols are lacking, this study aims to determine a preliminary comparison of plasma levels of cholestanol and lathosterol among Italian unaffected newborns, children and healthy adults. METHODS The sterols were extracted from 130 plasma samples (24 newborns, 33 children and 73 adults) by a liquid-liquid separation method and quantified by gas chromatography coupled with a flame ionization detector. RESULTS Cholesterol, cholestanol and lathosterol levels together with the cholestanol/cholesterol and lathosterol/cholesterol ratios are statistically different among the three groups. Cholesterol levels progressively increased from newborns to children and to adults, whereas cholestanol/cholesterol and cholestanol/lathosterol ratios progressively decreased from newborns to children and to adults. Lathosterol levels were higher in adults than in both newborns and children. In the total population a positive correlation was observed between cholesterol levels and both cholestanol (correlation coefficient = 0.290, p = 0.001) and lathosterol levels (correlation coefficient = 0.353, p < 0.0001). CONCLUSIONS Although this study can only be considered an explorative experience due to the low number of analyzed samples, we revealed several differences of plasma cholestanol and lathosterol levels and their ratios to cholesterol levels among newborns, children and adults. These evidences indicate the need of age-related reference values of cholestanol and lathosterol concentrations, including also newborns and children.
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Affiliation(s)
- Monica Gelzo
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Sergio Pansini 5, 80131, Naples, Italy
- CEINGE Biotecnologie Avanzate s.c. a r.l., Via Gaetano Salvatore 486, 80145, Naples, Italy
| | - Maria Donata Di Taranto
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Sergio Pansini 5, 80131, Naples, Italy
- CEINGE Biotecnologie Avanzate s.c. a r.l., Via Gaetano Salvatore 486, 80145, Naples, Italy
| | - Concetta Sica
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Sergio Pansini 5, 80131, Naples, Italy
| | - Antonio Boscia
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Sergio Pansini 5, 80131, Naples, Italy
| | - Francesco Papagni
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Sergio Pansini 5, 80131, Naples, Italy
| | - Giuliana Fortunato
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Sergio Pansini 5, 80131, Naples, Italy
- CEINGE Biotecnologie Avanzate s.c. a r.l., Via Gaetano Salvatore 486, 80145, Naples, Italy
| | - Gaetano Corso
- Department of Clinical and Experimental Medicine, University of Foggia, Viale L. Pinto 1, 71122, Foggia, Italy.
| | - Antonio Dello Russo
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Sergio Pansini 5, 80131, Naples, Italy
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Gelzo M, Di Taranto MD, Sica C, Boscia A, Papagni F, Fortunato G, Corso G, Dello Russo A. Age-related changes of cholestanol and lathosterol plasma concentrations: an explorative study. Lipids Health Dis 2019; 18:235. [PMID: 31888647 PMCID: PMC6937658 DOI: 10.1186/s12944-019-1176-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 12/23/2019] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Cerebrotendinous xanthomatosis (CTX) and Lathosterolosis represent two treatable inherited disorders of cholesterol metabolism that are characterized by the accumulation of cholestanol and lathosterol, respectively. The age of the patients suspected of having these disorders is highly variable due to the very different phenotypes. The early diagnosis of these disorders is important because specific therapeutic treatment could prevent the disease progression. The biochemical diagnosis of these defects is generally performed analyzing the sterol profile. Since age-related levels of these sterols are lacking, this study aims to determine a preliminary comparison of plasma levels of cholestanol and lathosterol among Italian unaffected newborns, children and healthy adults. METHODS The sterols were extracted from 130 plasma samples (24 newborns, 33 children and 73 adults) by a liquid-liquid separation method and quantified by gas chromatography coupled with a flame ionization detector. RESULTS Cholesterol, cholestanol and lathosterol levels together with the cholestanol/cholesterol and lathosterol/cholesterol ratios are statistically different among the three groups. Cholesterol levels progressively increased from newborns to children and to adults, whereas cholestanol/cholesterol and cholestanol/lathosterol ratios progressively decreased from newborns to children and to adults. Lathosterol levels were higher in adults than in both newborns and children. In the total population a positive correlation was observed between cholesterol levels and both cholestanol (correlation coefficient = 0.290, p = 0.001) and lathosterol levels (correlation coefficient = 0.353, p < 0.0001). CONCLUSIONS Although this study can only be considered an explorative experience due to the low number of analyzed samples, we revealed several differences of plasma cholestanol and lathosterol levels and their ratios to cholesterol levels among newborns, children and adults. These evidences indicate the need of age-related reference values of cholestanol and lathosterol concentrations, including also newborns and children.
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Affiliation(s)
- Monica Gelzo
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Sergio Pansini 5, 80131, Naples, Italy
- CEINGE Biotecnologie Avanzate s.c. a r.l., Via Gaetano Salvatore 486, 80145, Naples, Italy
| | - Maria Donata Di Taranto
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Sergio Pansini 5, 80131, Naples, Italy
- CEINGE Biotecnologie Avanzate s.c. a r.l., Via Gaetano Salvatore 486, 80145, Naples, Italy
| | - Concetta Sica
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Sergio Pansini 5, 80131, Naples, Italy
| | - Antonio Boscia
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Sergio Pansini 5, 80131, Naples, Italy
| | - Francesco Papagni
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Sergio Pansini 5, 80131, Naples, Italy
| | - Giuliana Fortunato
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Sergio Pansini 5, 80131, Naples, Italy
- CEINGE Biotecnologie Avanzate s.c. a r.l., Via Gaetano Salvatore 486, 80145, Naples, Italy
| | - Gaetano Corso
- Department of Clinical and Experimental Medicine, University of Foggia, Viale L. Pinto 1, 71122, Foggia, Italy.
| | - Antonio Dello Russo
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Sergio Pansini 5, 80131, Naples, Italy
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Mouro FM, Miranda-Lourenço C, Sebastião AM, Diógenes MJ. From Cannabinoids and Neurosteroids to Statins and the Ketogenic Diet: New Therapeutic Avenues in Rett Syndrome? Front Neurosci 2019; 13:680. [PMID: 31333401 PMCID: PMC6614559 DOI: 10.3389/fnins.2019.00680] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 06/13/2019] [Indexed: 12/21/2022] Open
Abstract
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused mainly by mutations in the MECP2 gene, being one of the leading causes of mental disability in females. Mutations in the MECP2 gene are responsible for 95% of the diagnosed RTT cases and the mechanisms through which these mutations relate with symptomatology are still elusive. Children with RTT present a period of apparent normal development followed by a rapid regression in speech and behavior and a progressive deterioration of motor abilities. Epilepsy is one of the most common symptoms in RTT, occurring in 60 to 80% of RTT cases, being associated with worsening of other symptoms. At this point, no cure for RTT is available and there is a pressing need for the discovery of new drug candidates to treat its severe symptoms. However, despite being a rare disease, in the last decade research in RTT has grown exponentially. New and exciting evidence has been gathered and the etiopathogenesis of this complex, severe and untreatable disease is slowly being unfolded. Advances in gene editing techniques have prompted cure-oriented research in RTT. Nonetheless, at this point, finding a cure is a distant reality, highlighting the importance of further investigating the basic pathological mechanisms of this disease. In this review, we focus our attention in some of the newest evidence on RTT clinical and preclinical research, evaluating their impact in RTT symptomatology control, and pinpointing possible directions for future research.
