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Hou Y, Fu Z, Wang C, Kucharzewska P, Guo Y, Zhang S. 27-Hydroxycholesterol in cancer development and drug resistance. J Enzyme Inhib Med Chem 2025; 40:2507670. [PMID: 40401382 PMCID: PMC12100970 DOI: 10.1080/14756366.2025.2507670] [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: 01/06/2025] [Revised: 04/25/2025] [Accepted: 05/13/2025] [Indexed: 05/23/2025] Open
Abstract
27-Hydroxycholesterol (27HC), a cholesterol metabolite, functions both as a selective oestrogen receptor (ER) modulator and a ligand for liver X receptors (LXRs). The discovery of 27HC involvement in carcinogenesis has unveiled new research avenues, yet its precise role remains controversial and context-dependent. In this review, we provide an overview of the biosynthesis and metabolism of 27HC and explore its cancer-associated signalling, with a particular focus on ER- and LXR-mediated pathways. Given the tissue-specific dual role of 27HC, we discuss its differential impact across various cancer types. Furthermore, we sort out 27HC-contributed drug resistance mechanisms from the perspectives of drug efflux, cellular proliferation, apoptosis, epithelial-mesenchymal transition (EMT), antioxidant defence, epigenetic modification, and metabolic reprogramming. Finally, we highlight the chemical inhibitors to mitigate 27HC-driven cancer progression and drug resistance. This review offers an updated role of 27HC in cancer biology, setting the stage for future research and the development of targeted therapeutics.
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Affiliation(s)
- Yaxin Hou
- Department of Cell Biology, School of Medicine, Nankai University, Tianjin, China
| | - Zhiguang Fu
- Department of Tumor Radiotherapy, Air Force Medical Center, People’s Liberation Army of China (PLA), Beijing, China
| | - Chenhui Wang
- Department of Cell Biology, School of Medicine, Nankai University, Tianjin, China
| | - Paulina Kucharzewska
- Center of Cellular Immunotherapies, Warsaw University of Life Sciences, Warsaw, Poland
| | - Yuan Guo
- Department of Cell Biology, School of Medicine, Nankai University, Tianjin, China
| | - Sihe Zhang
- Department of Cell Biology, School of Medicine, Nankai University, Tianjin, China
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2
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Lei K, Chen Y, Wu J, Lin Y, Bai Y, Cao H, Che Q, Guo J, Su Z. Mechanism of liver x receptor alpha in intestine, liver and adipose tissues in metabolic associated fatty liver disease. Int J Biol Macromol 2025; 307:142275. [PMID: 40112983 DOI: 10.1016/j.ijbiomac.2025.142275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 03/16/2025] [Accepted: 03/17/2025] [Indexed: 03/22/2025]
Abstract
Metabolism associated fatty liver disease (MAFLD) has emerged as a growing global health challenge with limited effective treatments. Research on nuclear receptors offers promising new therapeutic avenues for MAFLD. The liver X receptor (LXR) has gained attention for its roles in tumors and metabolic and inflammatory diseases; However, its effects on MAFLD treatment remain a subject of debate. This review explores the therapeutic role of LXRα in MAFLD, focusing on its functions in the intestine, hepatic and adipose tissue, and summarizes recent advancements in LXRα ligands over the past five years. In the intestine, LXRα activation enhances the efflux of non-biliary cholesterol and reduces inflammation in the gut-liver axis by regulating intestinal high-density lipoprotein synthesis and its interaction with lipopolysaccharide. In the liver, LXRα activation facilitates cholesterol transport, influences hepatic lipid synthesis, and exerts anti-inflammatory effects. In adipose tissue, LXRα helps delay MAFLD progression by managing lipid autophagy and insulin resistance. Ligands that modulate LXRα transcriptional activity show considerable promise for MAFLD treatment.
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Affiliation(s)
- Kaiwen Lei
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yan Chen
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Jianxing Wu
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yiyu Lin
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yan Bai
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Hua Cao
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China
| | - Qishi Che
- Guangzhou Rainhome Pharm & Tech Co., Ltd, Science City, Guangzhou 510663, China
| | - Jiao Guo
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Zhengquan Su
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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Lu L, Li J, Zhang L, Zhang Y, Li Z, Lan J, Zeng R, Fang S, Zhang T, Ding Y. A rapid quantitative UPLC-MS/MS method for analysis of key regulatory oxysterols in biological samples for liver cancer. J Steroid Biochem Mol Biol 2024; 243:106577. [PMID: 38971336 DOI: 10.1016/j.jsbmb.2024.106577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 06/27/2024] [Accepted: 07/04/2024] [Indexed: 07/08/2024]
Abstract
An UPLC-APCI-MS/MS method was developed for the simultaneous determination of cholesterol, 7-dehydrocholesterol (7DHC) and eight oxysterols including 27-hydroxycholesterol (27OHC), 7α-hydroxycholesterol (7αOHC), 7β-hydroxycholesterol (7βOHC), 24S-hydroxycholesterol (24SOHC), 25-hydroxycholesterol (25OHC), 7α,24S-dihydroxycholesterol (7α,24SdiOHC), 7α,25-dihydroxycholesterol (7α,25diOHC), and 7α,27-dihydroxycholesterol (7α,27diOHC). It has been used for quantitative analysis of cholesterol, 7DHC and eight oxysterols in hepatocellular carcinoma (HCC) cells, plasma and tumor tissue samples. And the above compounds were extracted from the biological matrix (plasma and tissue) using liquid-liquid extraction with hexane/isopropanol after saponification to cleave the steroids from their esterified forms without further derivatization. Then cholesterol, 7DHC and oxysterols were separated on a reversed phase column (Agilent Zorbax Eclipse plus, C18) within 8 min using a gradient elution with 0.1 % formic acid in H2O and methanol and detected by an APCI triple quadrupole mass spectrometer. The lower limit of quantification (LLOQ) of the cholesterol, 7DHC and oxysterols ranged from 3.9 ng/mL to 31.25 ng/mL, and the recoveries ranged from 83.0 % to 113.9 %. Cholesterol, 7DHC and several oxysterols including 27OHC, 7αOHC and 7βOHC were successfully quantified in HCC cells, plasma, tissues and urine of HCC mice. Results showed that 27OHC was at high levels in three kind of HCC cells and tumor tissues as well as plasma samples from both HepG2 and Huh7 bearing mice model，and the high levels of 27OHC in tumors were associated with HCC development. Moreover, the levels of cholesterol in HCC cells and tumor issues varied in different HCC cells and mice model. Oxysterols profiling in biological samples might provide complementary information in cancer diagnosis.
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Affiliation(s)
- Lu Lu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; National Innovation Platform for medical industry-education integration, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jie Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lijuan Zhang
- National Innovation Platform for medical industry-education integration, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yong Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhe Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; The MOE Innovation Centre for Basic Medicine Research on Qi-Blood TCM Theories, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jinshuai Lan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; The MOE Innovation Centre for Basic Medicine Research on Qi-Blood TCM Theories, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ruifeng Zeng
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Shiyuan Fang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tong Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Yue Ding
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; National Innovation Platform for medical industry-education integration, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; The MOE Innovation Centre for Basic Medicine Research on Qi-Blood TCM Theories, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Kaul R, Paul P, Harfouche M, Saliba R, Chaari A. Microbiome-modulating nutraceuticals ameliorate dyslipidemia in type 2 diabetes: A systematic review, meta-analysis, and meta-regression of clinical trials. Diabetes Metab Res Rev 2024; 40:e3675. [PMID: 37381688 DOI: 10.1002/dmrr.3675] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 03/26/2023] [Accepted: 05/19/2023] [Indexed: 06/30/2023]
Abstract
AIMS Type 2 Diabetes is intrinsically linked to cardiovascular disease (CVD) via diabetic dyslipidemia, both of which remain global health concerns with annually increasing prevalence. Given the established links between gut microbiome dysbiosis and metabolic diseases, its modulation is an attractive target to ameliorate metabolic imbalances in such patients. There is a need to quantitively summarise, analyse, and describe future directions in this field. METHODS We conducted a systematic review, meta-analysis, and meta-regression following searches in major scientific databases for clinical trials investigating the effect of pro/pre/synbiotics on lipid profile published until April 2022. Data were pooled using random-effects meta-analysis and reported as mean differences with 95% confidence intervals (CIs). PROSPERO No. CRD42022348525. RESULTS Data from 47 trial comparisons across 42 studies (n = 2692) revealed that, compared to placebo/control groups, the administration of pro/pre/synbiotics was associated with statistically significant changes in total cholesterol (-9.97 mg/dL [95% CI: -15.08; -4.87], p < 0.0001), low-density lipoprotein (-6.29 mg/dL [95% CI: -9.25; -3.33], p < 0.0001), high-density lipoprotein (+3.21 mg/dL [95% CI: 2.20; 4.22], p < 0.0001), very-low-density lipoprotein (-4.52 mg/dL [95% CI: -6.36; -2.67], p < 0.0001) and triglyceride (-22.93 mg/dL [95% CI: -33.99; -11.87], p < 0.001). These results are influenced by patient characteristics such as age or baseline BMI, and intervention characteristics such as dosage and duration. CONCLUSIONS Our study shows that adjunct supplementation with a subset of pro/pre/synbiotics ameliorates dyslipidemia in diabetic individuals and has the potential to reduce CVD risk. However, widespread inter-study heterogeneity and the presence of several unknown confounders limit their adoption in clinical practice; future trials should be designed with these in mind.
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Affiliation(s)
- Ridhima Kaul
- Medical Education Division, Weill Cornell Medicine-Qatar, Cornell University, Qatar Foundation - Education City, Doha, Qatar
| | - Pradipta Paul
- Medical Education Division, Weill Cornell Medicine-Qatar, Cornell University, Qatar Foundation - Education City, Doha, Qatar
| | - Manale Harfouche
- Infectious Disease Epidemiology Group, Weill Cornell Medicine - Qatar, Cornell University, Qatar Foundation - Education City, Doha, Qatar
- World Health Organization Collaborating Centre for Disease Epidemiology Analytics on HIV/AIDS, Sexually Transmitted Infections, and Viral Hepatitis, Weill Cornell Medicine - Qatar, Cornell University, Qatar Foundation - Education City, Doha, Qatar
| | - Reya Saliba
- Health Sciences Library, Weill Cornell Medicine - Qatar, Cornell University, Qatar Foundation - Education City, Doha, Qatar
| | - Ali Chaari
- Premedical Division, Weill Cornell Medicine - Qatar, Qatar Foundation - Education City, Doha, Qatar
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Wu H, Wu X, Zhao M, Yan J, Li C, Zhang Z, Tang S, Wang R, Fei W. Regulating Cholesterol in Tumorigenesis: A Novel Paradigm for Tumor Nanotherapeutics. Int J Nanomedicine 2024; 19:1055-1076. [PMID: 38322754 PMCID: PMC10844012 DOI: 10.2147/ijn.s439828] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 01/23/2024] [Indexed: 02/08/2024] Open
Abstract
During the past decade, "membrane lipid therapy", which involves the regulation of the structure and function of tumor cell plasma membranes, has emerged as a new strategy for cancer treatment. Cholesterol is an important component of the tumor plasma membrane and serves an essential role in tumor initiation and progression. This review elucidates the role of cholesterol in tumorigenesis (including tumor cell proliferation, invasion/metastasis, drug resistance, and immunosuppressive microenvironment) and elaborates on the potential therapeutic targets for tumor treatment by regulating cholesterol. More meaningfully, this review provides an overview of cholesterol-integrated membrane lipid nanotherapeutics for cancer therapy through cholesterol regulation. These strategies include cholesterol biosynthesis interference, cholesterol uptake disruption, cholesterol metabolism regulation, cholesterol depletion, and cholesterol-based combination treatments. In summary, this review demonstrates the tumor nanotherapeutics based on cholesterol regulation, which will provide a reference for the further development of "membrane lipid therapy" for tumors.
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Affiliation(s)
- Huifeng Wu
- Department of Urology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Xiaodong Wu
- Department of Gynecologic Oncology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
| | - Mengdan Zhao
- Department of Pharmacy, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
| | - Jingjing Yan
- Department of Pharmacy, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
| | - Chaoqun Li
- Department of Pharmacy, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
| | - Zhewei Zhang
- Department of Urology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Sangsang Tang
- Department of Gynecologic Oncology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
| | - Rong Wang
- Department of Pharmacy, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
| | - Weidong Fei
- Department of Pharmacy, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
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Ksila M, Ghzaiel I, Sassi K, Zarrouk A, Leoni V, Poli G, Rezig L, Pires V, Meziane S, Atanasov AG, Hammami S, Hammami M, Masmoudi-Kouki O, Hamdi O, Jouanny P, Samadi M, Vejux A, Ghrairi T, Lizard G. Therapeutic Applications of Oxysterols and Derivatives in Age-Related Diseases, Infectious and Inflammatory Diseases, and Cancers. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1440:379-400. [PMID: 38036890 DOI: 10.1007/978-3-031-43883-7_19] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Abstract
Oxysterols, resulting from the oxidation of cholesterol, are formed either by autoxidation, enzymatically, or by both processes. These molecules, which are provided in more or less important quantities depending on the type of diet, are also formed in the body and their presence is associated with a normal physiological activity. Their increase and decrease at the cellular level and in biological fluids can have significant consequences on health due or not to the interaction of some of these molecules with different types of receptors but also because oxysterols are involved in the regulation of RedOx balance, cytokinic and non-cytokinic inflammation, lipid metabolism, and induction of cell death. Currently, various pathologies such as age-related diseases, inflammatory and infectious diseases, and several cancers are associated with abnormal levels of oxysterols. Due to the important biological activities of oxysterols, their interaction with several receptors and their very likely implications in several diseases, this review focuses on these molecules and on oxysterol derivatives, which are often more efficient, in a therapeutic context. Currently, several oxysterol derivatives are developed and are attracting a lot of interest.
