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Gu Y, Bi X, Liu X, Qian Q, Wen Y, Hua S, Fu Q, Zheng Y, Sun S. Roles of ABCA1 in Chronic Obstructive Pulmonary Disease. COPD 2025; 22:2493701. [PMID: 40302380 DOI: 10.1080/15412555.2025.2493701] [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: 02/06/2025] [Revised: 04/03/2025] [Accepted: 04/10/2025] [Indexed: 05/02/2025]
Abstract
Chronic obstructive pulmonary disease (COPD) is one of the common chronic respiratory diseases, which causes a heavy burden to patients and society. Increasing studies suggest that ABCA1 plays an important role in COPD. ABCA1 belongs to a large class of ATP-binding (ABC) transporters. It is not only involved in the reverse transport of cholesterol, but also in the regulation of apoptosis, pyroptosis, cellular inflammation and cellular immunity. Meanwhile, ABCA1 is involved in several signaling pathways, such as SREBP pathway, LXR pathway, MAPK pathway, p62/mTOR pathway, CTRP1 pathway and so on. In addition, the ABCA1 participates in the disorder of lipid metabolism in COPD by regulating the formation of RCT and HDL, regulates the inflammation of COPD by removing excess cholesterol in macrophages, and promotes the differentiation of COPD phenotype into emphysema type. Accordingly, the ABCA1 may be a therapeutic target for COPD.
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Affiliation(s)
- Ying Gu
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Xiaoqing Bi
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Xiaofei Liu
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Qingqing Qian
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Yiqiong Wen
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Shu Hua
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Qiaoli Fu
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Yuanyuan Zheng
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Shibo Sun
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, China
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Wang S, Zhao J, Xie J. Targeting Lipid Metabolism in Obese Asthma: Perspectives and Therapeutic Opportunities. Int Arch Allergy Immunol 2024; 186:280-294. [PMID: 39427653 DOI: 10.1159/000540405] [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: 05/10/2024] [Accepted: 07/15/2024] [Indexed: 10/22/2024] Open
Abstract
BACKGROUND Obese asthma represents a unique phenotype of asthma characterized by severe symptoms, poor medication controls, increased frequency of exacerbations, and an overall diminished quality of life. Numerous factors, including the complex interactions between environment, mechanical processes, inflammatory responses, and metabolites disturbance, contribute to the onset of obese asthma. SUMMARY Notably, multiple metabolomics studies in the last several years have revealed the significant abnormalities in lipid metabolism among obese asthmatic patients. Several bioactive lipid messengers participate in the development of obese asthma has also been observed. Here, we present and discuss the latest advances regarding how bioactive lipid molecules contribute to the pathogenic process and mechanisms underlying obese asthma. The key roles of potentially significant effector cells and the pathways by which they respond to diverse lipid metabolites are also described. We finally summarize current lipid-related therapeutic options for the treatment of obese asthma and discuss their application prospects. KEY MESSAGES This review underscores the impacts of abnormal lipid metabolism in the etiopathogenesis of obese asthma and asks for further investigation to elucidate the intricate correlations among lipids, obesity, and asthma.
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Affiliation(s)
- Shanshan Wang
- Department of Respiratory and Critical Care Medicine, National Clinical Research Center of Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianping Zhao
- Department of Respiratory and Critical Care Medicine, National Clinical Research Center of Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jungang Xie
- Department of Respiratory and Critical Care Medicine, National Clinical Research Center of Respiratory Disease, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Manickasamy MK, Sajeev A, BharathwajChetty B, Alqahtani MS, Abbas M, Hegde M, Aswani BS, Shakibaei M, Sethi G, Kunnumakkara AB. Exploring the nexus of nuclear receptors in hematological malignancies. Cell Mol Life Sci 2024; 81:78. [PMID: 38334807 PMCID: PMC10858172 DOI: 10.1007/s00018-023-05085-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 11/16/2023] [Accepted: 12/03/2023] [Indexed: 02/10/2024]
Abstract
Hematological malignancies (HM) represent a subset of neoplasms affecting the blood, bone marrow, and lymphatic systems, categorized primarily into leukemia, lymphoma, and multiple myeloma. Their prognosis varies considerably, with a frequent risk of relapse despite ongoing treatments. While contemporary therapeutic strategies have extended overall patient survival, they do not offer cures for advanced stages and often lead to challenges such as acquisition of drug resistance, recurrence, and severe side effects. The need for innovative therapeutic targets is vital to elevate both survival rates and patients' quality of life. Recent research has pivoted towards nuclear receptors (NRs) due to their role in modulating tumor cell characteristics including uncontrolled proliferation, differentiation, apoptosis evasion, invasion and migration. Existing evidence emphasizes NRs' critical role in HM. The regulation of NR expression through agonists, antagonists, or selective modulators, contingent upon their levels, offers promising clinical implications in HM management. Moreover, several anticancer agents targeting NRs have been approved by the Food and Drug Administration (FDA). This review highlights the integral function of NRs in HM's pathophysiology and the potential benefits of therapeutically targeting these receptors, suggesting a prospective avenue for more efficient therapeutic interventions against HM.