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Affiliation(s)
- Francisco Melo Mouro
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Catarina Miranda-Lourenço
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Ana Maria Sebastião
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Maria José Diógenes
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
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Comparative analysis of proteomic and metabolomic profiles of different species of Paris. J Proteomics 2019; 200:11-27. [PMID: 30890455 DOI: 10.1016/j.jprot.2019.02.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 01/12/2019] [Accepted: 02/01/2019] [Indexed: 02/08/2023]
Abstract
An extract prepared from species of Paris is the most widely consumed herbal product in China. The genus Paris includes a variety of genotypes with different medicinal component contents but only two are defined as official sources. Closely related species have different medicinal properties because of differential expression of proteins and metabolites. To better understand the molecular basis of these differences, we examined proteomic and metabolomic changes in rhizomes of P. polyphylla var. chinensis, P. polyphylla var. yunnanensis, and P. fargesii var. fargesii using a technique known as sequential window acquisition of all theoretical mass spectra as well as gas chromatography-time-of-flight mass spectrometry. In total, 419 proteins showed significant abundance changes, and 33 metabolites could be used to discriminate Paris species. A complex analysis of proteomic and metabolomic data revealed a higher efficiency of sucrose utilization and an elevated protein abundance in the sugar metabolic pathway of P. polyphylla var. chinensis. The pyruvate content and efficiency of acetyl-CoA-utilization in saponin biosynthesis were also higher in P. polyphylla var. chinensis than in the other two species. The results expand our understanding of the proteome and metabolome of Paris and offer new insights into the species-specific traits of these herbaceous plants. SIGNIFICANCE: The traditional Chinese medicine Paris is the most widely consumed herbal product for the treatment of joint pain, rheumatoid arthritis and antineoplastic. All Paris species have roughly the same morphological characteristics; however, different members have different medicinal compound contents. Efficient exploitation of genetic diversity is a key factor in the development of rare medicinal plants with improved agronomic traits and malleability to challenging environmental conditions. Nevertheless, only a partial understanding of physiological and molecular mechanisms of different plants of Paris can be achieved without proteomics. To better understand the molecular basis of these differences and facilitate the use of other Paris species, we examine proteomic metabolomic changes in rhizomes of Paris using the technique known as SWATH-MS and GC/TOF-MS. Our research has provided information that can be used in other studies to compare metabolic traits in different Paris species. Our findings can also serve as a theoretical basis for the selection and cultivation of other Paris species with a higher medicinal value.
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28
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Anderson R, Rust S, Ashworth J, Clayton-Smith J, Taylor RL, Clayton PT, Morris AAM. Lathosterolosis: A Relatively Mild Case with Cataracts and Learning Difficulties. JIMD Rep 2018; 44:79-84. [PMID: 30097991 DOI: 10.1007/8904_2018_127] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 07/12/2018] [Accepted: 07/13/2018] [Indexed: 12/03/2022] Open
Abstract
Lathosterolosis is a rare defect of cholesterol synthesis. Only four previous cases have been reported, two of whom were siblings. We report a fifth patient, with a relatively mild phenotype. He presented at 5 years of age with bilateral posterior cataracts, which were managed with lensectomies and intraocular lens implants. He also had learning difficulties, with a full-scale IQ of 64 at 11 years of age. His head circumference is between the 0.4th and 2nd centiles, and he has mild hypotonia and subtle dysmorphism (a high-arched palate, anteverted nostrils, long philtrum and clinodactyly of toes). The diagnosis was established after sequencing a panel of genes associated with cataracts, which revealed compound heterozygous SC5D mutations: c.479C>G p.(Pro160Arg) and c.630C>A p.(Asp210Glu). The plasma lathosterol concentration was markedly raised at 219.8 μmol/L (control range 0.53-16.0), confirming the diagnosis. The c.630C>A p.(Asp210Glu) mutation has been reported in one previous patient, who also had a relatively mild phenotype (Ho et al., JIMD Rep 12:129-134, 2014). The mutation leads to a relatively conservative amino acid substitution, consistent with some residual enzyme activity. Our patient's family did not notice any benefit from treatment with simvastatin. In summary, milder patients with lathosterolosis may present with learning difficulties, cataracts and very subtle dysmorphism. The diagnosis will be missed unless plasma sterols are analysed or relevant genes sequenced.
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Affiliation(s)
- R Anderson
- Willink Metabolic Unit, Manchester Academic Health Sciences Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - S Rust
- Paediatric Psychosocial Service, Manchester Academic Health Sciences Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - J Ashworth
- Paediatric Ophthalmology Department, Manchester Academic Health Sciences Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - J Clayton-Smith
- Genomic Medicine, Manchester Academic Health Sciences Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.,Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - R L Taylor
- Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - P T Clayton
- Centre for Translational Omics, Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK
| | - A A M Morris
- Willink Metabolic Unit, Manchester Academic Health Sciences Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, UK. .,Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
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Coman D, Vissers LE, Riley LG, Kwint MP, Hauck R, Koster J, Geuer S, Hopkins S, Hallinan B, Sweetman L, Engelke UF, Burrow TA, Cardinal J, McGill J, Inwood A, Gurnsey C, Waterham HR, Christodoulou J, Wevers RA, Pitt J. Squalene Synthase Deficiency: Clinical, Biochemical, and Molecular Characterization of a Defect in Cholesterol Biosynthesis. Am J Hum Genet 2018; 103:125-130. [PMID: 29909962 DOI: 10.1016/j.ajhg.2018.05.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Accepted: 05/11/2018] [Indexed: 01/12/2023] Open
Abstract
Mendelian disorders of cholesterol biosynthesis typically result in multi-system clinical phenotypes, underlining the importance of cholesterol in embryogenesis and development. FDFT1 encodes for an evolutionarily conserved enzyme, squalene synthase (SS, farnesyl-pyrophosphate farnesyl-transferase 1), which catalyzes the first committed step in cholesterol biosynthesis. We report three individuals with profound developmental delay, brain abnormalities, 2-3 syndactyly of the toes, and facial dysmorphisms, resembling Smith-Lemli-Opitz syndrome, the most common cholesterol biogenesis defect. The metabolite profile in plasma and urine suggested that their defect was at the level of squalene synthase. Whole-exome sequencing was used to identify recessive disease-causing variants in FDFT1. Functional characterization of one variant demonstrated a partial splicing defect and altered promoter and/or enhancer activity, reflecting essential mechanisms for regulating cholesterol biosynthesis/uptake in steady state.