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Affiliation(s)
- Mohamed Ksila
- Bio-PeroxIL Laboratory, EA7270, University of Bourgogne & Inserm, Dijon, France
- Laboratory of Neurophysiology, Cellular Physiopathology and Valorisation of Biomolecules (LR18ES03), Department of Biology, Faculty of Sciences, University Tunis El Manar, Tunis, Tunisia
| | - Imen Ghzaiel
- Bio-PeroxIL Laboratory, EA7270, University of Bourgogne & Inserm, Dijon, France
- Laboratory of Rangeland Ecosystems and Valorization of Spontaneous Plants and Associated Microorganisms (LR16IRA03), Arid Regions Institute, University of Gabes, Medenine, Tunisia
| | - Khouloud Sassi
- Bio-PeroxIL Laboratory, EA7270, University of Bourgogne & Inserm, Dijon, France
| | - Amira Zarrouk
- Laboratory of Rangeland Ecosystems and Valorization of Spontaneous Plants and Associated Microorganisms (LR16IRA03), Arid Regions Institute, University of Gabes, Medenine, Tunisia
- Faculty of Medicine, University of Sousse, Laboratory of Biochemistry, Sousse, Tunisia
| | - Valerio Leoni
- Department of Laboratory Medicine, University of Milano-Bicocca, Azienda Socio Sanitaria Territoriale Brianza ASST-Brianza, Desio Hospital, Desio, Italy
| | - Giuseppe Poli
- Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, Turin, Italy
| | - Leila Rezig
- University of Carthage, National Institute of Applied Sciences and Technology, LR11ES26, LIP-MB 'Laboratory of Protein Engineering and Bioactive Molecules', Tunis, Tunisia
- University of Carthage, High Institute of Food Industries, El Khadra City, Tunis, Tunisia
| | - Vivien Pires
- Bio-PeroxIL Laboratory, EA7270, University of Bourgogne & Inserm, Dijon, France
| | - Smail Meziane
- Institut Européen des Antioxydants (IEA), Neuves-Maisons, France
| | - Atanas G Atanasov
- Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Magdalenka, Poland
| | - Sonia Hammami
- Laboratory of Rangeland Ecosystems and Valorization of Spontaneous Plants and Associated Microorganisms (LR16IRA03), Arid Regions Institute, University of Gabes, Medenine, Tunisia
- University Hospital Fattouma Bourguiba, Monastir, Tunisia
| | - Mohamed Hammami
- Laboratory of Rangeland Ecosystems and Valorization of Spontaneous Plants and Associated Microorganisms (LR16IRA03), Arid Regions Institute, University of Gabes, Medenine, Tunisia
| | - Olfa Masmoudi-Kouki
- Laboratory of Neurophysiology, Cellular Physiopathology and Valorisation of Biomolecules (LR18ES03), Department of Biology, Faculty of Sciences, University Tunis El Manar, Tunis, Tunisia
| | - Oumaima Hamdi
- University Hospital Fattouma Bourguiba, Monastir, Tunisia
- Pôle Personnes Agées, CHU de Dijon, Centre de Champmaillot, Dijon Cedex, France
| | - Pierre Jouanny
- Pôle Personnes Agées, CHU de Dijon, Centre de Champmaillot, Dijon Cedex, France
| | - Mohammad Samadi
- Laboratory of Chemistry and Physics Multi-Scale Approach to Complex Environments, Department of Chemistry, University Lorraine, Metz, France
| | - Anne Vejux
- Bio-PeroxIL Laboratory, EA7270, University of Bourgogne & Inserm, Dijon, France
| | - Taoufik Ghrairi
- Laboratory of Neurophysiology, Cellular Physiopathology and Valorisation of Biomolecules (LR18ES03), Department of Biology, Faculty of Sciences, University Tunis El Manar, Tunis, Tunisia
| | - Gérard Lizard
- Bio-PeroxIL Laboratory, EA7270, University of Bourgogne & Inserm, Dijon, France.
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André R, Pacheco R, Alves AC, Santos HM, Bourbon M, Serralheiro ML. The Hypocholesterolemic Potential of the Edible Algae Fucus vesiculosus: Proteomic and Quantitative PCR Analysis. Foods 2023; 12:2758. [PMID: 37509850 PMCID: PMC10379601 DOI: 10.3390/foods12142758] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/29/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
A brown seaweed consumed worldwide, Fucus vesiculosus, has been used to prevent atherosclerosis and hypercholesterolemia, among other uses. However, the mechanisms of action that lead to these effects are not yet fully understood. This work aims to study the in vitro effect of an aqueous extract of F. vesiculosus, previously characterized as rich in phlorotannins and peptides, on the expression of different proteins involved in the synthesis and transport of cholesterol. A proteomic analysis, Western blot, and qRT-PCR analysis were performed to identify protein changes in HepG2 cells exposed to 0.25 mg/mL of the F. vesiculosus extract for 24 h. The proteomic results demonstrated that, in liver cells, the extract decreases the expression of four proteins involved in the cholesterol biosynthesis process (CYP51A1, DHCR24, HMGCS1 and HSD17B7). Additionally, a 12.76% and 18.40% decrease in the expression of two important transporters proteins of cholesterol, NPC1L1 and ABCG5, respectively, was also observed, as well as a 30% decrease in NPC1L1 mRNA levels in the cells exposed to the extract compared to control cells. Our study reveals some of the mechanisms underlying the actions of bioactive compounds from F. vesiculosus that may explain its previously reported hypocholesterolemic effect, future prospecting its use as a functional food.
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Affiliation(s)
- Rebeca André
- BioISI-Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
| | - Rita Pacheco
- Department of Chemical Engineering, ISEL-Instituto Superior de Engenharia de Lisboa, Rua Conselheiro Emídio Navarro, 1, 1959-007 Lisboa, Portugal
- Centro de Química Estrutural, Institute of Molecular Sciences, Universidade de Lisboa, 1749-016 Lisboa, Portugal
| | - Ana Catarina Alves
- BioISI-Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
- Unidade de I&D, Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal
| | - Hugo M Santos
- LAQV@REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal
- PROTEOMASS Scientific Society, Madan Park, Rúa dos Inventores, 2825-182 Caparica, Portugal
| | - Mafalda Bourbon
- BioISI-Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
- Unidade de I&D, Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal
| | - Maria Luísa Serralheiro
- BioISI-Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
- Department of Chemistry and Biochemistry, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, C8 Bldg, 1749-016 Lisboa, Portugal
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8
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Elamawy A, Hegazi E, Nassef E, Abouzed TK, Zaki AG, Ismail T. Dietary inclusion of nano-phosphorus improves growth performance, carcass quality, and growth-related traits of Nile tilapia (Oreochromis niloticus) and alleviates water phosphorus residues. FISH PHYSIOLOGY AND BIOCHEMISTRY 2023; 49:529-542. [PMID: 37138041 DOI: 10.1007/s10695-023-01199-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 04/18/2023] [Indexed: 05/05/2023]
Abstract
Supplementation of phosphorus nanoparticles is a promising strategy to reduce water pollution, improve phosphorus concentration in fish diet, and provide better production quality. We used 300 fingerlings of Nile tilapia that were randomly distributed into 3 groups; each one was attributed to 5 replicates of 20 fish per aquarium with initial weight (gm) (156 ± 1.25). The first diet contained traditional Di-calcium phosphate (D-group), the second supplemented with phosphorus nanoparticles in a dose equal to the previous conventional one (N-D group), and the last one included with phosphorus nanoparticles with the half dose of the conventional phosphorus group (1/2 N-D group). After 3 months of feeding, the N-D group showed the best growth performance including its feed conversion ratio (FCR), feed intake (FI), or body weight gain (BWG). Furthermore, the growth-related gene expression findings considering growth hormone receptor (GHR) and insulin-like growth factor-1 (IGF-1) were upregulated as well. Moreover, whole body chemical composition revealed higher Fe, Zn, P, and crude protein level in the N-D group than the other two groups. Lipoprotein lipase (LPL) and fatty acid synthetase (FAS) mRNA expression showed a significant increase in 1/2 N-D and N-D groups compared with the control group. To sum up, using of nano-phosphorus particles improved the growth rate and immunity response of Nile tilapia, besides decreasing water pollution.
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Affiliation(s)
- Anwar Elamawy
- Department of Nutrition and Clinical Nutrition, Faculty of Veterinary Medicine, Kafrelsheikh, Egypt
| | - Elsayed Hegazi
- Department of Nutrition and Clinical Nutrition, Faculty of Veterinary Medicine, Kafrelsheikh, Egypt
| | - Eldsokey Nassef
- Department of Nutrition and Clinical Nutrition, Faculty of Veterinary Medicine, Kafrelsheikh, Egypt
| | - Tarek K Abouzed
- Department of Biochemistry, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt
| | - Abeer G Zaki
- Biotechnology Department, Animal Health Research Institute, Giza, Egypt
| | - Taha Ismail
- Department of Nutrition and Clinical Nutrition, Faculty of Veterinary Medicine, Kafrelsheikh, Egypt.
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Abdi M, Esmaeili Gouvarchin Ghaleh H, Ranjbar R. Lactobacilli and Bifidobacterium as anti-atherosclerotic agents. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2022; 25:934-946. [PMID: 36159325 PMCID: PMC9464336 DOI: 10.22038/ijbms.2022.63860.14073] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 07/04/2022] [Indexed: 11/06/2022]
Abstract
Atherosclerosis is the thickening or hardening of the arteries which is caused by a buildup of atheromatous plaque in the inner lining of an artery. Hypercholesterolemia, inflammation, oxidative stress, and trimethylamine N-oxide (TMAO) are important risk factors for atherosclerosis. Therefore, this study aimed to review the anti-atherosclerotic effects of Lactobacilli and Bifidobacterium via improving lipid profile and reducing the effects of oxidative stress, inflammation, and TMAO. To prepare the present review, several databases such as Scopus, PubMed, and Google Scholar were searched, and relevant articles from 1990 until 2022 were selected and reviewed. The present review showed that Lactobacilli and Bifidobacterium reduce the risk of atherosclerosis in both in vitro and in vivo studies by breaking down or altering cholesterol metabolism with the help of their by-products and by reducing inflammation and oxidative stress and TMAO. Consumption of Lactobacilli and Bifidobacterium can be useful in prevention of atherosclerosis.
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Affiliation(s)
- Milad Abdi
- Research Center of Tropical and Infectious Diseases, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Reza Ranjbar
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran,Corresponding author: Reza Ranjbar. Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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10
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Kacher R, Mounier C, Caboche J, Betuing S. Altered Cholesterol Homeostasis in Huntington’s Disease. Front Aging Neurosci 2022; 14:797220. [PMID: 35517051 PMCID: PMC9063567 DOI: 10.3389/fnagi.2022.797220] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 03/18/2022] [Indexed: 12/25/2022] Open
Abstract
Huntington’s disease (HD) is an autosomal dominant genetic disorder caused by an expansion of the CAG repeat in the first exon of Huntingtin’s gene. The associated neurodegeneration mainly affects the striatum and the cortex at early stages and progressively spreads to other brain structures. Targeting HD at its earlier stages is under intense investigation. Numerous drugs were tested, with a rate of success of only 3.5% approved molecules used as symptomatic treatment. The restoration of cholesterol metabolism, which is central to the brain homeostasis and strongly altered in HD, could be an interesting disease-modifying strategy. Cholesterol is an essential membrane component in the central nervous system (CNS); alterations of its homeostasis have deleterious consequences on neuronal functions. The levels of several sterols, upstream of cholesterol, are markedly decreased within the striatum of HD mouse model. Transcription of cholesterol biosynthetic genes is reduced in HD cell and mouse models as well as post-mortem striatal and cortical tissues from HD patients. Since the dynamic of brain cholesterol metabolism is complex, it is essential to establish the best method to target it in HD. Cholesterol, which does not cross the blood-brain-barrier, is locally synthesized and renewed within the brain. All cell types in the CNS synthesize cholesterol during development but as they progress through adulthood, neurons down-regulate their cholesterol synthesis and turn to astrocytes for their full supply. Cellular levels of cholesterol reflect the dynamic balance between synthesis, uptake and export, all integrated into the context of the cross talk between neurons and glial cells. In this review, we describe the latest advances regarding the role of cholesterol deregulation in neuronal functions and how this could be a determinant factor in neuronal degeneration and HD progression. The pathways and major mechanisms by which cholesterol and sterols are regulated in the CNS will be described. From this overview, we discuss the main clinical strategies for manipulating cholesterol metabolism in the CNS, and how to reinstate a proper balance in HD.