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Affiliation(s)
- Mukesh Kumar Manickasamy
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Anjana Sajeev
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Bandari BharathwajChetty
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, 61421, Abha, Saudi Arabia
- BioImaging Unit, Space Research Centre, University of Leicester, Michael Atiyah Building, Leicester, LE1 7RH, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, 61421, Abha, Saudi Arabia
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Babu Santha Aswani
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Mehdi Shakibaei
- Chair of Vegetative Anatomy, Department of Human-Anatomy, Musculoskeletal Research Group and Tumor Biology, Institute of Anatomy, Ludwig-Maximilian-University, 80336, Munich, Germany
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India.
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Yang X, Weber AA, Mennillo E, Secrest P, Chang M, Wong S, Le S, Liu J, Benner CW, Karin M, Gordts PL, Tukey RH, Chen S. Effects of Early Life Oral Arsenic Exposure on Intestinal Tract Development and Lipid Homeostasis in Neonatal Mice: Implications for NAFLD Development. ENVIRONMENTAL HEALTH PERSPECTIVES 2023; 131:97001. [PMID: 37668303 PMCID: PMC10478510 DOI: 10.1289/ehp12381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 05/01/2023] [Accepted: 07/11/2023] [Indexed: 09/06/2023]
Abstract
BACKGROUND Newborns can be exposed to inorganic arsenic (iAs) through contaminated drinking water, formula, and other infant foods. Epidemiological studies have demonstrated a positive association between urinary iAs levels and the risk of developing nonalcoholic fatty liver disease (NAFLD) among U.S. adolescents and adults. OBJECTIVES The present study examined how oral iAs administration to neonatal mice impacts the intestinal tract, which acts as an early mediator for NAFLD. METHODS Neonatal mice were treated with a single dose of iAs via oral gavage. Effects on the small intestine were determined by histological examination, RNA sequencing, and biochemical analysis. Serum lipid profiling was analyzed by fast protein liquid chromatography (FPLC), and hepatosteatosis was characterized histologically and biochemically. Liver X receptor-alpha (LXR α ) knockout (L x r α - / - ) mice and liver-specific activating transcription factor 4 (ATF4)-deficient (A t f 4 Δ H e p ) mice were used to define their roles in iAs-induced effects during the neonatal stage. RESULTS Neonatal mice exposed to iAs via oral gavage exhibited accumulation of dietary fat in enterocytes, with higher levels of enterocyte triglycerides and free fatty acids. These mice also showed accelerated enterocyte maturation and a longer small intestine. This was accompanied by higher levels of liver-derived very low-density lipoprotein and low-density lipoprotein triglycerides, and a lower level of high-density lipoprotein cholesterol in the serum. Mice exposed during the neonatal period to oral iAs also developed hepatosteatosis. Compared with the control group, iAs-induced fat accumulation in enterocytes became more significant in neonatal L x r α - / - mice, accompanied by accelerated intestinal growth, hypertriglyceridemia, and hepatosteatosis. In contrast, regardless of enterocyte fat accumulation, hepatosteatosis was largely reduced in iAs-treated neonatal A t f 4 Δ H e p mice. CONCLUSION Exposure to iAs in neonatal mice resulted in excessive accumulation of fat in enterocytes, disrupting lipid homeostasis in the serum and liver, revealing the importance of the gut-liver axis and endoplasmic reticulum stress in mediating iAs-induced NAFLD at an early age. https://doi.org/10.1289/EHP12381.
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Affiliation(s)
- Xiaojing Yang
- Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego (UC San Diego), La Jolla, California, USA
| | - André A. Weber
- Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego (UC San Diego), La Jolla, California, USA
| | - Elvira Mennillo
- Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego (UC San Diego), La Jolla, California, USA
| | - Patrick Secrest
- Department of Medicine, Division of Endocrinology and Metabolism, UC San Diego, La Jolla, California, USA
| | - Max Chang
- Department of Medicine, School of Medicine, UC San Diego, La Jolla, California, USA
| | - Samantha Wong
- Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego (UC San Diego), La Jolla, California, USA
| | - Sabrina Le
- Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego (UC San Diego), La Jolla, California, USA
| | - Junlai Liu
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, UC San Diego, La Jolla, California, USA
| | | | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, UC San Diego, La Jolla, California, USA
| | - Philip L.S.M. Gordts
- Department of Medicine, Division of Endocrinology and Metabolism, UC San Diego, La Jolla, California, USA
| | - Robert H. Tukey
- Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego (UC San Diego), La Jolla, California, USA
| | - Shujuan Chen
- Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego (UC San Diego), La Jolla, California, USA
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Ravi PC, Thugu TR, Singh J, Dasireddy RR, Kumar SA, Isaac NV, Oladimeji A, DeTrolio V, Abdalla R, Mohan V, Iqbal J. Gallstone Disease and Its Correlation With Thyroid Disorders: A Narrative Review. Cureus 2023; 15:e45116. [PMID: 37842424 PMCID: PMC10568238 DOI: 10.7759/cureus.45116] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 09/12/2023] [Indexed: 10/17/2023] Open
Abstract
Over the years, several studies have revealed an important link between thyroid disorders and gallstone disease. According to these studies, hypothyroidism and hyperthyroidism are associated with cholesterol gallstone disease. This association between thyroid hormone disorders and cholesterol gallstone disease is due to the importance of thyroid hormones on cholesterol synthesis, bile functioning and content, and gallbladder motility. Several genes and receptors have been found on the thyroid gland, liver, and gallbladder to verify this association. These genes affect thyroid hormone secretion, lipid metabolism, and bile secretion. Defects in these various gene expression and protein functions lead to bile duct diseases. Other causes that lead to cholesterol gallstone disease are supersaturation of the bile with cholesterol and impaired gallbladder motility, which leads to bile stasis. This article has discussed these factors in detail while highlighting the association between thyroid hormones and cholesterol gallstone disease.