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Mast N, Lin JB, Anderson KW, Bjorkhem I, Pikuleva IA. Transcriptional and post-translational changes in the brain of mice deficient in cholesterol removal mediated by cytochrome P450 46A1 (CYP46A1). PLoS One 2017; 12:e0187168. [PMID: 29073233 PMCID: PMC5658173 DOI: 10.1371/journal.pone.0187168] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 10/13/2017] [Indexed: 01/12/2023] Open
Abstract
Cytochrome P450 46A1 (CYP46A1) converts cholesterol to 24-hydroxycholesterol and thereby controls the major pathways of cholesterol removal from the brain. Cyp46a1-/- mice have a reduction in the rate of cholesterol biosynthesis in the brain and significant impairments to memory and learning. To gain insights into the mechanisms underlying Cyp46a1-/- phenotype, we used Cyp46a1-/- mice and quantified their brain sterol levels and the expression of the genes pertinent to cholesterol homeostasis. We also compared the Cyp46a1-/- and wild type brains for protein phosphorylation and ubiquitination. The data obtained enable the following inferences. First, there seems to be a compensatory upregulation in the Cyp46a1-/- brain of the pathways of cholesterol storage and CYP46A1-independent removal. Second, transcriptional regulation of the brain cholesterol biosynthesis via sterol regulatory element binding transcription factors is not significantly activated in the Cyp46a1-/- brain to explain a compensatory decrease in cholesterol biosynthesis. Third, some of the liver X receptor target genes (Abca1) are paradoxically upregulated in the Cyp46a1-/- brain, possibly due to a reduced activation of the small GTPases RAB8, CDC42, and RAC as a result of a reduced phosphorylation of RAB3IP and PAK1. Fourth, the phosphorylation of many other proteins (a total of 146) is altered in the Cyp46a1-/- brain, including microtubule associated and neurofilament proteins (the MAP and NEF families) along with proteins related to synaptic vesicles and synaptic neurotransmission (e.g., SLCs, SHANKs, and BSN). Fifth, the extent of protein ubiquitination is increased in the Cyp46a1-/- brain, and the affected proteins pertain to ubiquitination (UBE2N), cognition (STX1B and ATP1A2), cytoskeleton function (TUBA1A and YWHAZ), and energy production (ATP1A2 and ALDOA). The present study demonstrates the diverse potential effects of CYP46A1 deficiency on brain functions and identifies important proteins that could be affected by this deficiency.
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Affiliation(s)
- Natalia Mast
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Joseph B. Lin
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Kyle W. Anderson
- Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg, Maryland, United States of America
- Institute for Bioscience and Biotechnology Research, Rockville, Maryland, United States of America
| | - Ingemar Bjorkhem
- Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institute, Huddinge, Sweden
| | - Irina A. Pikuleva
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America
- * E-mail:
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31
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Corso G, Dello Russo A, Gelzo M. Liver and the defects of cholesterol and bile acids biosynthesis: Rare disorders many diagnostic pitfalls. World J Gastroenterol 2017; 23:5257-5265. [PMID: 28839426 PMCID: PMC5550775 DOI: 10.3748/wjg.v23.i29.5257] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Revised: 05/01/2017] [Accepted: 07/04/2017] [Indexed: 02/06/2023] Open
Abstract
In recent decades, biotechnology produced a growth of knowledge on the causes and mechanisms of metabolic diseases that have formed the basis for their study, diagnosis and treatment. Unfortunately, it is well known that the clinical features of metabolic diseases can manifest themselves with very different characteristics and escape early detection. Also, it is well known that the prognosis of many metabolic diseases is excellent if diagnosed and treated early. In this editorial we briefly summarized two groups of inherited metabolic diseases, the defects of cholesterol biosynthesis and those of bile acids. Both groups show variable clinical manifestations but some clinical signs and symptoms are common in both the defects of cholesterol and bile acids. The differential diagnosis can be made analyzing sterol profiles in blood and/or bile acids in blood and urine by chromatographic techniques (GC-MS and LC-MS/MS). Several defects of both biosynthetic pathways are treatable so early diagnosis is crucial. Unfortunately their diagnosis is made too late, due either to the clinical heterogeneity of the syndromes (severe, mild and very mild) that to the scarcity of scientific dissemination of these rare diseases. Therefore, the delay in diagnosis leads the patient to the medical observation when the disease has produced irreversible damages to the body. Here, we highlighted simple clinical and laboratory descriptions that can potentially make you to suspect a defect in cholesterol biosynthesis and/or bile acids, as well, we suggest appropriate request of the laboratory tests that along with common clinical features can help to diagnose these defects.
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Mazzu-Nascimento T, Melo DG, Morbioli GG, Carrilho E, Vianna FSL, da Silva AA, Schuler-Faccini L. Teratogens: a public health issue - a Brazilian overview. Genet Mol Biol 2017; 40:387-397. [PMID: 28534929 PMCID: PMC5488458 DOI: 10.1590/1678-4685-gmb-2016-0179] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 10/07/2016] [Indexed: 12/20/2022] Open
Abstract
Congenital anomalies are already the second cause of infant mortality in Brazil, as in many other middle-income countries in Latin America. Birth defects are a result of both genetic and environmental factors, but a multifactorial etiology has been more frequently observed. Here, we address the environmental causes of birth defects - or teratogens - as a public health issue and present their mechanisms of action, categories and their respective maternal-fetal deleterious effects. We also present a survey from 2008 to 2013 of Brazilian cases involving congenital anomalies (annual average of 20,205), fetal deaths (annual average of 1,530), infant hospitalizations (annual average of 82,452), number of deaths of hospitalized infants (annual average of 2,175), and the average cost of hospitalizations (annual cost of $7,758). Moreover, we report on Brazilian cases of teratogenesis due to the recent Zika virus infection, and to the use of misoprostol, thalidomide, alcohol and illicit drugs. Special attention has been given to the Zika virus infection, now proven to be responsible for the microcephaly outbreak in Brazil, with 8,039 cases under investigation (from October 2015 to June 2016). From those cases, 1,616 were confirmed and 324 deaths occurred due to microcephaly complications or alterations on the central nervous system. Congenital anomalies impact life quality and raise costs in specialized care, justifying the classification of teratogens as a public health issue.