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Affiliation(s)
- Radhia Kacher
- Institut du Cerveau - Paris Brain Institute (ICM), AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, Sorbonne Université, Paris, France
- INSERM, U1216, Grenoble Institut Neurosciences, Université Grenoble Alpes, Grenoble, France
| | - Coline Mounier
- Neuroscience Paris Seine, Institut de Biologie Paris-Seine, Faculté des Sciences et Ingénierie, Sorbonne Université, Paris, France
- Centre National de la Recherche Scientifique, UMR 8246, Paris, France
- U1130, Institut National de la Santé et de la Recherche Médicale, Paris, France
| | - Jocelyne Caboche
- Neuroscience Paris Seine, Institut de Biologie Paris-Seine, Faculté des Sciences et Ingénierie, Sorbonne Université, Paris, France
- Centre National de la Recherche Scientifique, UMR 8246, Paris, France
- U1130, Institut National de la Santé et de la Recherche Médicale, Paris, France
| | - Sandrine Betuing
- Neuroscience Paris Seine, Institut de Biologie Paris-Seine, Faculté des Sciences et Ingénierie, Sorbonne Université, Paris, France
- Centre National de la Recherche Scientifique, UMR 8246, Paris, France
- U1130, Institut National de la Santé et de la Recherche Médicale, Paris, France
- *Correspondence: Sandrine Betuing,
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11
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Léger-Charnay E, Gambert S, Martine L, Dubus E, Maire MA, Buteau B, Morala T, Gigot V, Bron AM, Bretillon L, Masson EAY. Retinal cholesterol metabolism is perturbated in response to experimental glaucoma in the rat. PLoS One 2022; 17:e0264787. [PMID: 35275950 PMCID: PMC8916636 DOI: 10.1371/journal.pone.0264787] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 02/16/2022] [Indexed: 01/26/2023] Open
Abstract
Alterations of cholesterol metabolism have been described for many neurodegenerative pathologies, such as Alzheimer's disease in the brain and age-related macular degeneration in the retina. Recent evidence suggests that glaucoma, which is characterized by the progressive death of retinal ganglion cells, could also be associated with disruption of cholesterol homeostasis. In the present study we characterized cholesterol metabolism in a rat model of laser-induced intraocular hypertension, the main risk factor for glaucoma. Sterol levels were measured using gas-chromatography and cholesterol-related gene expression using quantitative RT-PCR at various time-points. As early as 18 hours after the laser procedure, genes implicated in cholesterol biosynthesis and uptake were upregulated (+49% and +100% for HMG-CoA reductase and LDLR genes respectively, vs. naive eyes) while genes involved in efflux were downregulated (-26% and -37% for ApoE and CYP27A1 genes, respectively). Cholesterol and precursor levels were consecutively elevated 3 days post-laser (+14%, +40% and +194% for cholesterol, desmosterol and lathosterol, respectively). Interestingly, counter-regulatory mechanisms were transcriptionally activated following these initial dysregulations, which were associated with the restoration of retinal cholesterol homeostasis, favorable to ganglion cell viability, one month after the laser-induced ocular hypertension. In conclusion, we report here for the first time that ocular hypertension is associated with transient major dynamic changes in retinal cholesterol metabolism.
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Affiliation(s)
- Elise Léger-Charnay
- Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, Dijon, France
| | - Ségolène Gambert
- Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, Dijon, France
- Laboratoire de Biochimie Médicale, Plateforme de Biologie Hospitalo-Universitaire, Dijon, France
| | - Lucy Martine
- Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, Dijon, France
| | - Elisabeth Dubus
- Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, Dijon, France
| | - Marie-Annick Maire
- Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, Dijon, France
| | - Bénédicte Buteau
- Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, Dijon, France
| | - Tristan Morala
- Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, Dijon, France
| | - Vincent Gigot
- Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, Dijon, France
| | - Alain M. Bron
- Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, Dijon, France
- Département d’Ophtalmologie, Centre Hospitalo-Universitaire de Dijon, Dijon, France
| | - Lionel Bretillon
- Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, Dijon, France
| | - Elodie A. Y. Masson
- Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, Dijon, France
- * E-mail:
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12
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Škara L, Huđek Turković A, Pezelj I, Vrtarić A, Sinčić N, Krušlin B, Ulamec M. Prostate Cancer-Focus on Cholesterol. Cancers (Basel) 2021; 13:4696. [PMID: 34572923 PMCID: PMC8469848 DOI: 10.3390/cancers13184696] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/08/2021] [Accepted: 09/15/2021] [Indexed: 12/24/2022] Open
Abstract
Prostate cancer (PC) is the most common malignancy in men. Common characteristic involved in PC pathogenesis are disturbed lipid metabolism and abnormal cholesterol accumulation. Cholesterol can be further utilized for membrane or hormone synthesis while cholesterol biosynthesis intermediates are important for oncogene membrane anchoring, nucleotide synthesis and mitochondrial electron transport. Since cholesterol and its biosynthesis intermediates influence numerous cellular processes, in this review we have described cholesterol homeostasis in a normal cell. Additionally, we have illustrated how commonly deregulated signaling pathways in PC (PI3K/AKT/MTOR, MAPK, AR and p53) are linked with cholesterol homeostasis regulation.
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Affiliation(s)
- Lucija Škara
- Department of Medical Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
- Group for Research on Epigenetic Biomarkers (Epimark), School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
- Centre of Excellence for Reproductive and Regenerative Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Ana Huđek Turković
- Faculty of Food Technology and Biotechnology, University of Zagreb, 10000 Zagreb, Croatia;
| | - Ivan Pezelj
- Department of Urology, University Clinical Hospital Center Sestre Milosrdnice, 10000 Zagreb, Croatia;
| | - Alen Vrtarić
- Department of Clinical Chemistry, University Clinical Hospital Center Sestre Milosrdnice, 10000 Zagreb, Croatia;
| | - Nino Sinčić
- Department of Medical Biology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
- Group for Research on Epigenetic Biomarkers (Epimark), School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
- Centre of Excellence for Reproductive and Regenerative Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Božo Krušlin
- Centre of Excellence for Reproductive and Regenerative Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
- Ljudevit Jurak Clinical Department of Pathology and Cytology, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Monika Ulamec
- Group for Research on Epigenetic Biomarkers (Epimark), School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
- Centre of Excellence for Reproductive and Regenerative Medicine, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
- Ljudevit Jurak Clinical Department of Pathology and Cytology, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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13
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Romero-Luna HE, Peredo-Lovillo AG, Jiménez-Fernández M. Probiotic and Potentially Probiotic Bacteria with Hypocholesterolemic Properties. FOOD REVIEWS INTERNATIONAL 2021. [DOI: 10.1080/87559129.2021.1926481] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Haydee Eliza Romero-Luna
- Subdirección de Posgrado e Investigación, Instituto Tecnológico Superior De Xalapa, Tecnológico Nacional De México, Xalapa Enríquez, Veracruz, México
| | - Audry Gustavo Peredo-Lovillo
- Subdirección de Posgrado e Investigación, Instituto Tecnológico Superior De Xalapa, Tecnológico Nacional De México, Xalapa Enríquez, Veracruz, México
| | - Maribel Jiménez-Fernández
- Departamento de Estabilidad de Alimentos, Centro De Investigación Y Desarrollo En Alimentos. Universidad Veracruzana. Dr. Castelazo Ayala S/n Industrial Ánimas, Xalapa, Veracruz, México
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14
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Nanjundaiah S, Chidambaram H, Chandrashekar M, Chinnathambi S. Role of Microglia in Regulating Cholesterol and Tau Pathology in Alzheimer's Disease. Cell Mol Neurobiol 2021; 41:651-668. [PMID: 32468440 PMCID: PMC11448617 DOI: 10.1007/s10571-020-00883-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 05/19/2020] [Indexed: 01/21/2023]
Abstract
Cholesterol, a principal constituent of the cell membrane, plays a crucial role in the brain by regulating the synaptic transmission, neuronal signaling, as well as neurodegenerative diseases. Defects in the cholesterol trafficking are associated with enhanced generation of hyperphosphorylated Tau and Amyloid-β protein. Tau, a major microtubule-associated protein in the brain, is the key regulator of the mature neuron. Abnormally hyperphosphorylated Tau hampers the major functions related to microtubule assembly by promoting neurofibrillary tangles of paired helical filaments, twisted ribbons, and straight filaments. The observed pathological changes due to impaired cholesterol and Tau protein accumulation cause Alzheimer's disease. Thus, in order to regulate the pathogenesis of Alzheimer's disease, regulation of cholesterol metabolism, as well as Tau phosphorylation, is essential. The current review provides an overview of (1) cholesterol synthesis in the brain, neurons, astrocytes, and microglia; (2) the mechanism involved in modulating cholesterol concentration between the astrocytes and brain; (3) major mechanisms involved in the hyperphosphorylation of Tau and amyloid-β protein; and (4) microglial involvement in its regulation. Thus, the answering key questions will provide an in-depth information on microglia involvement in managing the pathogenesis of cholesterol-modulated hyperphosphorylated Tau protein.
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Affiliation(s)
- Shwetha Nanjundaiah
- Neurobiology Group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune, 411008, India
| | - Hariharakrishnan Chidambaram
- Neurobiology Group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune, 411008, India
- Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India
| | - Madhura Chandrashekar
- School of Biomedical Engineering and Sciences, MIT University, Loni Kalbhor, Pune, 412201, India
| | - Subashchandrabose Chinnathambi
- Neurobiology Group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune, 411008, India.
- Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India.
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15
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Jung J, Lee SM, Lee MJ, Ryu JS, Song JH, Lee JE, Kang G, Kwon OS, Park JY. Lipidomics reveals that acupuncture modulates the lipid metabolism and inflammatory interaction in a mouse model of depression. Brain Behav Immun 2021; 94:424-436. [PMID: 33607237 DOI: 10.1016/j.bbi.2021.02.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 01/27/2021] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
Depression is a serious disease that has considerable impact on lipid metabolism and inflammatory responses. Recent studies have shown that leptin, which is well known as a mediator of energy homeostasis and is a cytokine in inflammatory response, plays an important role in depression. Acupuncture is widely used to treat depression; however, the underlying mechanisms and the effect of acupuncture on depression remain poorly understood. In this study, we utilized the chronic restraint stress (CRS) induced depression model and acupuncture treatment was performed at KI10, LR8, LU8, LR4 (AP) or non-acupoint (NP). Then, lipidomics was applied to investigate the effects of acupuncture on lipid metabolism and analyze leptin signals in the brain and changes of immune markers. Acupuncture treatment at AP improved depression-like behavior in an open-field test, forced swimming test, and marble burying test. Concurrently, CRS mice treated with AP acupuncture (CRS + AP) had significantly lower levels of aspartate aminotransaminase (AST, liver injury markers) and exhibited different lipid patterns in liver lipidomic profiles. In particular, triglycerides (TGs) contributed the change of lipid patterns. Compared to the CRS mice, TGs with relatively high degrees of unsaturated fatty acids increased in the CRS + AP mice, but did not change in CRS mice treated with NP acupuncture (CRS + NP). The levels of leptin in plasma and leptin receptor positive cells in the brain (hypothalamus and hippocampus) decreased and increased, respectively, in the CRS + AP mice, while opposite patterns were exhibited in the CRS and CRS + NP mice. These results indicated that acupuncture treatment at AP attenuated leptin insensitivity in CRS mice. Additionally, expression of pro-inflammatory cytokines such as interleukin-1 beta and tumor necrosis factor-alpha were decreased in the spleen, plasma, and liver of CRS + AP mice, which was one of results of alleviation of leptin resistance. In conclusion, these results show that AP acupuncture treatment effectively alleviated the depression-like behavior, affected immune responses, and altered hepatic lipid metabolism through the attenuation of leptin insensitivity.
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Affiliation(s)
- Jeeyoun Jung
- Clinical Medicine Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea.
| | - So Min Lee
- Clinical Medicine Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea
| | - Min-Ju Lee
- College of Korean Medicine, Daejeon University, 62 Daehak-ro, Dong-gu, Daejeon 34520, Republic of Korea
| | - Jae-Sang Ryu
- College of Korean Medicine, Daejeon University, 62 Daehak-ro, Dong-gu, Daejeon 34520, Republic of Korea
| | - Ji-Hye Song
- College of Korean Medicine, Daejeon University, 62 Daehak-ro, Dong-gu, Daejeon 34520, Republic of Korea
| | - Jung-Eun Lee
- Clinical Medicine Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea
| | - Geonhui Kang
- Clinical Trial Center, Wonkwang University Gwangju Hospital, 1140-23 Hoejae-ro, Nam-Gu, Gwangju 16729, Republic of Korea
| | - O Sang Kwon
- Department of Meridian and Acupuncture Points, College of Korean Medicine, Wonkwang University, Iksan 54538, Republic of Korea
| | - Ji-Yeun Park
- College of Korean Medicine, Daejeon University, 62 Daehak-ro, Dong-gu, Daejeon 34520, Republic of Korea.
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16
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Vona R, Iessi E, Matarrese P. Role of Cholesterol and Lipid Rafts in Cancer Signaling: A Promising Therapeutic Opportunity? Front Cell Dev Biol 2021; 9:622908. [PMID: 33816471 PMCID: PMC8017202 DOI: 10.3389/fcell.2021.622908] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 02/15/2021] [Indexed: 12/11/2022] Open
Abstract
Cholesterol is a lipid molecule that plays an essential role in a number of biological processes, both physiological and pathological. It is an essential structural constituent of cell membranes, and it is fundamental for biosynthesis, integrity, and functions of biological membranes, including membrane trafficking and signaling. Moreover, cholesterol is the major lipid component of lipid rafts, a sort of lipid-based structures that regulate the assembly and functioning of numerous cell signaling pathways, including those related to cancer, such as tumor cell growth, adhesion, migration, invasion, and apoptosis. Considering the importance of cholesterol metabolism, its homeostasis is strictly regulated at every stage: import, synthesis, export, metabolism, and storage. The alterations of this homeostatic balance are known to be associated with cardiovascular diseases and atherosclerosis, but mounting evidence also connects these behaviors to increased cancer risks. Although there is conflicting evidence on the role of cholesterol in cancer development, most of the studies consistently suggest that a dysregulation of cholesterol homeostasis could lead to cancer development. This review aims to discuss the current understanding of cholesterol homeostasis in normal and cancerous cells, summarizing key findings from recent preclinical and clinical studies that have investigated the role of major players in cholesterol regulation and the organization of lipid rafts, which could represent promising therapeutic targets.