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Affiliation(s)
| | - Thanmai Reddy Thugu
- Internal Medicine, Sri Padmavathi Medical College for Women, Sri Venkateswara Institute of Medical Sciences (SVIMS), Tirupati, IND
| | - Jugraj Singh
- Internal Medicine, Punjab Institute of Medical Sciences, Jalandhar, IND
| | | | - Sharanya Anil Kumar
- Medicine and Surgery, Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, IND
| | - Natasha Varghese Isaac
- Medicine, St. John's Medical College Hospital, Rajiv Gandhi University of Health Sciences (RGUHS), Bengaluru, IND
| | | | | | - Rasha Abdalla
- Medicine and Surgery, Shendi University, Shendi, SDN
| | - Vineetha Mohan
- Medicine and Surgery, Government Medical College Kottayam, Kottayam, IND
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Sun X, Zhang J, Liu H, Li M, Liu L, Yang Z, Hu W, Bai H, Xu J, Xing J, Xu Z, Mo A, Guo Z, Bai Y, Zhou Q, Wang Y, Zhang S, Zhang S. Lanosterol synthase loss of function decreases the malignant phenotypes of HepG2 cells by deactivating the Src/MAPK signaling pathway. Oncol Lett 2023; 26:295. [PMID: 37274468 PMCID: PMC10236266 DOI: 10.3892/ol.2023.13881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 02/23/2023] [Indexed: 06/06/2023] Open
Abstract
Cholesterol is critical for tumor cells to maintain their membrane components, cell morphology and activity functions. The inhibition of the cholesterol pathway may be an efficient strategy with which to limit tumor growth and the metastatic process. In the present study, lanosterol synthase (LSS) was knocked down by transfecting LSS short hairpin RNA into HepG2 cells, and cell growth, apoptosis and migratory potential were then detected by Cell Counting Kit-8 cell proliferation assay, flow cytometric analysis and wound healing assay, respectively. In addition, proteins associated with the regulation of the aforementioned cell biological behaviors were analyzed by western blot analysis. The activity of the Src/MAPK signaling pathway was measured by western blotting to elucidate the possible signal transduction mechanisms. LSS knockdown in the HepG2 liver cancer cell line inhibited cell proliferation, with cell cycle arrest at the S phase; it also decreased cell migratory ability and increased apoptosis. The expression proteins involved in the regulation of cell cycle, cell apoptosis and migration was altered by LSS knockdown in HepG2 cells. Furthermore, a decreased Src/MAPK activity was observed in the HepG2 cells subjected to LSS knockdown. LSS loss of function decreased the malignant phenotypes of HepG2 cells by deactivating the Src/MAPK signaling pathway and regulating expression of genes involved in cell cycle regulation, cell apoptosis and migration.
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Affiliation(s)
- Xiaomei Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Jun Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Hui Liu
- Department of Hyperbaric Oxygen, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230011, P.R. China
| | - Mingcong Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
- Department of Pathology, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230011, P.R. China
| | - Li Liu
- Center for Scientific Research, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Zhen Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Weikang Hu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Hongmei Bai
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Jiansheng Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
- Department of First Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Jun Xing
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
- Department of First Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Zhijun Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
- Department of First Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Aizhu Mo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
- Department of First Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Ziyi Guo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
- Department of First Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Yajie Bai
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
- Department of First Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Qing Zhou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Yuan Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Shengquan Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Sumei Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
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Zhang H, Wang J, Sun J, Wang Q, Guo L, Ju X. Regulatory mechanism underlying liver X receptor effects on the tumor microenvironment, inflammation and tumorigenesis. Expert Opin Ther Targets 2023; 27:989-998. [PMID: 37753584 DOI: 10.1080/14728222.2023.2264513] [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: 05/07/2023] [Accepted: 09/25/2023] [Indexed: 09/28/2023]
Abstract
INTRODUCTION Liver X receptors (LXRs) have emerged as novel targets for tumor treatment. LXRs within the tumor microenvironment show the capacity to impact tumorigenesis and tumor development by regulating the infiltration of immune cells and release of cytokines to moderate inflammation. AREAS COVERED In this review, we present a systematic description of recent progress in understanding the impact of LXRs on the tumor microenvironment and tumorigenesis. We also summarize the antitumor effects mediated by LXRs via their regulation of cytokine expression. Additionally, we discuss the limitations of LXR research in tumor studies to date. EXPERT OPINION Previous studies have demonstrated abnormal LXR expression in tumor tissues, and activation of LXRs has been shown to inhibit tumorigenesis and promote apoptosis in tumor cells. However, LXRs can also affect tumorigenesis by regulating immune cell functions within the tumor immune microenvironment. By summarizing the impact of LXRs on immune cells, we provide new insights into the multifaceted nature of LXRs as antitumor targets.