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Affiliation(s)
- Thiago Mazzu-Nascimento
- Instituto de Química de São Carlos, Universidade de São Paulo, São
Carlos, SP, Brazil
- Instituto Nacional de Ciência e Tecnologia de Bioanalítica, Campinas,
SP, Brazil
| | - Débora Gusmão Melo
- Departamento de Medicina, Centro de Ciências Biológicas e da Saúde,
Universidade Federal de São Carlos, São Carlos, SP, Brazil
| | - Giorgio Gianini Morbioli
- Instituto de Química de São Carlos, Universidade de São Paulo, São
Carlos, SP, Brazil
- Instituto Nacional de Ciência e Tecnologia de Bioanalítica, Campinas,
SP, Brazil
- School of Chemistry and Biochemistry, Georgia Institute of
Technology, Atlanta, GA, USA
| | - Emanuel Carrilho
- Instituto de Química de São Carlos, Universidade de São Paulo, São
Carlos, SP, Brazil
- Instituto Nacional de Ciência e Tecnologia de Bioanalítica, Campinas,
SP, Brazil
| | - Fernanda Sales Luiz Vianna
- Sistema Nacional de Informação sobre Agentes Teratogênicos (SIAT),
Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
- Programa de Pós-Graduação em Genética e Biologia Molecular,
Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio
Grande do Sul, Porto Alegre, RS, Brazil
| | - André Anjos da Silva
- Sistema Nacional de Informação sobre Agentes Teratogênicos (SIAT),
Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
- UNIVATES University, Lajeado, RS, Brazil
| | - Lavinia Schuler-Faccini
- Sistema Nacional de Informação sobre Agentes Teratogênicos (SIAT),
Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
- Programa de Pós-Graduação em Genética e Biologia Molecular,
Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio
Grande do Sul, Porto Alegre, RS, Brazil
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Kim Y, Kim C, Jang HY, Mook-Jung I. Inhibition of Cholesterol Biosynthesis Reduces γ-Secretase Activity and Amyloid-β Generation. J Alzheimers Dis 2016; 51:1057-68. [PMID: 26923021 DOI: 10.3233/jad-150982] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Amyloid-β (Aβ) is one of major molecules contributing to the pathogenesis of Alzheimer's disease (AD). Aβ is derived from amyloid-β protein precursor (AβPP) through sequential cleavages by β- and γ-secretases. Regulation of these components is thought to be an important factor in Aβ generation during the pathogenesis of AD. AβPP, β-secretase, and γ-secretase reside in lipid rafts, where cholesterol regulates the integrity and flexibility of membrane proteins and Aβ is generated. However, the relationship between cholesterol and Aβ generation is controversial. In this study, we aimed to elucidate the direct effects of cholesterol depletion on AβPP processing using AY9944, which blocks the last step of cholesterol biosynthesis and thus minimizes the unknown side effects of upstream inhibitors, such as HMG-CoA reductase inhibitors. Treatment with AY9944 decreased γ-secretase activity and Aβ generation. These results suggested that changes in membrane composition by lowering cholesterol with AY9944 affected γ-secretase activity and Aβ generation, which is associated with AD pathogenesis.
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Liu Z, Zhang C, Khodadadi-Jamayran A, Dang L, Han X, Kim K, Li H, Zhao R. Canonical microRNAs Enable Differentiation, Protect Against DNA Damage, and Promote Cholesterol Biosynthesis in Neural Stem Cells. Stem Cells Dev 2016; 26:177-188. [PMID: 27762676 DOI: 10.1089/scd.2016.0259] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Neural stem cells (NSCs) have the capacity to differentiate into neurons, astrocytes, and oligodendrocytes, and therefore represent a promising donor tissue source for treating neurodegenerative diseases and repairing injuries of the nervous system. However, it remains unclear how canonical microRNAs (miRNAs), the subset of miRNAs requiring the Drosha-Dgcr8 microprocessor and the type III RNase Dicer for biogenesis, regulate NSCs. In this study, we established and characterized Dgcr8-/- NSCs from conditionally Dgcr8-disrupted mouse embryonic brain. RNA-seq analysis demonstrated that disruption of Dgcr8 in NSCs causes a complete loss of canonical miRNAs and an accumulation of pri-miRNAs. Dgcr8-/- NSCs can be stably propagated in vitro, but progress through the cell cycle at reduced rates. When induced for differentiation, Dgcr8-/- NSCs failed to differentiate into neurons, astrocytes, or oligodendrocytes under permissive conditions. Compared to Dgcr8+/- NSCs, Dgcr8-/- NSCs exhibit significantly increased DNA damage. Comparative RNA-seq analysis and gene set enrichment analysis (GSEA) revealed that Dgcr8-/- NSCs significantly downregulate genes associated with neuronal differentiation, cell cycle progression, DNA replication, protein translation, and DNA damage repair. Furthermore, we discovered that Dgcr8-/- NSCs significantly downregulate genes responsible for cholesterol biosynthesis and demonstrated that Dgcr8-/- NSCs contain lower levels of cholesterol. Together, our data demonstrate that canonical miRNAs play essential roles in enabling lineage specification, protecting DNA against damage, and promoting cholesterol biosynthesis in NSCs.
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Affiliation(s)
- Zhong Liu
- 1 Department of Biochemistry and Molecular Genetics, Stem Cell Institute, University of Alabama at Birmingham , Birmingham, Alabama
| | - Cheng Zhang
- 2 Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine , Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Alireza Khodadadi-Jamayran
- 1 Department of Biochemistry and Molecular Genetics, Stem Cell Institute, University of Alabama at Birmingham , Birmingham, Alabama
| | - Lam Dang
- 3 Cancer Biology and Genetics Program, Center for Cell Engineering, Center for Stem Cell Biology, Sloan-Kettering Institute, Cell and Developmental Biology Program, Weill Medical College of Cornell University , New York, New York
| | - Xiaosi Han
- 4 Department of Neurology, University of Alabama at Birmingham , Birmingham, Alabama
| | - Kitai Kim
- 3 Cancer Biology and Genetics Program, Center for Cell Engineering, Center for Stem Cell Biology, Sloan-Kettering Institute, Cell and Developmental Biology Program, Weill Medical College of Cornell University , New York, New York
| | - Hu Li
- 2 Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine , Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Rui Zhao
- 1 Department of Biochemistry and Molecular Genetics, Stem Cell Institute, University of Alabama at Birmingham , Birmingham, Alabama
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Villani C, Sacchetti G, Bagnati R, Passoni A, Fusco F, Carli M, Invernizzi RW. Lovastatin fails to improve motor performance and survival in methyl-CpG-binding protein2-null mice. eLife 2016; 5:22409. [PMID: 27892851 PMCID: PMC5132339 DOI: 10.7554/elife.22409] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 11/18/2016] [Indexed: 01/25/2023] Open
Abstract
Previous studies provided evidence for the alteration of brain cholesterol homeostasis in 129.Mecp2-null mice, an experimental model of Rett syndrome. The efficacy of statins in improving motor symptoms and prolonging survival of mutant mice suggested a potential role of statins in the therapy of Rett syndrome. In the present study, we show that Mecp2 deletion had no effect on brain and reduced serum cholesterol levels and lovastatin (1.5 mg/kg, twice weekly as in the previous study) had no effects on motor deficits and survival when Mecp2 deletion was expressed on a background strain (C57BL/6J; B6) differing from that used in the earlier study. These findings indicate that the effects of statins may be background specific and raise important issues to consider when contemplating clinical trials. The reduction of the brain cholesterol metabolite 24S-hydroxycholesterol (24S-OHC) found in B6.Mecp2-null mice suggests the occurrence of changes in brain cholesterol metabolism and the potential utility of using plasma levels of 24S-OHC as a biomarker of brain cholesterol homeostasis in RTT. DOI:http://dx.doi.org/10.7554/eLife.22409.001
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Affiliation(s)
- Claudia Villani
- Laboratory of Neurochemistry and Behaviour, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy
| | - Giuseppina Sacchetti
- Laboratory of Neurochemistry and Behaviour, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy
| | - Renzo Bagnati
- Analytical Instrumentation Unit, Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy
| | - Alice Passoni
- Analytical Instrumentation Unit, Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy
| | - Federica Fusco
- Genetics of Neurodegenerative Diseases Unit, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy
| | - Mirjana Carli
- Laboratory of Neurochemistry and Behaviour, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy
| | - Roberto William Invernizzi
- Laboratory of Neurochemistry and Behaviour, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy
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Perturbed cholesterol homeostasis in aging spinal cord. Neurobiol Aging 2016; 45:123-135. [PMID: 27459933 DOI: 10.1016/j.neurobiolaging.2016.05.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 04/28/2016] [Accepted: 05/16/2016] [Indexed: 12/14/2022]
Abstract
The spinal cord is vital for the processing of sensorimotor information and for its propagation to and from both the brain and the periphery. Spinal cord function is affected by aging, however, the mechanisms involved are not well-understood. To characterize molecular mechanisms of spinal cord aging, microarray analyses of gene expression were performed on cervical spinal cords of aging rats. Of the metabolic and signaling pathways affected, cholesterol-associated pathways were the most comprehensively altered, including significant downregulation of cholesterol synthesis-related genes and upregulation of cholesterol transport and metabolism genes. Paradoxically, a significant increase in total cholesterol content was observed-likely associated with cholesterol ester accumulation. To investigate potential mechanisms for the perturbed cholesterol homeostasis, we quantified the expression of myelin and neuroinflammation-associated genes and proteins. Although there was minimal change in myelin-related expression, there was an increase in phagocytic microglial and astrogliosis markers, particularly in the white matter. Together, these results suggest that perturbed cholesterol homeostasis, possibly as a result of increased inflammatory activation in spinal cord white matter, may contribute to impaired spinal cord function with aging.