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Affiliation(s)
- Rosa Vona
- Center for Gender-Specific Medicine, Istituto Superiore di Sanità [Italian National Institute of Health], Rome, Italy
| | - Elisabetta Iessi
- Center for Gender-Specific Medicine, Istituto Superiore di Sanità [Italian National Institute of Health], Rome, Italy
| | - Paola Matarrese
- Center for Gender-Specific Medicine, Istituto Superiore di Sanità [Italian National Institute of Health], Rome, Italy
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17
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Goel D, Vohora D. Liver X receptors and skeleton: Current state-of-knowledge. Bone 2021; 144:115807. [PMID: 33333244 DOI: 10.1016/j.bone.2020.115807] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 11/26/2020] [Accepted: 12/11/2020] [Indexed: 12/25/2022]
Abstract
The liver X receptors (LXR) is a nuclear receptor that acts as a prominent regulator of lipid homeostasis and inflammatory response. Its therapeutic effectiveness against various diseases like Alzheimer's disease and atherosclerosis has been investigated in detail. Emerging pieces of evidence now reveal that LXR is also a crucial modulator of bone remodeling. However, the molecular mechanisms underlying the pharmacological actions of LXR on the skeleton and its role in osteoporosis are poorly understood. Therefore, in the current review, we highlight LXR and its actions through different molecular pathways modulating skeletal homeostasis. The studies described in this review propound that LXR in association with estrogen, PTH, PPARγ, RXR hedgehog, and canonical Wnt signaling regulates osteoclastogenesis and bone resorption. It regulates RANKL-induced expression of c-Fos, NFATc1, and NF-κB involved in osteoclast differentiation. Additionally, several studies suggest suppression of RANKL-induced osteoclast differentiation by synthetic LXR ligands. Given the significance of modulation of LXR in various physiological and pathological settings, our findings indicate that therapeutic targeting of LXR might potentially prevent or treat osteoporosis and improve bone quality.
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Affiliation(s)
- Divya Goel
- Department of Pharmacology, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi 110062, India
| | - Divya Vohora
- Department of Pharmacology, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi 110062, India.
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18
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Tsai YJ, Shen PH, Luo SD, Wu WB. Liver X Receptor Expression and Pentraxin 3 Production in Chronic Rhinosinusitis and Sinonasal Mucosal Fibroblast Cells. J Clin Med 2021; 10:452. [PMID: 33503887 PMCID: PMC7865759 DOI: 10.3390/jcm10030452] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 01/16/2021] [Accepted: 01/19/2021] [Indexed: 12/15/2022] Open
Abstract
The long pentraxin 3 (PTX3) is a prototypic molecule for recognizing pathogens. Liver X receptors (LXRs), belonging to nuclear receptors (NRs) for cholesterol metabolism through heterodimerizing with other NRs, were recently reported to participate in inflammation. However, their roles in chronic rhinosinusitis without nasal polyps (CRSsNP) are unclear. Therefore, this study was sought to explore roles of LXRs in chronic rhinosinusitis (CRS) sinonasal tissues and derived fibroblasts. Immunohistochemistry indicated that LXRα and β expression and lipid/fat deposition were differentially expressed in the control and CRSsNP nasal mucosa. GW7647 (a peroxisome proliferator activated receptor α (PPARα) agonist) and GW3965 (a dual agonist for LXRα and β) significantly caused PTX3 induction in the fibroblast cells. GW3965 induced PTX3 mRNA and protein expression, and the induction substantially led to PTX3 secretion. Meanwhile, an endogenous agonist-cholesterol had a similar enhancing effect on the induction of PTX3 protein. LXR siRNA knockdown to lower LXRα or β expression significantly compromised PTX3 induction. Interestingly, GW3965 also induced phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) activation and its inhibition reduced PTX3 expression. Collectively, we demonstrated here for the first time that CRSsNP nasal mucosa differentially expresses LXRα and β and deposits lipids/fats that may contain cholesterol metabolites to activate LXRs. Activation of LXRs leads to PTX3 production in sinonasal mucosa-derived fibroblasts. Our previous study showed PTX3 overexpression in the nasal cavity of CRSsNP, whereas this study highlights that cholesterol metabolites and LXR activation regulate PTX3 production and may contribute to antimicrobial activity and tissue repair during CRSsNP progression.
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Affiliation(s)
- Yih-Jeng Tsai
- Department of Otolaryngology Head and Neck Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan;
- School of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan
| | - Ping-Hung Shen
- Department of Otolaryngology, Kuang-Tien General Hospital, Taichung 43303, Taiwan;
- Department of Nursing, Hung-Kuang University, Taichung 433304, Taiwan
| | - Sheng-Dean Luo
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833253, Taiwan;
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Wen-Bin Wu
- School of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan
- Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City 242062, Taiwan
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19
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Zhang X, Wang K, Zhu L, Wang Q. Reverse Cholesterol Transport Pathway and Cholesterol Efflux in Diabetic Retinopathy. J Diabetes Res 2021; 2021:8746114. [PMID: 34746320 PMCID: PMC8564209 DOI: 10.1155/2021/8746114] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/16/2021] [Accepted: 10/01/2021] [Indexed: 11/21/2022] Open
Abstract
Cholesterol esters, synthesized from cholesterol with long-chain fatty acids, are essential components of plasma lipoproteins and cell membranes that participate in various metabolic processes in the body. Cholesterol can be excreted through the cholesterol reverse transport (RCT) pathway when excessive cholesterol is produced in the extrahepatic cells, which is regulated by the liver X receptor (LXR) and its downstream regulators ATP-binding cassette subfamily A member 1 (ABCA1) and ATP-binding cassette subfamily G member 1 (ABCG1) genes. Abnormal cholesterol metabolism is closely associated with the development of diabetic retinopathy (DR). However, the precise underlying mechanism of the RCT pathway in the pathogenesis of DR is still not fully understood. This review focused on cholesterol metabolism, with a particular emphasis on the RCT pathway and its correlation with the development of DR. Particular attention has been paid to the key regulators of the RCT pathway: LXR, ABCA1, and ABCG1 genes and their potential therapeutic targets in the management of DR.
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Affiliation(s)
- Xinyuan Zhang
- Beijing Institute of Ophthalmology, Department of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, China
- Beijing Retinal and Choroidal Vascular Study Group, China
| | - Kaiyue Wang
- Beijing Institute of Ophthalmology, Department of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, China
| | - Ling Zhu
- Save Sight Institute, University of Sydney, Australia
| | - Qiyun Wang
- Beijing Institute of Ophthalmology, Department of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, China
- Beijing Retinal and Choroidal Vascular Study Group, China
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20
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L-carnitine exerts a nutrigenomic effect via direct modulation of nuclear receptor signaling in adipocytes, hepatocytes and SKMC, demonstrating its nutritional impact. Nutr Res 2020; 85:84-98. [PMID: 33453499 DOI: 10.1016/j.nutres.2020.11.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 10/13/2020] [Accepted: 11/10/2020] [Indexed: 12/13/2022]
Abstract
L-carnitine is an indispensable metabolite facilitating the transport of fatty acids into the mitochondrial matrix and has been previously postulated to exert a nutrigenomic effect. However, the underlying molecular mechanisms remain mostly unclear. We hypothesized that L-carnitine interacts with nuclear receptors involved in metabolic regulation, thereby modulating downstream targets of cellular metabolism. Therefore, we investigated the effect of L-carnitine supplementation on protein activity, mRNA expression, and binding affinities of nuclear receptors as well as mRNA expression of downstream targets in skeletal muscle cells, hepatocytes, and differentiated adipocytes. L-carnitine supplementation to hepatocytes increased the protein activity of multiple nuclear receptors (RAR, RXR, VDR, PPAR, HNF4, ER, LXR). Diverging effects on the mRNA expression of PPAR-α, PPAR-δ, PPAR-γ, RAR-β, LXR-α, and RXR-α were observed in adipocytes, hepatocytes, and skeletal muscle cells. mRNA levels of PPAR-α, a key regulator of lipolysis and β-oxidation, were significantly upregulated, emphasizing a role of L-carnitine as a promoter of lipid catabolism. L-carnitine administration to hepatocytes modulated the transcription of key nuclear receptor target genes, including ALDH1A1, a promoter of adipogenesis, and OGT, a contributor to insulin resistance. Electrophoretic mobility shift assays proved L-carnitine to increase binding affinities of nuclear receptors to their promoter target sequences, suggesting a molecular mechanism for the observed transcriptional modulation. Overall, these findings indicate that L-carnitine modulates the activity and expression of nuclear receptors, thereby promoting lipolytic gene expression and decreasing transcription of target genes linked to adipogenesis and insulin resistance.
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21
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Ha NT, Lee CH. Roles of Farnesyl-Diphosphate Farnesyltransferase 1 in Tumour and Tumour Microenvironments. Cells 2020; 9:cells9112352. [PMID: 33113804 PMCID: PMC7693003 DOI: 10.3390/cells9112352] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/23/2020] [Accepted: 10/24/2020] [Indexed: 12/14/2022] Open
Abstract
Farnesyl-diphosphate farnesyltransferase 1 (FDFT1, squalene synthase), a membrane-associated enzyme, synthesizes squalene via condensation of two molecules of farnesyl pyrophosphate. Accumulating evidence has noted that FDFT1 plays a critical role in cancer, particularly in metabolic reprogramming, cell proliferation, and invasion. Based on these advances in our knowledge, FDFT1 could be a potential target for cancer treatment. This review focuses on the contribution of FDFT1 to the hallmarks of cancer, and further, we discuss the applicability of FDFT1 as a cancer prognostic marker and target for anticancer therapy.
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22
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Xue L, Qi H, Zhang H, Ding L, Huang Q, Zhao D, Wu BJ, Li X. Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy. Front Oncol 2020; 10:1510. [PMID: 32974183 PMCID: PMC7472741 DOI: 10.3389/fonc.2020.01510] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 07/14/2020] [Indexed: 12/14/2022] Open
Abstract
Recently, targeting metabolic reprogramming has emerged as a potential therapeutic approach for fighting cancer. Sterol regulatory element binding protein-2 (SREBP-2), a basic helix-loop-helix leucine zipper transcription factor, mainly regulates genes involved in cholesterol biosynthesis and homeostasis. SREBP-2 binds to the sterol regulatory elements (SREs) in the promoters of its target genes and activates the transcription of mevalonate pathway genes, such as HMG-CoA reductase (HMGCR), mevalonate kinase and other key enzymes. In this review, we first summarized the structure of SREBP-2 and its activation and regulation by multiple signaling pathways. We then found that SREBP-2 and its regulated enzymes, including HMGCR, FPPS, SQS, and DHCR4 from the mevalonate pathway, participate in the progression of various cancers, including prostate, breast, lung, and hepatocellular cancer, as potential targets. Importantly, preclinical and clinical research demonstrated that fatostatin, statins, and N-BPs targeting SREBP-2, HMGCR, and FPPS, respectively, alone or in combination with other drugs, have been used for the treatment of different cancers. This review summarizes new insights into the critical role of the SREBP-2-regulated mevalonate pathway for cancer and its potential for targeted cancer therapy.
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Affiliation(s)
- Linyuan Xue
- Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Hongyu Qi
- Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - He Zhang
- Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Lu Ding
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Qingxia Huang
- Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
- Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - Daqing Zhao
- Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - Boyang Jason Wu
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, United States
| | - Xiangyan Li
- Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
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23
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Lightbody RJ, Taylor JMW, Dempsie Y, Graham A. MicroRNA sequences modulating inflammation and lipid accumulation in macrophage “foam” cells: Implications for atherosclerosis. World J Cardiol 2020; 12:303-333. [PMID: 32843934 PMCID: PMC7415235 DOI: 10.4330/wjc.v12.i7.303] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 06/03/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
Accumulation of macrophage “foam” cells, laden with cholesterol and cholesteryl ester, within the intima of large arteries, is a hallmark of early “fatty streak” lesions which can progress to complex, multicellular atheromatous plaques, involving lipoproteins from the bloodstream and cells of the innate and adaptive immune response. Sterol accumulation triggers induction of genes encoding proteins mediating the atheroprotective cholesterol efflux pathway. Within the arterial intima, however, this mechanism is overwhelmed, leading to distinct changes in macrophage phenotype and inflammatory status. Over the last decade marked gains have been made in understanding of the epigenetic landscape which influence macrophage function, and in particular the importance of small non-coding micro-RNA (miRNA) sequences in this context. This review identifies some of the miRNA sequences which play a key role in regulating “foam” cell formation and atherogenesis, highlighting sequences involved in cholesterol accumulation, those influencing inflammation in sterol-loaded cells, and novel sequences and pathways which may offer new strategies to influence macrophage function within atherosclerotic lesions.