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Affiliation(s)
- Heng Zhang
- Department of General Surgery, Nanjing Lishui District People's Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, China
| | - Jing Wang
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jiang Sun
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Qiang Wang
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Lanfang Guo
- Department of Clinical Laboratory Medicine, The Fourth People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xiaoli Ju
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
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Dietary oxidized frying oil activates hepatic stellate cells and accelerates the severity of carbon tetrachloride- and thioacetamide-induced liver fibrosis in mice. J Nutr Biochem 2023; 115:109267. [PMID: 36641072 DOI: 10.1016/j.jnutbio.2023.109267] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 11/18/2022] [Accepted: 01/05/2023] [Indexed: 01/13/2023]
Abstract
Deep-frying is a common cooking practice worldwide, and after repeated heating's, the oil undergoes various chemical reactions, including hydrolysis, polymerization, lipid oxidation, and the Maillard reaction. Studies have pointed out that oxidized dietary frying oil may cause teratogenesis in mice and increase cancer and cardiovascular risks. The liver is the main organ involved in dietary nutrient catabolism, detoxification, bile production, and lipid metabolism. Nevertheless, the effects of oxidized frying oil exposure on the activation of hepatic stellate cells (HSCs) and liver fibrosis are still unclear. In this study, we showed that exposure to oxidized frying oil enhanced the sensitivity of HSCs to transforming growth factor (TGF)-β1-induced α-smooth muscle actin (α-SMA), collagen 1a2, collagen 1a1, metalloproteinase-2, and phosphorylated smad2/3 activation. In both carbon tetrachloride (CCl4)- and thioacetamide (TAA)-induced liver fibrosis mouse models, we showed that long-term administration of a 10% fried oil-containing diet significantly upregulated fibrogenesis genes expression and deposition of hepatic collagen. Furthermore, long-term fried oil exposure not only promoted macrophage infiltration and increased inflammatory-related gene expression, but also accumulated excess cholesterol and lipid peroxidation in the liver tissues. In conclusion, our study demonstrated that feeding a fried oil-containing diet may trigger TGF-β1-induced HSCs activation and thereby promote liver damage and fibrosis progression through enhancing the inflammatory response and lipid peroxidation.
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Lu ZN, He HW, Zhang N. Advances in understanding the regulatory mechanism of organic solute transporter α-β. Life Sci 2022; 310:121109. [DOI: 10.1016/j.lfs.2022.121109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 10/09/2022] [Accepted: 10/17/2022] [Indexed: 11/07/2022]
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10
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Zhang H, Lianto P, Li W, Xu M, Moore JB, Thorne JL. Associations between liver X receptor polymorphisms and blood lipids: A systematic review and meta-analysis. Steroids 2022; 185:109057. [PMID: 35679909 DOI: 10.1016/j.steroids.2022.109057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 04/07/2022] [Accepted: 06/02/2022] [Indexed: 12/22/2022]
Abstract
Genetic susceptibility to dyslipidaemia remains incompletely understood. The liver X receptors (LXRs), members of the nuclear receptor superfamily of ligand dependent transcription factors, are homeostatic regulators of lipid metabolism. Multiple single nucleotide polymorphisms (SNPs)have been identified previously in the coding and regulatory regions of the LXRs. The aim of this systematic review and meta-analysis was to summarise associations between SNPs of LXRs (α and β isoforms) with blood lipid and lipoprotein traits. Five databases (PubMed, Ovid Embase, Scopus, Web of Science, and the Cochrane Library) were systematically searched for population-based studies that assessed associations between one or more blood lipid/lipoprotein traits and LXR SNPs. Of seventeen articles included in the qualitative synthesis, ten were eligible for meta-analysis. Nine LXRα SNPs and five LXRβ SNPs were identified, and the three most studied LXRα SNPs were quantitatively summarised. Carriers of the minor allele A of LXRα rs12221497 (-115G>A) had higher triglyceride levels than GG homozygotes (0.13 mmol/L; 95%CI: [0.03, 0.23], P = 0.01). Heterozygote carriers of LXRα rs2279238 (297C/T) had higher total cholesterol levels (0.12 mmol/L; (95%CI: [0.01, 0.23], P = 0.04) than either CC or TT homozygotes. For LXRα rs11039155 (-6G>A), no significant differences in blood levels of either triglyceride (P = 0.39) or HDL-C (P = 0.98) were detected between genotypes in meta-analyses. In addition, there were no strong associations for other SNPs of LXRα and LXRβ. This study provides the evidence of an association between LXRα, but not LXRβ, SNPs and blood-lipid traits. Systematic review registration: PROSPERO No. CRD42021246158.