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Flasiński M, Wydro P, Broniatowski M, Hąc-Wydro K, Fontaine P. Crucial Role of the Double Bond Isomerism in the Steroid B-Ring on the Membrane Properties of Sterols. Grazing Incidence X-Ray Diffraction and Brewster Angle Microscopy Studies. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2015; 31:7364-7373. [PMID: 26061794 DOI: 10.1021/acs.langmuir.5b00896] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Three cholesterol precursors-desmosterol, zymosterol, and lanosterol-were comprehensively characterized in monolayers formed at the air/water interface. The studies were based on registration of the surface pressure (π)-area (A) isotherms complemented with in situ analysis performed with application of modern physicochemical techniques: grazing incidence X-ray diffraction (GIXD) and Brewster angle microscopy (BAM). In this approach we were interested in the correlation between molecular structures of the studied sterols found in the cholesterol biosynthetic pathway and their membrane properties. Our results revealed that only desmosterol behaves in Langmuir monolayers comparably to cholesterol, the molecules of which arrange in the monolayers into a hexagonal lattice, while the two remaining sterols possess extremely different properties. We found that molecules of both zymosterol and lanosterol are organized on the water surface in the two-dimensional oblique unit cells despite the fact that they are oriented perpendicular to the monolayer plane. The comparison of chemical structures of the investigated sterols leads to the conclusion that the only structural motive that can be responsible for such unusual behavior is the double bond in the B sterol ring, which is located in desmosterol in a different position from in the other two sterols. This issue, which was neglected in the scientific literature, seems to have crucial importance for sterol activity in biomembranes. We showed that this structural modification in sterol molecules is directly responsible for their adaptation to proper functioning in biomembranes.
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Affiliation(s)
- Michał Flasiński
- †Department of Environmental Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 3, 30-387, Kraków, Poland
| | - Paweł Wydro
- ‡Department of Physical Chemistry and Electrochemistry, Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060, Kraków, Poland
| | - Marcin Broniatowski
- †Department of Environmental Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 3, 30-387, Kraków, Poland
| | - Katarzyna Hąc-Wydro
- †Department of Environmental Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 3, 30-387, Kraków, Poland
| | - Philippe Fontaine
- §Synchrotron Soleil, L'Orme des Merisiers, Saint Aubin, BP 48, 91192 Gif-sur-Yvette Cedex, France
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Wang J, Sun JY, Sha CJ, Shao YF, Liu YH, Li YX, Duan ZW, Liu WH. Optimization, validation and application of an assay for the activity of HMG-CoA reductase in vitro by LC-MS/MS. J Pharm Anal 2015; 5:383-388. [PMID: 29403953 PMCID: PMC5762244 DOI: 10.1016/j.jpha.2015.06.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Revised: 06/12/2015] [Accepted: 06/29/2015] [Indexed: 12/24/2022] Open
Abstract
A stable HMG-CoA reductase (HMGR) reaction in vitro was developed by a sensitive, selective and precise liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The optimized enzyme reaction condition contained 1.5 μg of HMGR, 20 nM of NADPH with 50 min of reaction time. The method was validated by several intra- and inter-day assays. The production transitions of m/z 147.0/59.1 and m/z 154.0/59.1 were used to detect and quantify mevalonolactone (MVAL) and MVAL-D7, respectively. The accuracy and precision of the method were evaluated over the concentration range of 0.005-1.000 μg/mL for MVAL and 0.010-0.500 μg/mL for lovastatin acid in three validation batch runs. The lower limit of quantitation was found to be 0.005 μg/mL for MVAL and 0.010 μg/mL for lovastatin acid. Intra-day and inter-day precision ranged from 0.95% to 2.39% and 2.26% to 3.38% for MVAL, 1.46% to 3.89% and 0.57% to 5.10% for lovastatin acid, respectively. The results showed that the active ingredients in Xuezhikang capsules were 12.2 and 14.5 mg/g, respectively. This assay method could be successfully applied to the quality control study of Xuezhikang capsule for the first time.
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Affiliation(s)
- Jing Wang
- School of Pharmacy, Yantai University, Yantai 264005, China
| | - Ji-Ye Sun
- State Key Laboratory of Long-acting and Targeting Drug Delivery System, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Chun-Jie Sha
- State Key Laboratory of Long-acting and Targeting Drug Delivery System, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Yu-Feng Shao
- State Key Laboratory of Long-acting and Targeting Drug Delivery System, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Yan-Hong Liu
- School of Pharmacy, Yantai University, Yantai 264005, China
| | - You-Xin Li
- State Key Laboratory of Long-acting and Targeting Drug Delivery System, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
| | - Zhen-Wen Duan
- Peking University WBL Biotech Co., Ltd., Beijing 100080, China
| | - Wan-Hui Liu
- School of Pharmacy, Yantai University, Yantai 264005, China
- State Key Laboratory of Long-acting and Targeting Drug Delivery System, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China
- Corresponding author at: School of Pharmacy, Yantai University, Yantai 264005, China.