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Affiliation(s)
- Richard James Lightbody
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Janice Marie Walsh Taylor
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Yvonne Dempsie
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Annette Graham
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
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24
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The cholesterol synthesis enzyme lanosterol 14α-demethylase is post-translationally regulated by the E3 ubiquitin ligase MARCH6. Biochem J 2020; 477:541-555. [PMID: 31904814 PMCID: PMC6993871 DOI: 10.1042/bcj20190647] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 12/22/2019] [Accepted: 01/02/2020] [Indexed: 01/07/2023]
Abstract
Cholesterol synthesis is a tightly controlled pathway, with over 20 enzymes involved. Each of these enzymes can be distinctly regulated, helping to fine-tune the production of cholesterol and its functional intermediates. Several enzymes are degraded in response to increased sterol levels, whilst others remain stable. We hypothesised that an enzyme at a key branch point in the pathway, lanosterol 14α-demethylase (LDM) may be post-translationally regulated. Here, we show that the preceding enzyme, lanosterol synthase is stable, whilst LDM is rapidly degraded. Surprisingly, this degradation is not triggered by sterols. However, the E3 ubiquitin ligase membrane-associated ring-CH-type finger 6 (MARCH6), known to control earlier rate-limiting steps in cholesterol synthesis, also control levels of LDM and the terminal cholesterol synthesis enzyme, 24-dehydrocholesterol reductase. Our work highlights MARCH6 as the first example of an E3 ubiquitin ligase that targets multiple steps in a biochemical pathway and indicates new facets in the control of cholesterol synthesis.
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25
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Inflammation Triggers Liver X Receptor-Dependent Lipogenesis. Mol Cell Biol 2020; 40:MCB.00364-19. [PMID: 31658997 DOI: 10.1128/mcb.00364-19] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 10/21/2019] [Indexed: 12/29/2022] Open
Abstract
Immune cell function can be modulated by changes in lipid metabolism. Our studies indicate that cholesterol and fatty acid synthesis increases in macrophages between 12 and 18 h after the activation of Toll-like receptors with proinflammatory stimuli and that the upregulation of lipogenesis may contribute to the resolution of inflammation. The inflammation-dependent increase in lipogenesis requires the induction of the liver X receptors, members of the nuclear receptor superfamily of transcription factors, by type I interferons in response to inflammatory signals. Instead of the well-established role for liver X receptors in stimulating cholesterol efflux, we demonstrate that liver X receptors are necessary for the proper resumption of cholesterol synthesis in response to inflammatory signals. Thus, liver X receptors function as bidirectional regulators of cholesterol homeostasis, driving efflux when cholesterol levels are high and facilitating synthesis in response to inflammatory signals. Liver X receptor activity is also required for the proper shutdown of a subset of type I interferon-stimulated genes as inflammation subsides, placing the receptors in a negative-feedback loop that may contribute to the resolution of the inflammatory response.
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26
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Carpenter KJ, Valfort AC, Steinauer N, Chatterjee A, Abuirqeba S, Majidi S, Sengupta M, Di Paolo RJ, Shornick LP, Zhang J, Flaveny CA. LXR-inverse agonism stimulates immune-mediated tumor destruction by enhancing CD8 T-cell activity in triple negative breast cancer. Sci Rep 2019; 9:19530. [PMID: 31863071 PMCID: PMC6925117 DOI: 10.1038/s41598-019-56038-1] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 12/05/2019] [Indexed: 01/21/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive subtype that is untreatable with hormonal or HER2-targeted therapies and is also typically unresponsive to checkpoint-blockade immunotherapy. Within the tumor microenvironment dysregulated immune cell metabolism has emerged as a key mechanism of tumor immune-evasion. We have discovered that the Liver-X-Receptors (LXRα and LXRβ), nuclear receptors known to regulate lipid metabolism and tumor-immune interaction, are highly activated in TNBC tumor associated myeloid cells. We therefore theorized that inhibiting LXR would induce immune-mediated TNBC-tumor clearance. Here we show that pharmacological inhibition of LXR activity induces tumor destruction primarily through stimulation of CD8+ T-cell cytotoxic activity and mitochondrial metabolism. Our results imply that LXR inverse agonists may be a promising new class of TNBC immunotherapies.
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Affiliation(s)
- Katherine J Carpenter
- The Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA
| | - Aurore-Cecile Valfort
- The Center for Clinical Pharmacology, Saint Louis College of Pharmacy, Saint Louis, MO, 63110, USA
| | - Nick Steinauer
- The Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA
| | - Arindam Chatterjee
- The Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA
| | - Suomia Abuirqeba
- The Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA
| | - Shabnam Majidi
- The Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA
| | - Monideepa Sengupta
- The Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA
| | - Richard J Di Paolo
- The Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA.,The Alvin J. Siteman Cancer Center at Barnes-Jewish and Washington University School of Medicine in Saint Louis, Saint Louis, MO, 63110, USA
| | - Laurie P Shornick
- The Department of Biology, Saint Louis University, Saint Louis, MO, 63103, USA
| | - Jinsong Zhang
- The Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA.,The Alvin J. Siteman Cancer Center at Barnes-Jewish and Washington University School of Medicine in Saint Louis, Saint Louis, MO, 63110, USA
| | - Colin A Flaveny
- The Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA. .,The Alvin J. Siteman Cancer Center at Barnes-Jewish and Washington University School of Medicine in Saint Louis, Saint Louis, MO, 63110, USA.
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27
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Liu Y, Izem L, Morton RE. Identification of a hormone response element that mediates suppression of APOF by LXR and PPARα agonists. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1865:158583. [PMID: 31812787 DOI: 10.1016/j.bbalip.2019.158583] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 11/21/2019] [Accepted: 12/01/2019] [Indexed: 12/18/2022]
Abstract
Apolipoprotein F (ApoF) regulates cholesteryl ester transfer protein activity. We previously observed that hepatic APOF mRNA levels are decreased by high fat, cholesterol-enriched diets. Here we show in human liver C3A cells that APOF mRNA levels are reduced by agonists of LXR and PPARα nuclear receptors. This negative regulation requires co-incubation with the RXR agonist, retinoic acid. Bioinformatic analysis of the ~2 kb sequence upstream of the APOF promoter identified one potential LXR and 4 potential PPARα binding sites clustered between nucleotides -2007 and -1961. ChIP analysis confirmed agonist-dependent binding of LXRα, PPARα, and RXRα to this hormone response element complex (HREc). A luciferase reporter containing the 2 kb 5' APOF sequence was negatively regulated by LXR and PPARα ligands as seen in cells. This regulation was maintained in constructs lacking the ~1700 nucleotides between the HREc and the APOF proximal promoter. Mutations of the HREc that disrupted LXRα and PPARα binding led to the loss of reporter construct inhibition by agonists of these nuclear receptors. siRNA knockdown studies showed that APOF gene regulation by LXRα or PPARα agonists did not require an interaction between these two nuclear receptors. Thus, APOF is subject to negative regulation by agonist-activated LXR or PPARα nuclear receptors binding to a regulatory element ~1900 bases 5' to the APOF promoter. High fat, cholesterol-enriched diets likely reduce APOF gene expression via these receptors interacting at this regulatory site.
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Affiliation(s)
- Yan Liu
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, United States of America
| | - Lahoucine Izem
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, United States of America
| | - Richard E Morton
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, United States of America.
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28
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Griffin S, Healey GD, Sheldon IM. Isoprenoids increase bovine endometrial stromal cell tolerance to the cholesterol-dependent cytolysin from Trueperella pyogenes. Biol Reprod 2019; 99:749-760. [PMID: 29688258 PMCID: PMC6203874 DOI: 10.1093/biolre/ioy099] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 04/23/2018] [Indexed: 12/11/2022] Open
Abstract
Preventing postpartum uterine disease depends on the ability of endometrial cells to tolerate the presence of the bacteria that invade the uterus after parturition. Postpartum uterine disease and endometrial pathology in cattle are most associated with the pathogen Trueperella pyogenes. Trueperella pyogenes secretes a cholesterol-dependent cytolysin, pyolysin, which causes cytolysis by forming pores in the plasma membrane of endometrial stromal cells. The aim of the present study was to identify cell-intrinsic pathways that increase bovine endometrial stromal cell tolerance to pyolysin. Pyolysin caused dose-dependent cytolysis of bovine endometrial stromal cells and leakage of lactate dehydrogenase into supernatants. Cell tolerance to pyolysin was increased by inhibitors that target the mevalonate and cholesterol synthesis pathway, but not the mitogen-activated protein kinase, cell cycle, or metabolic pathways. Cellular cholesterol was reduced and cell tolerance to pyolysin was increased by supplying the mevalonate-derived isoprenoid farnesyl pyrophosphate, or by inhibiting farnesyl-diphosphate farnesyltransferase 1 or geranylgeranyl diphosphate synthase 1 to increase the abundance of farnesyl pyrophosphate. Supplying the mevalonate-derived isoprenoid geranylgeranyl pyrophosphate also increased cell tolerance to pyolysin, but independent of changes in cellular cholesterol. However, geranylgeranyl pyrophosphate inhibits nuclear receptor subfamily 1 group H receptors (NR1H, also known as liver X receptors), and reducing the expression of the genes encoding NR1H3 or NR1H2 increased stromal cell tolerance to pyolysin. In conclusion, mevalonate-derived isoprenoids increased bovine endometrial stromal cell tolerance to pyolysin, which was associated with reducing cellular cholesterol and inhibiting NR1H receptors.
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Affiliation(s)
- Sholeem Griffin
- Swansea University Medical School, Swansea University, Swansea, UK
| | - Gareth D Healey
- Swansea University Medical School, Swansea University, Swansea, UK
| | - I Martin Sheldon
- Swansea University Medical School, Swansea University, Swansea, UK
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29
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Mouzat K, Chudinova A, Polge A, Kantar J, Camu W, Raoul C, Lumbroso S. Regulation of Brain Cholesterol: What Role Do Liver X Receptors Play in Neurodegenerative Diseases? Int J Mol Sci 2019; 20:E3858. [PMID: 31398791 PMCID: PMC6720493 DOI: 10.3390/ijms20163858] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 08/06/2019] [Accepted: 08/06/2019] [Indexed: 12/11/2022] Open
Abstract
Liver X Receptors (LXR) alpha and beta are two members of nuclear receptor superfamily documented as endogenous cholesterol sensors. Following conversion of cholesterol in oxysterol, both LXR isoforms detect intracellular concentrations and act as transcription factors to promote expression of target genes. Among their numerous physiological roles, they act as central cholesterol-lowering factors. In the central nervous system (CNS), cholesterol has been shown to be an essential determinant of brain function, particularly as a major constituent of myelin and membranes. In the brain, LXRs act as cholesterol central regulators, and, beyond this metabolic function, LXRs have additional roles such as providing neuroprotective effects and lowering neuroinflammation. In many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and multiple sclerosis (MS), dysregulations of cholesterol and oxysterol have been reported. In this paper, we propose to focus on recent advances in the knowledge of the LXRs roles on brain cholesterol and oxysterol homeostasis, neuroinflammation, neuroprotection, and their putative involvement in neurodegenerative disorders. We will discuss their potential use as candidates for both molecular diagnosis and as promising pharmacological targets in the treatment of ALS, AD, or MS patients.
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Affiliation(s)
- Kevin Mouzat
- Motoneuron Disease: Pathophysiology and Therapy, The Neuroscience Institute of Montpellier, University of Montpellier, Montpellier, Laboratoire de Biochimie et Biologie Moléculaire, Nimes University Hospital, 30029 Nîmes, France.
| | - Aleksandra Chudinova
- Motoneuron Disease: Pathophysiology and Therapy, The Neuroscience Institute of Montpellier, University of Montpellier, Montpellier, Laboratoire de Biochimie et Biologie Moléculaire, Nimes University Hospital, 30029 Nîmes, France
| | - Anne Polge
- Laboratoire de Biochimie et Biologie Moléculaire, Nimes University Hospital, University of Montpellier, 30029 Nîmes, France
| | - Jovana Kantar
- Motoneuron Disease: Pathophysiology and Therapy, The Neuroscience Institute of Montpellier, University of Montpellier, Montpellier, Laboratoire de Biochimie et Biologie Moléculaire, Nimes University Hospital, 30029 Nîmes, France
| | - William Camu
- ALS Reference Center, Montpellier University Hospital and University of Montpellier, Inserm UMR1051, 34000 Montpellier, France
| | - Cédric Raoul
- The Neuroscience Institute of Montpellier, Inserm UMR1051, University of Montpellier, 34091 Montpellier, France
| | - Serge Lumbroso
- Motoneuron Disease: Pathophysiology and Therapy, The Neuroscience Institute of Montpellier, University of Montpellier, Montpellier, Laboratoire de Biochimie et Biologie Moléculaire, Nimes University Hospital, 30029 Nîmes, France
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30
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Xu DP, Jiang SL, Zhao CS, Fang DA, Hu HY. Comparative transcriptomics analysis of the river pufferfish (Takifugu obscurus) by tributyltin exposure: Clues for revealing its toxic injury mechanism. FISH & SHELLFISH IMMUNOLOGY 2018; 82:536-543. [PMID: 30170111 DOI: 10.1016/j.fsi.2018.08.052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 08/23/2018] [Accepted: 08/24/2018] [Indexed: 06/08/2023]
Abstract
TBT residual in water had become a noticeable ecological problem for aquatic ecosystems. The river pufferfish (Takifugu obscurus) is a kind of an anadromous fish species and widely distributed in the East China Sea and the Yellow Sea. Because of the water contamination, the pufferfish wild resource had a sudden decline in recent years. Therefore, the study on the response of pufferfish to the TBT exposure may contribute to reveal toxic injury mechanism of T. obscurus under TBT exposure. In this study, the transcriptional library of T. obscurus liver and gill was constructed and sequenced by an improved Illumina HiseqX10 high-throughput sequencing platform under different concentrations of TBT acute stress. The blood cell numbers distinctly decreased after TBT exposure, showing the adverse effects of TBT invasion and self-adjusting ability of the pufferfish. The production of reactive oxygen species increased, demonstrating the oxidation resistance of T. obscurus when exposed to TBT. The obtained data were compared with the genome data of Takifugu rubripes and transcriptional resource database. On this basis, gene function annotation, analysis and classification were carried out by bioinformatics method, and differential genes related to toxic injury function were screened out. Meanwhile, new toxic related genes and related signal pathways were sought to provide new theoretical guidance for the pathogenesis of T. obscurus exposed to TBT. This study not only enriched the transcriptome data of T. obscurus under environmental stress, but also provided a new research method for the response mechanism of T. obscurus under the stimulation of environmental factors.