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Affiliation(s)
- Huifeng Zhang
- School of Food Science and Nutrition, University of Leeds, Leeds LS2 9JT, UK; Clinical Nutrition Department, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China
| | - Priscilia Lianto
- School of Food Science and Nutrition, University of Leeds, Leeds LS2 9JT, UK
| | - Weiming Li
- Clinical Nutrition Department, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an 710061, China
| | - Mengfan Xu
- School of Food Science and Nutrition, University of Leeds, Leeds LS2 9JT, UK
| | - J Bernadette Moore
- School of Food Science and Nutrition, University of Leeds, Leeds LS2 9JT, UK
| | - James L Thorne
- School of Food Science and Nutrition, University of Leeds, Leeds LS2 9JT, UK.
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Zhao J, Zhang H, Fan X, Yu X, Huai J. Lipid Dyshomeostasis and Inherited Cerebellar Ataxia. Mol Neurobiol 2022; 59:3800-3828. [PMID: 35420383 PMCID: PMC9148275 DOI: 10.1007/s12035-022-02826-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 04/01/2022] [Indexed: 12/04/2022]
Abstract
Cerebellar ataxia is a form of ataxia that originates from dysfunction of the cerebellum, but may involve additional neurological tissues. Its clinical symptoms are mainly characterized by the absence of voluntary muscle coordination and loss of control of movement with varying manifestations due to differences in severity, in the site of cerebellar damage and in the involvement of extracerebellar tissues. Cerebellar ataxia may be sporadic, acquired, and hereditary. Hereditary ataxia accounts for the majority of cases. Hereditary ataxia has been tentatively divided into several subtypes by scientists in the field, and nearly all of them remain incurable. This is mainly because the detailed mechanisms of these cerebellar disorders are incompletely understood. To precisely diagnose and treat these diseases, studies on their molecular mechanisms have been conducted extensively in the past. Accumulating evidence has demonstrated that some common pathogenic mechanisms exist within each subtype of inherited ataxia. However, no reports have indicated whether there is a common mechanism among the different subtypes of inherited cerebellar ataxia. In this review, we summarize the available references and databases on neurological disorders characterized by cerebellar ataxia and show that a subset of genes involved in lipid homeostasis form a new group that may cause ataxic disorders through a common mechanism. This common signaling pathway can provide a valuable reference for future diagnosis and treatment of ataxic disorders.
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Affiliation(s)
- Jin Zhao
- The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Xinxiang, 453000, China
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, 453003, China
| | - Huan Zhang
- The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Xinxiang, 453000, China
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, 453003, China
| | - Xueyu Fan
- The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Xinxiang, 453000, China
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, 453003, China
| | - Xue Yu
- The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Xinxiang, 453000, China
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, 453003, China
| | - Jisen Huai
- The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Xinxiang, 453000, China.
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, 453003, China.
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12
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Xie Y, Sun R, Gao L, Guan J, Wang J, Bell A, Zhu J, Zhang M, Xu M, Lu P, Cai X, Ren S, Xu P, Monga SP, Ma X, Yang D, Liu Y, Lu B, Xie W. Chronic Activation of LXRα Sensitizes Mice to Hepatocellular Carcinoma. Hepatol Commun 2022; 6:1123-1139. [PMID: 34981658 PMCID: PMC9035576 DOI: 10.1002/hep4.1880] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/27/2021] [Accepted: 11/18/2021] [Indexed: 01/26/2023] Open
Abstract
The oxysterol receptor liver X receptor (LXR) is a nuclear receptor best known for its function in the regulation of lipid and cholesterol metabolism. LXRs, both the α and β isoforms, have been suggested as potential therapeutic targets for several cancer types. However, there was a lack of report on whether and how LXRα plays a role in the development of hepatocellular carcinoma (HCC). In the current study, we found that systemic activation of LXRα in the VP-LXRα knock-in (LXRαKI) mice or hepatocyte-specific activation of LXRα in the VP-LXRα transgenic mice sensitized mice to liver tumorigenesis induced by the combined treatment of diethylnitrosamine (DEN) and 3,3',5,5'-tetrachloro-1,4-bis (pyridyloxy) benzene (TCPOBOP). Mechanistically, the LXRα-responsive up-regulation of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway and the complement system, and down-regulation of bile acid metabolism, may have contributed to increased tumorigenesis. Accumulations of secondary bile acids and oxysterols were found in both the serum and liver tissue of LXRα activated mice. We also observed an induction of monocytic myeloid-derived suppressor cells accompanied by down-regulation of dendritic cells and cytotoxic T cells in DEN/TCPOBOP-induced liver tumors, indicating that chronic activation of LXRα may have led to the activation of innate immune suppression. The HCC sensitizing effect of LXRα activation was also observed in the c-MYC driven HCC model. Conclusion: Our results indicated that chronic activation of LXRα promotes HCC, at least in part, by promoting innate immune suppressor as a result of accumulation of oxysterols, as well as up-regulation of the IL-6/Janus kinase/STAT3 signaling and complement pathways.