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Altunayar C, Sahin I, Kazanci N. A comparative study of the effects of cholesterol and desmosterol on zwitterionic DPPC model membranes. Chem Phys Lipids 2015; 188:37-45. [DOI: 10.1016/j.chemphyslip.2015.03.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Revised: 03/24/2015] [Accepted: 03/26/2015] [Indexed: 10/23/2022]
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Salilew-Wondim D, Wang Q, Tesfaye D, Schellander K, Hoelker M, Hossain MM, Tsang BK. Polycystic ovarian syndrome is accompanied by repression of gene signatures associated with biosynthesis and metabolism of steroids, cholesterol and lipids. J Ovarian Res 2015; 8:24. [PMID: 25887459 PMCID: PMC4414284 DOI: 10.1186/s13048-015-0151-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 03/30/2015] [Indexed: 12/12/2022] Open
Abstract
Background Polycystic ovarian syndrome (PCOS) is a spectrum of heterogeneous disorders of reproduction and metabolism in women with potential systemic sequel such as diabetes and obesity. Although, PCOS is believed to be caused by genetic abnormalities, the genetic background that can be associated with PCOS phenotypes remains unclear due to the complexity of the trait. In this study, we used a rat model which exhibits reproductive and metabolic abnormalities similar to the human PCOS to unravel the molecular mechanisms underlining this complex syndrome. Methods Female Sprague–Dawley rats were randomly assigned to DHT and control (CTL) groups. Rats in the DHT group were implanted with a silicone capsule continuous-releasing 83 μg 5α-dihydrotestosterone (DHT) per day for 12 weeks to mimic the hyperandrogenic state in women with PCOS. The animals were euthanized at 15 weeks of age and the pairs of ovaries were excised and the ovarian cortex tissues were used for gene expression analysis. Total RNA was from the ovarian cortex was amplified, labeled and hybridized to the Affymetrix GeneChip® Rat Genome 230 2.0 Array. A linear model system for microarray data analysis was used to identify genes affected in DHT treated rat ovaries and the molecular pathway of those genes were analyzed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis tool. Results A total of 573 gene transcripts, including CPA1, CDH1, INSL3, AMH, ALDH1B1, INHBA, CYP17A1, RBP4, GAS6, GAS7 and GATA4, were activated while 430 others including HSD17B7, HSD3B6, STAR, HMGCS1, HMGCR, CYP51, CYP11A1 and CYP19A1 were repressed in DHT-treated ovaries. Functional annotation of the dysregulated genes revealed that biosynthesis and metabolism of steroids, cholesterol and lipids to be the most top functions enriched by the repressed genes. However, cell differentiation/proliferation, transcriptional regulation, neurogenesis, cell adhesion and blood vessel development processes were enriched by activated genes. Conclusion The dysregulation of genes associated with biosynthesis and metabolism of steroids, cholesterol and lipids, cell differentiation/proliferation in DHT- treated ovaries could be a molecular clue for abnormal steroidogenesis, estrous cycle irregularity, abnormal folliculogenesis, anovulation and lipid metabolism in PCOS patients. Electronic supplementary material The online version of this article (doi:10.1186/s13048-015-0151-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Dessie Salilew-Wondim
- Institute of Animal Science, Animal Breeding and Husbandry Group, University of Bonn, Endenicher Allee 15, Bonn, 53115, Germany.
| | - Qi Wang
- Reproductive Biology Unit and Division of Reproductive Medicine, Department of Obstetrics & Gynecology and Cellular & Molecular Medicine, Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, K1H 8L6, ON, Canada. .,Chronic Disease Program, Ottawa Hospital Research Institute, The Ottawa Hospital (General Campus), Critical Care Wing, 3rd Floor, Room W3107, 501 Smyth Road, Ottawa, K1H 8L6, ON, Canada.
| | - Dawit Tesfaye
- Institute of Animal Science, Animal Breeding and Husbandry Group, University of Bonn, Endenicher Allee 15, Bonn, 53115, Germany.
| | - Karl Schellander
- Institute of Animal Science, Animal Breeding and Husbandry Group, University of Bonn, Endenicher Allee 15, Bonn, 53115, Germany.
| | - Michael Hoelker
- Institute of Animal Science, Animal Breeding and Husbandry Group, University of Bonn, Endenicher Allee 15, Bonn, 53115, Germany.
| | - Md Munir Hossain
- Department of Animal Breeding and Genetics, Bangladesh Agricultural University, Mymensingh, 2202, Bangladesh.
| | - Benjamin K Tsang
- Reproductive Biology Unit and Division of Reproductive Medicine, Department of Obstetrics & Gynecology and Cellular & Molecular Medicine, Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, K1H 8L6, ON, Canada. .,Chronic Disease Program, Ottawa Hospital Research Institute, The Ottawa Hospital (General Campus), Critical Care Wing, 3rd Floor, Room W3107, 501 Smyth Road, Ottawa, K1H 8L6, ON, Canada. .,Department of Agricultural Biotechnology, World Class University Major in Biomodulation, College of Agriculture and Life Sciences, Seoul National University, Seoul, 151-921, South Korea.
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Saher G, Stumpf SK. Cholesterol in myelin biogenesis and hypomyelinating disorders. Biochim Biophys Acta Mol Cell Biol Lipids 2015; 1851:1083-94. [PMID: 25724171 DOI: 10.1016/j.bbalip.2015.02.010] [Citation(s) in RCA: 127] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 02/05/2015] [Accepted: 02/12/2015] [Indexed: 02/05/2023]
Abstract
The largest pool of free cholesterol in mammals resides in myelin membranes. Myelin facilitates rapid saltatory impulse propagation by electrical insulation of axons. This function is achieved by ensheathing axons with a tightly compacted stack of membranes. Cholesterol influences myelination at many steps, from the differentiation of myelinating glial cells, over the process of myelin membrane biogenesis, to the functionality of mature myelin. Cholesterol emerged as the only integral myelin component that is essential and rate-limiting for the development of myelin in the central and peripheral nervous system. Moreover, disorders that interfere with sterol synthesis or intracellular trafficking of cholesterol and other lipids cause hypomyelination and neurodegeneration. This review summarizes recent results on the roles of cholesterol in CNS myelin biogenesis in normal development and under different pathological conditions. This article is part of a Special Issue entitled Brain Lipids.
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Affiliation(s)
- Gesine Saher
- Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
| | - Sina Kristin Stumpf
- Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
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42
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Garcia-Cazorla À, Mochel F, Lamari F, Saudubray JM. The clinical spectrum of inherited diseases involved in the synthesis and remodeling of complex lipids. A tentative overview. J Inherit Metab Dis 2015; 38:19-40. [PMID: 25413954 DOI: 10.1007/s10545-014-9776-6] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Revised: 09/16/2014] [Accepted: 09/23/2014] [Indexed: 12/19/2022]
Abstract
Over one hundred diseases related to inherited defects of complex lipids synthesis and remodeling are now reported. Most of them were described within the last 5 years. New descriptions and phenotypes are expanding rapidly. While the associated clinical phenotype is currently difficult to outline, with only a few patients identified, it appears that all organs and systems may be affected. The main clinical presentations can be divided into (1) Diseases affecting the central and peripheral nervous system. Complex lipid synthesis disorders produce prominent motor manifestations due to upper and/or lower motoneuron degeneration. Motor signs are often complex, associated with other neurological and extra-neurological signs. Three neurological phenotypes, spastic paraparesis, neurodegeneration with brain iron accumulation and peripheral neuropathies, deserve special attention. Many apparently well clinically defined syndromes are not distinct entities, but rather clusters on a continuous spectrum, like for the PNPLA6-associated diseases, extending from Boucher-Neuhauser syndrome via Gordon Holmes syndrome to spastic ataxia and pure hereditary spastic paraplegia; (2) Muscular/cardiac presentations; (3) Skin symptoms mostly represented by syndromic (neurocutaneous) and non syndromic ichthyosis; (4) Retinal dystrophies with syndromic and non syndromic retinitis pigmentosa, Leber congenital amaurosis, cone rod dystrophy, Stargardt disease; (5) Congenital bone dysplasia and segmental overgrowth disorders with congenital lipomatosis; (6) Liver presentations characterized mainly by transient neonatal cholestatic jaundice and non alcoholic liver steatosis with hypertriglyceridemia; and (7) Renal and immune presentations. Lipidomics and molecular functional studies could help to elucidate the mechanism(s) of dominant versus recessive inheritance observed for the same gene in a growing number of these disorders.