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Affiliation(s)
- Dong-Po Xu
- Key Laboratory of Biotic Environment and Ecological Safety in Anhui Province, College of Life Sciences, Anhui Normal University, Wuhu, Anhui, 241000, China; Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, Jiangsu, 214081, China
| | - Shu-Lun Jiang
- Wuxi Fisheries College, Nanjing Agricultural University, Xuejiali 69, Wuxi, 214128, China
| | - Chang-Sheng Zhao
- Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, Jiangsu, 214081, China
| | - Di-An Fang
- Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, Jiangsu, 214081, China
| | - Hao-Yuan Hu
- Key Laboratory of Biotic Environment and Ecological Safety in Anhui Province, College of Life Sciences, Anhui Normal University, Wuhu, Anhui, 241000, China.
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31
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Saran AR, Kalinowska D, Oh S, Janknecht R, DiTacchio L. JMJD5 links CRY1 function and proteasomal degradation. PLoS Biol 2018; 16:e2006145. [PMID: 30500822 PMCID: PMC6291157 DOI: 10.1371/journal.pbio.2006145] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 12/12/2018] [Accepted: 11/16/2018] [Indexed: 01/02/2023] Open
Abstract
The circadian oscillator is a molecular feedback circuit whose orchestration involves posttranslational control of the activity and protein levels of its components. Although controlled proteolysis of circadian proteins is critical for oscillator function, our understanding of the underlying mechanisms remains incomplete. Here, we report that JmjC domain-containing protein 5 (JMJD5) interacts with CRYPTOCHROME 1 (CRY1) in an F-box/leucine-rich repeat protein 3 (FBXL3)-dependent manner and facilitates targeting of CRY1 to the proteasome. Genetic deletion of JMJD5 results in greater CRY1 stability, reduced CRY1 association with the proteasome, and disruption of circadian gene expression. We also report that in the absence of JMJD5, AMP-regulated protein kinase (AMPK)-induced CRY1 degradation is impaired, establishing JMJD5 as a key player in this mechanism. JMJD5 cooperates with CRY1 to repress circadian locomotor output cycles protein kaput (CLOCK)-brain and muscle ARNT-like protein 1 (BMAL1), thus linking CRY1 destabilization to repressive function. Finally, we find that ablation of JMJD5 impacts FBXL3- and CRY1-related functions beyond the oscillator.
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Affiliation(s)
- Anand R. Saran
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Diana Kalinowska
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Sangphil Oh
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Ralf Janknecht
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Luciano DiTacchio
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States of America
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Beyond the Foam Cell: The Role of LXRs in Preventing Atherogenesis. Int J Mol Sci 2018; 19:ijms19082307. [PMID: 30087224 PMCID: PMC6121590 DOI: 10.3390/ijms19082307] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 08/01/2018] [Accepted: 08/02/2018] [Indexed: 12/24/2022] Open
Abstract
Atherosclerosis is a chronic condition associated with cardiovascular disease. While largely identified by the accumulation of lipid-laden foam cells within the aorta later on in life, atherosclerosis develops over several stages and decades. During atherogenesis, various cell types of the aorta acquire a pro-inflammatory phenotype that initiates the cascade of signaling events facilitating the formation of these foam cells. The liver X receptors (LXRs) are nuclear receptors that upon activation induce the expression of transporters responsible for promoting cholesterol efflux. In addition to promoting cholesterol removal from the arterial wall, LXRs have potent anti-inflammatory actions via the transcriptional repression of key pro-inflammatory cytokines. These beneficial functions sparked an interest in the potential to target LXRs and the development of agonists as anti-atherogenic agents. These early studies focused on mediating the contributions of macrophages to the underlying pathogenesis. However, further evidence has since demonstrated that LXRs reduce atherosclerosis through their actions in multiple cell types apart from those monocytes/macrophages that infiltrate the lesion. LXRs and their target genes have profound effects on multiple other cells types of the hematopoietic system. Furthermore, LXRs can also mediate dysfunction within vascular cell types of the aorta including endothelial and smooth muscle cells. Taken together, these studies demonstrate the whole-body benefits of LXR activation with respect to anti-atherogenesis, and that LXRs remain a viable target for the treatment of atherosclerosis, with a reach which extends beyond plaque macrophages.
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Analysis of diet-induced differential methylation, expression, and interactions of lncRNA and protein-coding genes in mouse liver. Sci Rep 2018; 8:11537. [PMID: 30069000 PMCID: PMC6070528 DOI: 10.1038/s41598-018-29993-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 06/29/2018] [Indexed: 12/11/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) regulate expression of protein-coding genes in cis through chromatin modifications including DNA methylation. Here we interrogated whether lncRNA genes may regulate transcription and methylation of their flanking or overlapping protein-coding genes in livers of mice exposed to a 12-week cholesterol-rich Western-style high fat diet (HFD) relative to a standard diet (STD). Deconvolution analysis of cell type-specific marker gene expression suggested similar hepatic cell type composition in HFD and STD livers. RNA-seq and validation by nCounter technology revealed differential expression of 14 lncRNA genes and 395 protein-coding genes enriched for functions in steroid/cholesterol synthesis, fatty acid metabolism, lipid localization, and circadian rhythm. While lncRNA and protein-coding genes were co-expressed in 53 lncRNA/protein-coding gene pairs, both were differentially expressed only in 4 lncRNA/protein-coding gene pairs, none of which included protein-coding genes in overrepresented pathways. Furthermore, 5-methylcytosine DNA immunoprecipitation sequencing and targeted bisulfite sequencing revealed no differential DNA methylation of genes in overrepresented pathways. These results suggest lncRNA/protein-coding gene interactions in cis play a minor role mediating hepatic expression of lipid metabolism/localization and circadian clock genes in response to chronic HFD feeding.
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Finno CJ, Bordbari MH, Gianino G, Ming-Whitfield B, Burns E, Merkel J, Britton M, Durbin-Johnson B, Sloma EA, McMackin M, Cortopassi G, Rivas V, Barro M, Tran CK, Gennity I, Habib H, Xu L, Puschner B, Miller AD. An innate immune response and altered nuclear receptor activation defines the spinal cord transcriptome during alpha-tocopherol deficiency in Ttpa-null mice. Free Radic Biol Med 2018; 120. [PMID: 29526809 PMCID: PMC5940542 DOI: 10.1016/j.freeradbiomed.2018.02.037] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Mice with deficiency in tocopherol (alpha) transfer protein gene develop peripheral tocopherol deficiency and sensory neurodegeneration. Ttpa-/- mice maintained on diets with deficient α-tocopherol (α-TOH) had proprioceptive deficits by six months of age, axonal degeneration and neuronal chromatolysis within the dorsal column of the spinal cord and its projections into the medulla. Transmission electron microscopy revealed degeneration of dorsal column axons. We addressed the potential pathomechanism of α-TOH deficient neurodegeneration by global transcriptome sequencing within the spinal cord and cerebellum. RNA-sequencing of the spinal cord in Ttpa-/- mice revealed upregulation of genes associated with the innate immune response, indicating a molecular signature of microglial activation as a result of tocopherol deficiency. For the first time, low level Ttpa expression was identified in the murine spinal cord. Further, the transcription factor liver X receptor (LXR) was strongly activated by α-TOH deficiency, triggering dysregulation of cholesterol biosynthesis. The aberrant activation of transcription factor LXR suppressed the normal induction of the transcription factor retinoic-related orphan receptor-α (RORA), which is required for neural homeostasis. Thus we find that α-TOH deficiency induces LXR, which may lead to a molecular signature of microglial activation and contribute to sensory neurodegeneration.
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Affiliation(s)
- Carrie J Finno
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, United States.
| | - Matthew H Bordbari
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, United States
| | - Giuliana Gianino
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, United States
| | - Brittni Ming-Whitfield
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, United States
| | - Erin Burns
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, United States
| | - Janel Merkel
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, United States
| | - Monica Britton
- Bioinformatics Core Facility, Genome Center, University of California, Davis, CA 95616, United States
| | - Blythe Durbin-Johnson
- Bioinformatics Core Facility, Genome Center, University of California, Davis, CA 95616, United States
| | - Erica A Sloma
- Department of Biomedical Sciences, Section of Anatomic Pathology, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, United States
| | - Marissa McMackin
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, United States
| | - Gino Cortopassi
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, United States
| | - Victor Rivas
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, United States
| | - Marietta Barro
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, United States
| | - Cecilia K Tran
- Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States
| | - Ingrid Gennity
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, United States
| | - Hadi Habib
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, United States
| | - Libin Xu
- Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States
| | - Birgit Puschner
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, United States
| | - Andrew D Miller
- Department of Biomedical Sciences, Section of Anatomic Pathology, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, United States
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Sèdes L, Thirouard L, Maqdasy S, Garcia M, Caira F, Lobaccaro JMA, Beaudoin C, Volle DH. Cholesterol: A Gatekeeper of Male Fertility? Front Endocrinol (Lausanne) 2018; 9:369. [PMID: 30072948 PMCID: PMC6060264 DOI: 10.3389/fendo.2018.00369] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 06/19/2018] [Indexed: 12/14/2022] Open
Abstract
Cholesterol is essential for mammalian cell functions and integrity. It is an important structural component maintaining the permeability and fluidity of the cell membrane. The balance between synthesis and catabolism of cholesterol should be tightly regulated to ensure normal cellular processes. Male reproductive function has been demonstrated to be dependent on cholesterol homeostasis. Here we review data highlighting the impacts of cholesterol homeostasis on male fertility and the molecular mechanisms implicated through the signaling pathways of some nuclear receptors.
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Systems Pharmacology Dissection of Cholesterol Regulation Reveals Determinants of Large Pharmacodynamic Variability between Cell Lines. Cell Syst 2017; 5:604-619.e7. [PMID: 29226804 PMCID: PMC5747350 DOI: 10.1016/j.cels.2017.11.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Revised: 08/17/2017] [Accepted: 11/02/2017] [Indexed: 01/06/2023]
Abstract
In individuals, heterogeneous drug-response phenotypes result from a complex interplay of dose, drug specificity, genetic background, and environmental factors, thus challenging our understanding of the underlying processes and optimal use of drugs in the clinical setting. Here, we use mass-spectrometry-based quantification of molecular response phenotypes and logic modeling to explain drug-response differences in a panel of cell lines. We apply this approach to cellular cholesterol regulation, a biological process with high clinical relevance. From the quantified molecular phenotypes elicited by various targeted pharmacologic or genetic treatments, we generated cell-line-specific models that quantified the processes beneath the idiotypic intracellular drug responses. The models revealed that, in addition to drug uptake and metabolism, further cellular processes displayed significant pharmacodynamic response variability between the cell lines, resulting in cell-line-specific drug-response phenotypes. This study demonstrates the importance of integrating different types of quantitative systems-level molecular measurements with modeling to understand the effect of pharmacological perturbations on complex biological processes.
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Alford SH, Divine G, Chao C, Habel LA, Janakiraman N, Wang Y, Feigelson HS, Scholes D, Roblin D, Epstein MM, Engel L, Havstad S, Wells K, Yood MU, Fortuny J, Johnson CC. Serum cholesterol trajectories in the 10 years prior to lymphoma diagnosis. Cancer Causes Control 2017; 29:143-156. [PMID: 29192350 DOI: 10.1007/s10552-017-0987-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 11/21/2017] [Indexed: 12/13/2022]
Abstract
PURPOSE Many studies suggest a role for cholesterol in cancer development. Serum cholesterol levels have been observed to be low in newly diagnosed lymphoma cases. The objective of these analyses was to examine the time-varying relationship of cholesterol with lymphomagenesis in the 10 years prior to diagnosis by lymphoma subtype. METHODS Participants were selected from the combined membership of six National Cancer Institute-funded Cancer Research Network health plans from 1998 to 2008, excluding members with human immunodeficiency virus, cancer (except lymphoma), or organ transplants. Incident lymphoma cases within this population were ascertained and matched with up to five controls. Total serum cholesterol, high-density lipoprotein, and low-density lipoprotein were collected from plan databases. Multilevel, multivariable longitudinal models were fit after choosing the best polynomial order by deviance statistics for selected lymphoma histotypes to examine pre-diagnosis cholesterol trajectories: Hodgkin lymphoma (n = 519) and all non-Hodgkin lymphomas combined (n = 12,635) as well as six subtypes of the latter. RESULTS For all categories, lymphoma cases had statistically significantly lower estimated total serum cholesterol, high-density lipoprotein, and low-density lipoprotein levels than controls in the years prior to diagnosis/index date. Between-group differences were most pronounced 3-4 years prior to diagnosis, when cases' cholesterol levels declined steeply. CONCLUSIONS This analysis is the first to examine changes in serum cholesterol for a decade prior to lymphoma diagnosis. A drop in cholesterol levels was evident several years before diagnosis. Our results suggest that cholesterol-related pathways have an important relationship with lymphomagenesis and low cholesterol could be a preclinical lymphoma marker.