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Affiliation(s)
- Yang Xie
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Runzi Sun
- Department of ImmunologyUniversity of PittsburghPittsburghPAUSA
| | - Li Gao
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
- Department of GastroenterologyPeking University People’s HospitalBeijingChina
| | - Jibin Guan
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Jingyuan Wang
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Aaron Bell
- Division of Experimental PathologyDepartment of PathologyUniversity of PittsburghPittsburghPAUSA
| | - Junjie Zhu
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Min Zhang
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Meishu Xu
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Peipei Lu
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Xinran Cai
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Songrong Ren
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Pengfei Xu
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Satdarshan P. Monga
- Division of Experimental PathologyDepartment of PathologyUniversity of PittsburghPittsburghPAUSA
- Pittsburgh Liver Research CenterUniversity of Pittsburgh Medical Center and University of Pittsburgh School of MedicinePittsburghPAUSA
| | - Xiaochao Ma
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Da Yang
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
| | - Yulan Liu
- Department of GastroenterologyPeking University People’s HospitalBeijingChina
| | - Binfeng Lu
- Department of ImmunologyUniversity of PittsburghPittsburghPAUSA
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical SciencesUniversity of PittsburghPittsburghPAUSA
- Department of Pharmacology and Chemical BiologyUniversity of PittsburghPittsburghPAUSA
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13
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Shiragannavar VD, Gowda NGS, Santhekadur PK. Discovery of eukaryotic cellular receptor for withaferin A, a multifaceted drug from Withania somnifera plant. MEDICINE IN DRUG DISCOVERY 2022. [DOI: 10.1016/j.medidd.2022.100127] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
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14
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Smirne C, Croce E, Di Benedetto D, Cantaluppi V, Comi C, Sainaghi PP, Minisini R, Grossini E, Pirisi M. Oxidative Stress in Non-Alcoholic Fatty Liver Disease. LIVERS 2022; 2:30-76. [DOI: 10.3390/livers2010003] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a challenging disease caused by multiple factors, which may partly explain why it still remains an orphan of adequate therapies. This review highlights the interaction between oxidative stress (OS) and disturbed lipid metabolism. Several reactive oxygen species generators, including those produced in the gastrointestinal tract, contribute to the lipotoxic hepatic (and extrahepatic) damage by fatty acids and a great variety of their biologically active metabolites in a “multiple parallel-hit model”. This leads to inflammation and fibrogenesis and contributes to NAFLD progression. The alterations of the oxidant/antioxidant balance affect also metabolism-related organelles, leading to lipid peroxidation, mitochondrial dysfunction, and endoplasmic reticulum stress. This OS-induced damage is at least partially counteracted by the physiological antioxidant response. Therefore, modulation of this defense system emerges as an interesting target to prevent NAFLD development and progression. For instance, probiotics, prebiotics, diet, and fecal microbiota transplantation represent new therapeutic approaches targeting the gut microbiota dysbiosis. The OS and its counter-regulation are under the influence of individual genetic and epigenetic factors as well. In the near future, precision medicine taking into consideration genetic or environmental epigenetic risk factors, coupled with new OS biomarkers, will likely assist in noninvasive diagnosis and monitoring of NAFLD progression and in further personalizing treatments.
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Affiliation(s)
- Carlo Smirne
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Eleonora Croce
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Davide Di Benedetto
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Vincenzo Cantaluppi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Cristoforo Comi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Pier Paolo Sainaghi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Elena Grossini
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
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15
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Momtazi-Borojeni AA, Abdollahi E, Jaafari MR, Banach M, Watts GF, Sahebkar A. Negatively-charged Liposome Nanoparticles Can Prevent Dyslipidemia and Atherosclerosis Progression in the Rabbit Model. Curr Vasc Pharmacol 2022; 20:69-76. [PMID: 34414873 DOI: 10.2174/1570161119666210820115150] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 06/13/2021] [Accepted: 06/21/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM Negatively charged nanoliposomes have a strong attraction towards plasma lipoprotein particles and can thereby regulate lipid metabolism. Here, the impact of such nanoliposomes on dyslipidaemia and progression of atherosclerosis was investigated in a rabbit model. METHODS Two sets of negatively-charged nanoliposome formulations including [Hydrogenated Soy Phosphatidylcholine (HSPC)/1,2-distearoyl-sn-glycero-3- phosphoglycerol (DSPG)] and [1,2- Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC)/1,2-Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPG)/Cholesterol] were evaluated. Rabbits fed a high-cholesterol diet were randomly divided into 3 groups (n=5/group) intravenously administrated with HSPC/DSPG formulation (DSPG group; 100 mmol/kg), DMPC/DMPG formulation (DMPG group; 100 mmol/kg), or the normal saline (control group; 0.9% NaCl) over a 4-week period. The atherosclerotic lesions of the aortic arch wall were studied using haematoxylin and eosin staining. RESULTS Both DSPG and DMPG nanoliposome formulations showed a nano-sized range in diameter with a negatively-charged surface and a polydispersity index of <0.1. After 4 weeks administration, the nanoliposome formulations decreased triglycerides (-62±3% [DSPG group] and -58±2% [DMPG group]), total cholesterol (-58±9% [DSPG group] and -37±5% [DMPG group]), and lowdensity lipoprotein cholesterol (-64±6% [DSPG group] and -53±10% [DMPG group]) levels, and increased high-density lipoprotein cholesterol (+67±28% [DSPG group] and +35±19% [DMPG group]) levels compared with the controls. The nanoliposomes showed a significant decrease in the severity of atherosclerotic lesions: mean values of the intima to media ratio in DMPG (0.96±0.1 fold) and DSPG (0.54±0.02 fold) groups were found to be significantly lower than that in the control (1.2±0.2 fold) group (p<0.05). CONCLUSION Anionic nanoliposomes containing [HSPC/DSPG] and [DMPC/DMPG] correct dyslipidaemia and inhibit the progression of atherosclerosis.