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Affiliation(s)
- Àngels Garcia-Cazorla
- Department of Neurology, Neurometabolic Unit, Hospital Sant Joan de Déu and CIBERER, ISCIII, Barcelona, Spain,
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44
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Justice MJ, Buchovecky CM, Kyle SM, Djukic A. A role for metabolism in Rett syndrome pathogenesis: New clinical findings and potential treatment targets. Rare Dis 2013; 1:e27265. [PMID: 25003017 DOI: 10.4161/rdis.27265] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Revised: 11/14/2013] [Accepted: 11/19/2013] [Indexed: 12/11/2022] Open
Abstract
Rett syndrome (RTT), an X-linked neurological disorder caused by mutations in MECP2, may have a metabolic component. We reported a genetic suppressor screen in a Mecp2-null mouse model to identify pathways for therapeutic improvement of RTT symptoms. Of note, one suppressor mutation implied that cholesterol homeostasis was perturbed in Mecp2 null mice; indeed, cholesterol synthesis was elevated in the brain and body system. Remarkably, the genetic effect of downregulating the cholesterol pathway could be mimicked chemically by statin drugs, improving motor symptoms, and increasing longevity in the mouse. Our work linked cholesterol metabolism to RTT pathology for the first time. Both neurological and systemic effects of perturbed cholesterol homeostasis overlap with many RTT symptoms. Here we show in patients that peripheral cholesterol, triglycerides, and/or LDLs may be elevated early in RTT disease onset, providing a biomarker for patients that could be aided by therapeutic interventions that modulate lipid metabolism.
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Affiliation(s)
- Monica J Justice
- Department of Molecular and Human Genetics; Baylor College of Medicine; Houston, TX USA
| | - Christie M Buchovecky
- Department of Molecular and Human Genetics; Baylor College of Medicine; Houston, TX USA
| | - Stephanie M Kyle
- Department of Molecular and Human Genetics; Baylor College of Medicine; Houston, TX USA
| | - Aleksandra Djukic
- Tri-state Rett Syndrome Clinic; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Bronx, NY USA
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Kuzaj P, Kuhn J, Faust I, Knabbe C, Hendig D. Measurement of HMG CoA reductase activity in different human cell lines by ultra-performance liquid chromatography tandem mass spectrometry. Biochem Biophys Res Commun 2013; 443:641-5. [PMID: 24333427 DOI: 10.1016/j.bbrc.2013.12.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Accepted: 12/03/2013] [Indexed: 10/25/2022]
Abstract
Hydroxymethylglutaryl coenzyme A reductase (HMGCR) catalyzes the rate limiting step in cholesterol biosynthesis converting HMG-CoA into mevalonic acid (MVA), which equilibrates with mevalonic acid lactone (MVL) under neutral pH conditions. We developed a fast, sensitive, and efficient method to determine HMGCR activity in human cell lines measuring MVL levels by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Convenient prepared samples containing MVL-D7 as an internal standard were injected, separated, and eluted from an ACQUITY HSS PFP column. Measurement of MVL was performed by electrospray ionization mass spectrometry with multiple reaction monitoring. Calibration curves were linear and reproducible in the range of 0.15-165 μg/l (r>0.99). Lower limit of quantification was 0.12 μg/l. Intra- and interassay imprecision were <1.3% and <2.9%, respectively. HMGCR enzymatic activity measurements of cells cultivated under different cell culture conditions (with 10% FCS, with 10% lipoprotein-deficient serum and under serum starvation) revealed the applicability of this test system for various experimental settings. This efficient UPLC-MS/MS assay permits rapid and high sensitive determination of HMGCR enzyme activity, tracing potential alterations in cholesterol biosynthesis.
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Affiliation(s)
- Patricia Kuzaj
- Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Georgstraße 11, 32 545 Bad Oeynhausen, Germany
| | - Joachim Kuhn
- Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Georgstraße 11, 32 545 Bad Oeynhausen, Germany
| | - Isabel Faust
- Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Georgstraße 11, 32 545 Bad Oeynhausen, Germany
| | - Cornelius Knabbe
- Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Georgstraße 11, 32 545 Bad Oeynhausen, Germany
| | - Doris Hendig
- Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Georgstraße 11, 32 545 Bad Oeynhausen, Germany.
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Turner RJ, Bushnell CD, Register TC, Sharp FR. Gender-dependent correlations of carotid intima-media thickness with gene expression in blood. Transl Stroke Res 2013; 2:171-8. [PMID: 22287995 DOI: 10.1007/s12975-011-0066-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The mechanisms underlying gender differences in stroke incidence, risk, and outcome are uncertain. We sought to determine whether transcriptional profiles of circulating blood cells of men and women differentially correlated with carotid artery intima-media thickness (CIMT), a predictor of atherosclerosis and stroke risk. Gene expression in whole blood was measured using Affymetrix expression arrays in men (n=17) and women (n=35), aged 45-64 years, with at least one risk factor for stroke. Mean average CIMT was measured using B-mode ultrasound. Expression levels of 746 genes positively and 292 genes negatively correlated with CIMT only in women (p<0.05); 881 genes positively and 597 genes negatively correlated with CIMT only in men (p<0.05). Forty-one genes correlated with CIMT in men and women, but in opposite directions. These genes were associated with estrogen, cholesterol and lipid metabolism, inflammation, coagulation, and vasoreactivity. This pilot study provides the first proof of principle that gene expression in blood cells correlates with CIMT. These results point to potential pathophysiological mechanisms underlying sex differences in stroke risk. Since the sample size is small, the findings are preliminary and need to be confirmed in independent, larger studies.