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Affiliation(s)
- Sharon Hensley Alford
- Department of Public Health Sciences, Henry Ford Health System, One Ford Place, 3E, Detroit, MI, 48202, USA
| | - George Divine
- Department of Public Health Sciences, Henry Ford Health System, One Ford Place, 3E, Detroit, MI, 48202, USA
| | - Chun Chao
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA
| | - Laurel A Habel
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | | | - Yun Wang
- Department of Public Health Sciences, Henry Ford Health System, One Ford Place, 3E, Detroit, MI, 48202, USA
| | | | - Delia Scholes
- Kaiser Permanente Washington, KPWA Health Research Institute, Seattle, WA, USA
| | - Doug Roblin
- School of Public Health, Georgia State University, Atlanta, GA, USA
| | - Mara M Epstein
- Department of Medicine, The Meyers Primary Care Institute, University of Massachusetts Medical School, Worcester, MA, USA
| | - Lawrence Engel
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Suzanne Havstad
- Department of Public Health Sciences, Henry Ford Health System, One Ford Place, 3E, Detroit, MI, 48202, USA
| | - Karen Wells
- Department of Public Health Sciences, Henry Ford Health System, One Ford Place, 3E, Detroit, MI, 48202, USA
| | | | | | - Christine Cole Johnson
- Department of Public Health Sciences, Henry Ford Health System, One Ford Place, 3E, Detroit, MI, 48202, USA.
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Fessler MB. The challenges and promise of targeting the Liver X Receptors for treatment of inflammatory disease. Pharmacol Ther 2017; 181:1-12. [PMID: 28720427 DOI: 10.1016/j.pharmthera.2017.07.010] [Citation(s) in RCA: 116] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The Liver X Receptors (LXRs) are oxysterol-activated transcription factors that upregulate a suite of genes that together promote coordinated mobilization of excess cholesterol from cells and from the body. The LXRs, like other nuclear receptors, are anti-inflammatory, inhibiting signal-dependent induction of pro-inflammatory genes by nuclear factor-κB, activating protein-1, and other transcription factors. Synthetic LXR agonists have been shown to ameliorate atherosclerosis and a wide range of inflammatory disorders in preclinical animal models. Although this has suggested potential for application to human disease, systemic LXR activation is complicated by hepatic steatosis and hypertriglyceridemia, consequences of lipogenic gene induction in the liver by LXRα. The past several years have seen the development of multiple advanced LXR therapeutics aiming to avoid hepatic lipogenesis, including LXRβ-selective agonists, tissue-selective agonists, and transrepression-selective agonists. Although several synthetic LXR agonists have made it to phase I clinical trials, none have progressed due to unforeseen adverse reactions or undisclosed reasons. Nonetheless, several sophisticated pharmacologic strategies, including structure-guided drug design, cell-specific drug targeting, as well as non-systemic drug routes have been initiated and remain to be comprehensively explored. In addition, recent studies have identified potential utility for targeting the LXRs during therapy with other agents, such as glucocorticoids and rexinoids. Despite the pitfalls encountered to date in translation of LXR agonists to human disease, it appears likely that this accelerating field will ultimately yield effective and safe applications for LXR targeting in humans.
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Affiliation(s)
- Michael B Fessler
- National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, P.O. Box 12233, MD D2-01, Research Triangle Park, NC 27709, United States.
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Cedó L, Santos D, Ludwig IA, Silvennoinen R, García-León A, Kaipiainen L, Carbó JM, Valledor AF, Gylling H, Motilva MJ, Kovanen PT, Lee-Rueckert M, Blanco-Vaca F, Escolà-Gil JC. Phytosterol-mediated inhibition of intestinal cholesterol absorption in mice is independent of liver X receptor. Mol Nutr Food Res 2017; 61. [DOI: 10.1002/mnfr.201700055] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 02/24/2017] [Accepted: 02/27/2017] [Indexed: 01/22/2023]
Affiliation(s)
- Lídia Cedó
- Institut d'Investigacions Biomèdiques (IIB) Sant Pau; Barcelona Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas; CIBERDEM, Hospitalet de Llobregat Spain
| | - David Santos
- Institut d'Investigacions Biomèdiques (IIB) Sant Pau; Barcelona Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas; CIBERDEM, Hospitalet de Llobregat Spain
| | - Iziar A. Ludwig
- Food Technology Department, UTPV-XaRTA, Agrotecnio Center; University of Lleida; Lleida Spain
| | | | - Annabel García-León
- Institut d'Investigacions Biomèdiques (IIB) Sant Pau; Barcelona Spain
- Departament de Bioquímica, Biología Molecular i Biomedicina; Universitat Autònoma de Barcelona; Barcelona Spain
| | - Leena Kaipiainen
- University of Helsinki and Helsinki University Central Hospital; Department of Internal Medicine; Helsinki Finland
| | - José M. Carbó
- Department of Cellular Biology, Physiology and Immunology; School of Biology, University of Barcelona; Barcelona Spain
| | - Annabel F. Valledor
- Department of Cellular Biology, Physiology and Immunology; School of Biology, University of Barcelona; Barcelona Spain
| | - Helena Gylling
- University of Helsinki and Helsinki University Central Hospital; Department of Internal Medicine; Helsinki Finland
| | - Maria-José Motilva
- Food Technology Department, UTPV-XaRTA, Agrotecnio Center; University of Lleida; Lleida Spain
| | | | | | - Francisco Blanco-Vaca
- Institut d'Investigacions Biomèdiques (IIB) Sant Pau; Barcelona Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas; CIBERDEM, Hospitalet de Llobregat Spain
- Departament de Bioquímica, Biología Molecular i Biomedicina; Universitat Autònoma de Barcelona; Barcelona Spain
| | - Joan Carles Escolà-Gil
- Institut d'Investigacions Biomèdiques (IIB) Sant Pau; Barcelona Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas; CIBERDEM, Hospitalet de Llobregat Spain
- Departament de Bioquímica, Biología Molecular i Biomedicina; Universitat Autònoma de Barcelona; Barcelona Spain
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Xu EG, Mager EM, Grosell M, Hazard ES, Hardiman G, Schlenk D. Novel transcriptome assembly and comparative toxicity pathway analysis in mahi-mahi (Coryphaena hippurus) embryos and larvae exposed to Deepwater Horizon oil. Sci Rep 2017; 7:44546. [PMID: 28295044 PMCID: PMC5353654 DOI: 10.1038/srep44546] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 02/10/2017] [Indexed: 12/13/2022] Open
Abstract
The impacts of Deepwater Horizon (DWH) oil on morphology and function during embryonic development have been documented for a number of fish species, including the economically and ecologically important pelagic species, mahi-mahi (Coryphaena hippurus). However, further investigations on molecular events and pathways responsible for developmental toxicity have been largely restricted due to the limited molecular data available for this species. We sought to establish the de novo transcriptomic database from the embryos and larvae of mahi-mahi exposed to water accommodated fractions (HEWAFs) of two DWH oil types (weathered and source oil), in an effort to advance our understanding of the molecular aspects involved during specific toxicity responses. By high throughput sequencing (HTS), we obtained the first de novo transcriptome of mahi-mahi, with 60,842 assembled transcripts and 30,518 BLAST hits. Among them, 2,345 genes were significantly regulated in 96hpf larvae after exposure to weathered oil. With comparative analysis to a reference-transcriptome-guided approach on gene ontology and tox-pathways, we confirmed the novel approach effective for exploring tox-pathways in non-model species, and also identified a list of co-expressed genes as potential biomarkers which will provide information for the construction of an Adverse Outcome Pathway which could be useful in Ecological Risk Assessments.
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Affiliation(s)
- Elvis Genbo Xu
- Department of Environmental Sciences, University of California, Riverside, CA 92521, USA
| | - Edward M Mager
- Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA
| | - Martin Grosell
- Department of Marine Biology and Ecology, University of Miami, Miami, FL 33149, USA
| | - E Starr Hazard
- Center for Genomic Medicine, Medical University of South Carolina, Charleston, SC 29403, USA.,Computational Biology Resource Center, Medical University of South Carolina, Charleston, SC 29403, USA
| | - Gary Hardiman
- Center for Genomic Medicine, Medical University of South Carolina, Charleston, SC 29403, USA.,Departments of Medicine &Public Health Sciences, Medical University of South Carolina, Charleston, SC 29403, USA.,Laboratory for Marine Systems Biology, Hollings Marine Laboratory, Charleston, SC 29412, USA
| | - Daniel Schlenk
- Department of Environmental Sciences, University of California, Riverside, CA 92521, USA
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Lee KS, Kwon YS, Kim S, Moon DS, Kim HJ, Nam KS. Regulatory mechanism of mineral-balanced deep sea water on hypocholesterolemic effects in HepG2 hepatic cells. Biomed Pharmacother 2017; 86:405-413. [DOI: 10.1016/j.biopha.2016.12.046] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 12/01/2016] [Accepted: 12/08/2016] [Indexed: 10/20/2022] Open
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González-Calvo L, Dervishi E, Joy M, Sarto P, Martin-Hernandez R, Serrano M, Ordovás JM, Calvo JH. Genome-wide expression profiling in muscle and subcutaneous fat of lambs in response to the intake of concentrate supplemented with vitamin E. BMC Genomics 2017; 18:92. [PMID: 28095783 PMCID: PMC5240399 DOI: 10.1186/s12864-016-3405-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 12/09/2016] [Indexed: 01/20/2023] Open
Abstract
Background The objective of this study was to acquire a broader, more comprehensive picture of the transcriptional changes in the L. Thoracis muscle (LT) and subcutaneous fat (SF) of lambs supplemented with vitamin E. Furthermore, we aimed to identify novel genes involved in the metabolism of vitamin E that might also be involved in meat quality. In the first treatment, seven lambs were fed a basal concentrate from weaning to slaughter (CON). In the second treatment, seven lambs received basal concentrate from weaning to 4.71 ± 2.62 days and thereafter concentrate supplemented with 500 mg dl-α-tocopheryl acetate/kg (VE) during the last 33.28 ± 1.07 days before slaughter. Results The addition of vitamin E to the diet increased the α-tocopherol muscle content and drastically diminished the lipid oxidation of meat. Gene expression profiles for treatments VE and CON were clearly separated from each other in the LT and SF. Vitamin E supplementation had a dramatic effect on subcutaneous fat gene expression, showing general up-regulation of significant genes, compared to CON treatment. In LT, vitamin E supplementation caused down-regulation of genes related to intracellular signaling cascade. Functional analysis of SF showed that vitamin E supplementation caused up-regulation of the lipid biosynthesis process, cholesterol, and sterol and steroid biosynthesis, and it down-regulated genes related to the stress response. Conclusions Different gene expression patterns were found between the SF and LT, suggesting tissue specific responses to vitamin E supplementation. Our study enabled us to identify novel genes and metabolic pathways related to vitamin E metabolism that might be implicated in meat quality. Further exploration of these genes and vitamin E could lead to a better understanding of how vitamin E affects the oxidative process that occurs in manufactured meat products. Electronic supplementary material The online version of this article (doi:10.1186/s12864-016-3405-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | - Elda Dervishi
- University of Alberta, 116 St and 85 Ave, Edmonton, AB, T6G 2R3, Canada
| | - Margalida Joy
- Unidad de Tecnología en Producción Animal, CITA, 59059, Zaragoza, Spain
| | - Pilar Sarto
- Unidad de Tecnología en Producción Animal, CITA, 59059, Zaragoza, Spain
| | | | | | - Jose M Ordovás
- Jean Mayer-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
| | - Jorge H Calvo
- Unidad de Tecnología en Producción Animal, CITA, 59059, Zaragoza, Spain. .,ARAID, 50004, Zaragoza, Spain.