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Affiliation(s)
| | - Elham Abdollahi
- Department of Gynecology, Woman Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud R Jaafari
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran | Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, Lodz, Poland | Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
| | - Gerald F Watts
- Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran | Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran | School of Medicine, The University of Western Australia, Perth, Australia | School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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16
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Schade DS, Gonzales K, Kaminsky N, Adolphe A, Shey L, Eaton RP. Resolving the Egg and Cholesterol Intake Controversy: New Clinical Insights Into Cholesterol Regulation by the Liver and Intestine. Endocr Pract 2021; 28:102-109. [PMID: 34547473 DOI: 10.1016/j.eprac.2021.09.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 08/19/2021] [Accepted: 09/09/2021] [Indexed: 11/17/2022]
Abstract
OBJECTIVE Cardiovascular disease is the number one cause of death. Achieving American Heart Association low-density lipoprotein (LDL) cholesterol treatment goals is very difficult for many patients. The importance of a low cholesterol diet is controversial and not emphasized by most physicians. Of critical importance is determining whether each individual is a "hyper- or hypo-absorber" of dietary cholesterol. Furthermore, the quantity of each individual's baseline daily dietary cholesterol and saturated fat intake is important in assessing the effect of added egg yolk cholesterol and saturated fat on blood LDL cholesterol. METHODS Gut cholesterol is absorbed via a specific enteric receptor (the Niemann- Pick-like receptor). Dietary cholesterol contributes one fourth of the absorbed cholesterol, while the remaining gut cholesterol is derived from secreted bile cholesterol. This dietary quantity of cholesterol is significant when other determinants are constant. For some individuals, dietary cholesterol has no adverse effects and in others, a significant elevation in blood LDL cholesterol may occur. RESULTS There are no readily available blood tests to determine the effect of egg yolk cholesterol and saturated fat on an individual's plasma LDL cholesterol. However, a one month trial of a low cholesterol and saturated fat diet will provide the needed information to make clinical decisions. CONCLUSION This article delineates the mechanisms that are altered by genetic and environmental factors that determine the net effects of dietary cholesterol and saturated fat on circulating LDL cholesterol. It then makes a practical clinical recommendation based on these mechanisms.
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Affiliation(s)
- David S Schade
- Division of Endocrinology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
| | - Kristen Gonzales
- Division of Endocrinology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
| | - Neil Kaminsky
- Division of Endocrinology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
| | - Allen Adolphe
- Division of Internal Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
| | - Lynda Shey
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Diabetes Comprehensive Care Center, Albuquerque, New Mexico
| | - Robert Philip Eaton
- Division of Endocrinology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
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17
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Li H, Yu XH, Ou X, Ouyang XP, Tang CK. Hepatic cholesterol transport and its role in non-alcoholic fatty liver disease and atherosclerosis. Prog Lipid Res 2021; 83:101109. [PMID: 34097928 DOI: 10.1016/j.plipres.2021.101109] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a quickly emerging global health problem representing the most common chronic liver disease in the world. Atherosclerotic cardiovascular disease represents the leading cause of mortality in NAFLD patients. Cholesterol metabolism has a crucial role in the pathogenesis of both NAFLD and atherosclerosis. The liver is the major organ for cholesterol metabolism. Abnormal hepatic cholesterol metabolism not only leads to NAFLD but also drives the development of atherosclerotic dyslipidemia. The cholesterol level in hepatocytes reflects the dynamic balance between endogenous synthesis, uptake, esterification, and export, a process in which cholesterol is converted to neutral cholesteryl esters either for storage in cytosolic lipid droplets or for secretion as a major constituent of plasma lipoproteins, including very-low-density lipoproteins, chylomicrons, high-density lipoproteins, and low-density lipoproteins. In this review, we describe decades of research aimed at identifying key molecules and cellular players involved in each main aspect of hepatic cholesterol metabolism. Furthermore, we summarize the recent advances regarding the biological processes of hepatic cholesterol transport and its role in NAFLD and atherosclerosis.
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Affiliation(s)
- Heng Li
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China
| | - Xiao-Hua Yu
- Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 460106, China
| | - Xiang Ou
- Department of Endocrinology, the First Hospital of Changsha, Changsha, Hunan 410005, China
| | - Xin-Ping Ouyang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China.
| | - Chao-Ke Tang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China.