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Affiliation(s)
- Renée J Turner
- Department of Neurology and M.I.N.D. Institute, University of California at Davis, Sacramento, CA 95817, USA
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Cañueto J, Girós M, González-Sarmiento R. The role of the abnormalities in the distal pathway of cholesterol biosynthesis in the Conradi-Hünermann-Happle syndrome. Biochim Biophys Acta Mol Cell Biol Lipids 2013; 1841:336-44. [PMID: 24036494 DOI: 10.1016/j.bbalip.2013.09.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Revised: 09/02/2013] [Accepted: 09/04/2013] [Indexed: 11/28/2022]
Abstract
Conradi-Hünermann-Happle syndrome (CDPX2, OMIM 302960) is an inherited X-linked dominant variant of chondrodysplasia punctata (CP) caused by mutations in one gene of the distal pathway of cholesterol biosynthesis. It exhibits intense phenotypic variation and primarily affects the skin, bones and eyes. The ichthyosis following Blaschko's lines, chondrodysplasia punctata and cataracts are the typical clinical findings. The cardinal biochemical features are an increase in 8(9)-cholestenol and 8-dehydrocholesterol (8DHC), which suggest a deficiency in 3β-hydroxysteroid-Δ8,Δ7-isomerase, also called emopamil binding protein (EBP). The EBP gene is located on the short arm of the X chromosome (Xp11.22-p11.23) and encodes a 230 amino acid protein with dual function. Explaining the clinical phenotype in CDPX2 implies an understanding of both the genetics and biochemical features of this disease. CDPX2 displays an X-linked dominant pattern of inheritance, which is responsible for the distribution of lesions in some tissues. The clinical phenotype in CDPX2 results directly from impairment in cholesterol biosynthesis, and indirectly from abnormalities in the hedgehog signaling protein pathways. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.
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Affiliation(s)
- Javier Cañueto
- Department of Dermatology, University Hospital of Salamanca, Paseo San Vicente 58-182, 37007 Salamanca, Spain; IBSAL (Instituto de Investigación Biosanitaria de Salamanca), Spain.
| | - Marisa Girós
- Seccio Errors Congenits del Metabolisme, Servei de Bioquímica Clínica i Genética Molecular, Hospital Clinic Barcelona, Barcelona, Spain
| | - Rogelio González-Sarmiento
- IBSAL (Instituto de Investigación Biosanitaria de Salamanca), Spain; Molecular Medicine Unit, Faculty of Medicine, University of Salamanca, Campus Miguel de Unamuno S/N, Salamanca 37007, Spain; Laboratory 14, IBMCC-CSIC, University of Salamanca, Campus Miguel de Unamuno S/N, Salamanca 37007, Spain
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A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome. Nat Genet 2013; 45:1013-20. [PMID: 23892605 PMCID: PMC3837522 DOI: 10.1038/ng.2714] [Citation(s) in RCA: 155] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Accepted: 06/24/2013] [Indexed: 12/13/2022]
Abstract
Mutations in methyl CpG binding protein 2 (MECP2) cause Rett Syndrome, the most severe autism spectrum disorder. Re-expressing Mecp2 in symptomatic Mecp2 null mice dramatically improves function and longevity, providing hope that therapeutic intervention is possible in humans. To identify pathways in disease pathology for therapeutic intervention, a dominant ENU mutagenesis suppressor screen was carried out in Mecp2 null mice. Five suppressors that ameliorate symptoms of Mecp2 loss were isolated. Here we show that a stop codon mutation in squalene epoxidase (Sqle), a rate-limiting enzyme in cholesterol biosynthesis underlies suppression in one line. Subsequently, we show that lipid metabolism is perturbed in the brain and liver of Mecp2 null males. Consistently, statin drugs improve systemic perturbations of lipid metabolism, alleviate motor symptoms and confer increased longevity in Mecp2 mutant mice. The genetic screen therefore points to cholesterol homeostasis as a potential target for the treatment of Rett patients.
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Cortes VA, Busso D, Mardones P, Maiz A, Arteaga A, Nervi F, Rigotti A. Retracted: Advances in the physiological and pathological implications of cholesterol. Biol Rev Camb Philos Soc 2013; 88:825-43. [DOI: 10.1111/brv.12025] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2012] [Revised: 01/22/2013] [Accepted: 01/25/2013] [Indexed: 01/07/2023]
Affiliation(s)
- Victor A. Cortes
- Department of Nutrition Diabetes and Metabolism; School of Medicine; Faculty of Medicine; Pontificia Universidad Catolica de Chile; Marcoleta 367 Edifico de Gastroenterologia 4 piso Santiago Chile
| | - Dolores Busso
- Department of Nutrition Diabetes and Metabolism; School of Medicine; Faculty of Medicine; Pontificia Universidad Catolica de Chile; Marcoleta 367 Edifico de Gastroenterologia 4 piso Santiago Chile
| | - Pablo Mardones
- Department of Nutrition Diabetes and Metabolism; School of Medicine; Faculty of Medicine; Pontificia Universidad Catolica de Chile; Marcoleta 367 Edifico de Gastroenterologia 4 piso Santiago Chile
| | - Alberto Maiz
- Department of Nutrition Diabetes and Metabolism; School of Medicine; Faculty of Medicine; Pontificia Universidad Catolica de Chile; Marcoleta 367 Edifico de Gastroenterologia 4 piso Santiago Chile
| | - Antonio Arteaga
- Department of Nutrition Diabetes and Metabolism; School of Medicine; Faculty of Medicine; Pontificia Universidad Catolica de Chile; Marcoleta 367 Edifico de Gastroenterologia 4 piso Santiago Chile
| | - Flavio Nervi
- Department of Gastroenterology; School of Medicine; Faculty of Medicine; Pontificia Universidad Catolica de Chile; Santiago Chile
| | - Attilio Rigotti
- Department of Nutrition Diabetes and Metabolism; School of Medicine; Faculty of Medicine; Pontificia Universidad Catolica de Chile; Marcoleta 367 Edifico de Gastroenterologia 4 piso Santiago Chile
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Cholesterol: its regulation and role in central nervous system disorders. CHOLESTEROL 2012; 2012:292598. [PMID: 23119149 PMCID: PMC3483652 DOI: 10.1155/2012/292598] [Citation(s) in RCA: 205] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2012] [Revised: 09/03/2012] [Accepted: 09/10/2012] [Indexed: 02/08/2023]
Abstract
Cholesterol is a major constituent of the human brain, and the brain is the most cholesterol-rich organ. Numerous lipoprotein receptors and apolipoproteins are expressed in the brain. Cholesterol is tightly regulated between the major brain cells and is essential for normal brain development. The metabolism of brain cholesterol differs markedly from that of other tissues. Brain cholesterol is primarily derived by de novo synthesis and the blood brain barrier prevents the uptake of lipoprotein cholesterol from the circulation. Defects in cholesterol metabolism lead to structural and functional central nervous system diseases such as Smith-Lemli-Opitz syndrome, Niemann-Pick type C disease, and Alzheimer's disease. These diseases affect different metabolic pathways (cholesterol biosynthesis, lipid transport and lipoprotein assembly, apolipoproteins, lipoprotein receptors, and signaling molecules). We review the metabolic pathways of cholesterol in the CNS and its cell-specific and microdomain-specific interaction with other pathways such as the amyloid precursor protein and discuss potential treatment strategies as well as the effects of the widespread use of LDL cholesterol-lowering drugs on brain functions.
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