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Finno CJ, Bordbari MH, Valberg SJ, Lee D, Herron J, Hines K, Monsour T, Scott E, Bannasch DL, Mickelson J, Xu L. Transcriptome profiling of equine vitamin E deficient neuroaxonal dystrophy identifies upregulation of liver X receptor target genes. Free Radic Biol Med 2016; 101:261-271. [PMID: 27751910 PMCID: PMC5154892 DOI: 10.1016/j.freeradbiomed.2016.10.009] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Revised: 10/11/2016] [Accepted: 10/13/2016] [Indexed: 12/31/2022]
Abstract
Specific spontaneous heritable neurodegenerative diseases have been associated with lower serum and cerebrospinal fluid α-tocopherol (α-TOH) concentrations. Equine neuroaxonal dystrophy (eNAD) has similar histologic lesions to human ataxia with vitamin E deficiency caused by mutations in the α-TOH transfer protein gene (TTPA). Mutations in TTPA are not present with eNAD and the molecular basis remains unknown. Given the neuropathologic phenotypic similarity of the conditions, we assessed the molecular basis of eNAD by global transcriptome sequencing of the cervical spinal cord. Differential gene expression analysis identified 157 significantly (FDR<0.05) dysregulated transcripts within the spinal cord of eNAD-affected horses. Statistical enrichment analysis identified significant downregulation of the ionotropic and metabotropic group III glutamate receptor, synaptic vesicle trafficking and cholesterol biosynthesis pathways. Gene co-expression analysis identified one module of upregulated genes significantly associated with the eNAD phenotype that included the liver X receptor (LXR) targets CYP7A1, APOE, PLTP and ABCA1. Validation of CYP7A1 and APOE dysregulation was performed in an independent biologic group and CYP7A1 was found to be additionally upregulated in the medulla oblongata of eNAD horses. Evidence of LXR activation supports a role for modulation of oxysterol-dependent LXR transcription factor activity by tocopherols. We hypothesize that the protective role of α-TOH in eNAD may reside in its ability to prevent oxysterol accumulation and subsequent activation of the LXR in order to decrease lipid peroxidation associated neurodegeneration.
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Affiliation(s)
- Carrie J Finno
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States.
| | - Matthew H Bordbari
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States
| | - Stephanie J Valberg
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, United States
| | - David Lee
- Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States
| | - Josi Herron
- Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States
| | - Kelly Hines
- Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States
| | - Tamer Monsour
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States
| | - Erica Scott
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States
| | - Danika L Bannasch
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, United States
| | - James Mickelson
- Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, United States
| | - Libin Xu
- Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States
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44
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Kuzu OF, Noory MA, Robertson GP. The Role of Cholesterol in Cancer. Cancer Res 2016; 76:2063-70. [PMID: 27197250 DOI: 10.1158/0008-5472.can-15-2613] [Citation(s) in RCA: 493] [Impact Index Per Article: 54.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 02/08/2016] [Indexed: 12/19/2022]
Abstract
The roles played by cholesterol in cancer development and the potential of therapeutically targeting cholesterol homeostasis is a controversial area in the cancer community. Several epidemiologic studies report an association between cancer and serum cholesterol levels or statin use, while others suggest that there is not one. Furthermore, the Cancer Genome Atlas (TCGA) project using next-generation sequencing has profiled the mutational status and expression levels of all the genes in diverse cancers, including those involved in cholesterol metabolism, providing correlative support for a role of the cholesterol pathway in cancer development. Finally, preclinical studies tend to more consistently support the role of cholesterol in cancer, with several demonstrating that cholesterol homeostasis genes can modulate development. Because of space limitations, this review provides selected examples of the epidemiologic, TCGA, and preclinical data, focusing on alterations in cholesterol homeostasis and its consequent effect on patient survival. In melanoma, this focused analysis demonstrated that enhanced expression of cholesterol synthesis genes was associated with decreased patient survival. Collectively, the studies in melanoma and other cancer types suggested a potential role of disrupted cholesterol homeostasis in cancer development but additional studies are needed to link population-based epidemiological data, the TCGA database results, and preclinical mechanistic evidence to concretely resolve this controversy. Cancer Res; 76(8); 2063-70. ©2016 AACR.
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Affiliation(s)
- Omer F Kuzu
- Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania
| | - Mohammad A Noory
- Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania
| | - Gavin P Robertson
- Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. Department of Pathology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. Department of Surgery, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. Penn State Hershey Melanoma Center, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. Penn State Melanoma Therapeutics Program, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. The Foreman Foundation for Melanoma Research, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
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45
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Graham A. Mitochondrial regulation of macrophage cholesterol homeostasis. Free Radic Biol Med 2015; 89:982-92. [PMID: 26416507 DOI: 10.1016/j.freeradbiomed.2015.08.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 07/28/2015] [Accepted: 08/11/2015] [Indexed: 12/19/2022]
Abstract
This review explores the relationship between mitochondrial structure and function in the regulation of macrophage cholesterol metabolism and proposes that mitochondrial dysfunction contributes to loss of the elegant homeostatic mechanisms which normally maintain cellular sterol levels within defined limits. Mitochondrial sterol 27-hydroxylase (CYP27A1) can generate oxysterol activators of liver X receptors which heterodimerise with retinoid X receptors, enhancing the transcription of ATP binding cassette transporters (ABCA1, ABCG1, and ABCG4), that can remove excess cholesterol via efflux to apolipoproteins A-1, E, and high density lipoprotein, and inhibit inflammation. The activity of CYP27A1 is regulated by the rate of supply of cholesterol substrate to the inner mitochondrial membrane, mediated by a complex of proteins. The precise identity of this dynamic complex remains controversial, even in steroidogenic tissues, but may include steroidogenic acute regulatory protein and the 18 kDa translocator protein, together with voltage-dependent anion channels, ATPase AAA domain containing protein 3A, and optic atrophy type 1 proteins. Certainly, overexpression of StAR and TSPO proteins can enhance macrophage cholesterol efflux to apoA-I and/or HDL, while perturbations in mitochondrial function, or changes in the expression of mitochondrial fusion proteins, alter the efficiency of cholesterol efflux. Molecules which can sustain or improve mitochondrial function or increase the activity of the protein complex involved in cholesterol transfer may have utility in resolving the problem of dysregulated macrophage cholesterol homeostasis, a condition which may contribute to inflammation, atherosclerosis, nonalcoholic steatohepatitis, osteoblastic bone resorption, and some disorders of the central nervous system.
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Affiliation(s)
- Annette Graham
- Department of Life Sciences, School of Health and Life Sciences, and Institute for Applied Health Research, Glasgow Caledonian University, 70 Cowcaddens Road, Glasgow G4 0BA, United Kingdom.
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46
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Kuder CH, Weivoda MM, Zhang Y, Zhu J, Neighbors JD, Wiemer DF, Hohl RJ. 3-Deoxyschweinfurthin B Lowers Cholesterol Levels by Decreasing Synthesis and Increasing Export in Cultured Cancer Cell Lines. Lipids 2015; 50:1195-207. [PMID: 26494560 DOI: 10.1007/s11745-015-4083-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 10/02/2015] [Indexed: 01/12/2023]
Abstract
The schweinfurthins have potent antiproliferative activity in multiple glioblastoma multiforme (GBM) cell lines; however, the mechanism by which growth is impeded is not fully understood. Previously, we demonstrated that the schweinfurthins reduce the level of key isoprenoid intermediates in the cholesterol biosynthetic pathway. Herein, we describe the effects of the schweinfurthins on cholesterol homeostasis. Intracellular cholesterol levels are greatly reduced in cells incubated with 3-deoxyschweinfurthin B (3dSB), an analog of the natural product schweinfurthin B. Decreased cholesterol levels are due to decreased cholesterol synthesis and increased cholesterol efflux; both of these cellular actions can be influenced by liver X-receptor (LXR) activation. The effects of 3dSB on ATP-binding cassette transporter 1 levels and other LXR targets are similar to that of 25-hydroxycholesterol, an LXR agonist. Unlike 25-hydroxycholesterol, 3dSB does not act as a direct agonist for LXR α or β. These data suggest that cholesterol homeostasis plays a significant role in the growth inhibitory activity of the schweinfurthins and may elucidate a mechanism that can be targeted in human cancers such as GBM.
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Affiliation(s)
- Craig H Kuder
- Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA
| | - Megan M Weivoda
- Department of Pharmacology, University of Iowa, Iowa City, IA, 52242, USA.,Department of Endocrinology, Mayo Clinic, Rochester, MN, USA
| | - Ying Zhang
- Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Junjia Zhu
- Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Jeffrey D Neighbors
- Department of Chemistry, University of Iowa, Iowa City, IA, 52242, USA.,Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - David F Wiemer
- Department of Pharmacology, University of Iowa, Iowa City, IA, 52242, USA.,Department of Chemistry, University of Iowa, Iowa City, IA, 52242, USA
| | - Raymond J Hohl
- Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA. .,Department of Pharmacology, University of Iowa, Iowa City, IA, 52242, USA. .,, Mail Code CH72, 500 University Drive, Hershey, PA, 17033-0850, USA. .,Departments of Medicine and Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA.
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47
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Flaveny CA, Griffett K, El-Gendy BEDM, Kazantzis M, Sengupta M, Amelio AL, Chatterjee A, Walker J, Solt LA, Kamenecka TM, Burris TP. Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis. Cancer Cell 2015; 28:42-56. [PMID: 26120082 PMCID: PMC4965273 DOI: 10.1016/j.ccell.2015.05.007] [Citation(s) in RCA: 157] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 03/27/2015] [Accepted: 05/12/2015] [Indexed: 02/07/2023]
Abstract
Malignant cells exhibit aerobic glycolysis (the Warburg effect) and become dependent on de novo lipogenesis, which sustains rapid proliferation and resistance to cellular stress. The nuclear receptor liver-X-receptor (LXR) directly regulates expression of key glycolytic and lipogenic genes. To disrupt these oncogenic metabolism pathways, we designed an LXR inverse agonist SR9243 that induces LXR-corepressor interaction. In cancer cells, SR9243 significantly inhibited the Warburg effect and lipogenesis by reducing glycolytic and lipogenic gene expression. SR9243 induced apoptosis in tumors without inducing weight loss, hepatotoxicity, or inflammation. Our results suggest that LXR inverse agonists may be an effective cancer treatment approach.
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Affiliation(s)
- Colin A Flaveny
- Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
| | - Kristine Griffett
- Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA
| | | | - Melissa Kazantzis
- Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Monideepa Sengupta
- Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA
| | - Antonio L Amelio
- Lineberger Comprehensive Cancer Center, Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA
| | - Arindam Chatterjee
- Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA
| | - John Walker
- Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA
| | - Laura A Solt
- Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Theodore M Kamenecka
- Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA
| | - Thomas P Burris
- Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63310, USA.
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48
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Graham A, Allen AM. Mitochondrial function and regulation of macrophage sterol metabolism and inflammatory responses. World J Cardiol 2015; 7:277-286. [PMID: 26015858 PMCID: PMC4438467 DOI: 10.4330/wjc.v7.i5.277] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Revised: 02/25/2015] [Accepted: 03/18/2015] [Indexed: 02/06/2023] Open
Abstract
The aim of this review is to explore the role of mitochondria in regulating macrophage sterol homeostasis and inflammatory responses within the aetiology of atherosclerosis. Macrophage generation of oxysterol activators of liver X receptors (LXRs), via sterol 27-hydroxylase, is regulated by the rate of flux of cholesterol to the inner mitochondrial membrane, via a complex of cholesterol trafficking proteins. Oxysterols are key signalling molecules, regulating the transcriptional activity of LXRs which coordinate macrophage sterol metabolism and cytokine production, key features influencing the impact of these cells within atherosclerotic lesions. The precise identity of the complex of proteins mediating mitochondrial cholesterol trafficking in macrophages remains a matter of debate, but may include steroidogenic acute regulatory protein and translocator protein. There is clear evidence that targeting either of these proteins enhances removal of cholesterol via LXRα-dependent induction of ATP binding cassette transporters (ABCA1, ABCG1) and limits the production of inflammatory cytokines; interventions which influence mitochondrial structure and bioenergetics also impact on removal of cholesterol from macrophages. Thus, molecules which can sustain or improve mitochondrial structure, the function of the electron transport chain, or increase the activity of components of the protein complex involved in cholesterol transfer, may therefore have utility in limiting or regressing atheroma development, reducing the incidence of coronary heart disease and myocardial infarction.
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49
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Lorbek G, Perše M, Jeruc J, Juvan P, Gutierrez-Mariscal FM, Lewinska M, Gebhardt R, Keber R, Horvat S, Björkhem I, Rozman D. Lessons from hepatocyte-specific Cyp51 knockout mice: impaired cholesterol synthesis leads to oval cell-driven liver injury. Sci Rep 2015; 5:8777. [PMID: 25739789 PMCID: PMC4350092 DOI: 10.1038/srep08777] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 02/02/2015] [Indexed: 12/22/2022] Open
Abstract
We demonstrate unequivocally that defective cholesterol synthesis is an independent determinant of liver inflammation and fibrosis. We prepared a mouse hepatocyte-specific knockout (LKO) of lanosterol 14α-demethylase (CYP51) from the part of cholesterol synthesis that is already committed to cholesterol. LKO mice developed hepatomegaly with oval cell proliferation, fibrosis and inflammation, but without steatosis. The key trigger was reduced cholesterol esters that provoked cell cycle arrest, senescence-associated secretory phenotype and ultimately the oval cell response, while elevated CYP51 substrates promoted the integrated stress response. In spite of the oval cell-driven fibrosis being histologically similar in both sexes, data indicates a female-biased down-regulation of primary metabolism pathways and a stronger immune response in males. Liver injury was ameliorated by dietary fats predominantly in females, whereas dietary cholesterol rectified fibrosis in both sexes. Our data place defective cholesterol synthesis as a focus of sex-dependent liver pathologies.
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Affiliation(s)
- Gregor Lorbek
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Martina Perše
- Medical Experimental Centre, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Jera Jeruc
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Peter Juvan
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Francisco M. Gutierrez-Mariscal
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Monika Lewinska
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Rolf Gebhardt
- Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | - Rok Keber
- Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Simon Horvat
- Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
- National Institute of Chemistry, Ljubljana, Slovenia
| | - Ingemar Björkhem
- Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institute, Karolinska University Hospital, Huddinge, Sweden
| | - Damjana Rozman
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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50
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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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