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18
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Lioudakis E, Lucitt M. Statin Disruption of Cholesterol Metabolism and Altered Innate Inflammatory Responses in Atherosclerosis. IMMUNOMETABOLISM 2021; 3. [DOI: 10.20900/immunometab20210023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 05/13/2021] [Indexed: 01/03/2025]
Abstract
Abstract
Atherosclerosis is well recognised as a disease associated with elevated cholesterol levels. Innate monocytes and macrophage cells laden with cholesterol have long been described as key players in driving low grade inflammation characteristic of atherosclerosis. In more recent times it has been shown how various mechanisms controlling metabolic and epigenetic reprogramming of these innate immune cells influence their inflammatory responses. In this review a general role of intracellular metabolism in reprogramming innate immune cells will be discussed with a particular emphasis on evidence supporting how innate reprogramming contributes to the pathophysiology of atherosclerosis. In addition the evidence for the role of statins in altering these metabolic adaptations to control the development and progression of atherosclerotic plaques is discussed.
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19
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Mattoso Miskulin Cardoso AP, Tavares Pereira M, Dos Santos Silva R, Medeiros de Carvalho Sousa LM, Giometti IC, Kowalewski MP, de Carvalho Papa P. Global transcriptome analysis implicates cholesterol availability in the regulation of canine cyclic luteal function. Gen Comp Endocrinol 2021; 307:113759. [PMID: 33771531 DOI: 10.1016/j.ygcen.2021.113759] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 01/06/2021] [Accepted: 03/10/2021] [Indexed: 12/24/2022]
Abstract
Considering the key role of the corpus luteum in the regulation of the canine diestrus, the present study aimed to investigate changes in the luteal transcriptome of pseudopregnant dogs (n = 18) from days (D) 10, 20, 30, 40, 50 and 60 post-ovulation. After RNAsequencing was performed, data was analyzed by resorting to several informatic tools. A total of 3300 genes were differently expressed among all samples (FDR < 0.01). By comparing different time points, enriched biological processes as response to estradiol and lipids (D20 vs D10) and intracellular cholesterol transport (D40 vs D60) were observed. Moreover, LXR/RXR (liver X receptor- retinoid X receptor) signaling appeared as an overrepresented pathway in all comparisons. Thus, the expression of 19 genes involved in intracellular cholesterol availability was further evaluated; most were affected by time (P < 0.05). Adding to the deep transcriptomic analysis, presented data implies the importance of cholesterol regulation in luteal physiology of pseudopregnant dogs.
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Affiliation(s)
| | - Miguel Tavares Pereira
- Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Renata Dos Santos Silva
- School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
| | | | - Ines Cristina Giometti
- Faculty of Veterinary Medicine, University of Western São Paulo, Presidente Prudente, Brazil
| | | | - Paula de Carvalho Papa
- School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil; Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
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20
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Ikonomopoulou MP, Lopez-Mancheño Y, Novelle MG, Martinez-Uña M, Gangoda L, Pal M, Costa-Machado LF, Fernandez-Marcos PJ, Ramm GA, Fernandez-Rojo MA. LXR stimulates a metabolic switch and reveals cholesterol homeostasis as a statin target in Tasmanian devil facial tumor disease. Cell Rep 2021; 34:108851. [PMID: 33730574 DOI: 10.1016/j.celrep.2021.108851] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 11/02/2020] [Accepted: 02/17/2021] [Indexed: 12/12/2022] Open
Abstract
Devil facial tumor disease (DFTD) and its lack of available therapies are propelling the Tasmanian devil population toward extinction. This study demonstrates that cholesterol homeostasis and carbohydrate energy metabolism sustain the proliferation of DFTD cells in a cell-type-dependent manner. In addition, we show that the liver-X nuclear receptor-β (LXRβ), a major cholesterol cellular sensor, and its natural ligand 24S-hydroxycholesterol promote the proliferation of DFTD cells via a metabolic switch toward aerobic glycolysis. As a proof of concept of the role of cholesterol homeostasis on DFTD proliferation, we show that atorvastatin, an FDA-approved statin-drug subtype used against human cardiovascular diseases that inhibits cholesterol synthesis, shuts down DFTD energy metabolism and prevents tumor growth in an in vivo DFTD-xenograft model. In conclusion, we show that intervention against cholesterol homeostasis and carbohydrate-dependent energy metabolism by atorvastatin constitutes a feasible biochemical treatment against DFTD, which may assist in the conservation of the Tasmanian devil.
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Affiliation(s)
- Maria P Ikonomopoulou
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; The University of Queensland, Brisbane, QLD, Australia; Translational Venomics Laboratory, Madrid Institute for Advanced Studies (IMDEA) Food, Madrid 28049, Spain.
| | - Yaiza Lopez-Mancheño
- Hepatic Regenerative Medicine Laboratory, Madrid Institute for Advanced Studies (IMDEA) Food, Madrid 28049, Spain
| | - Marta G Novelle
- Hepatic Regenerative Medicine Laboratory, Madrid Institute for Advanced Studies (IMDEA) Food, Madrid 28049, Spain
| | - Maite Martinez-Uña
- Hepatic Regenerative Medicine Laboratory, Madrid Institute for Advanced Studies (IMDEA) Food, Madrid 28049, Spain
| | - Lahiru Gangoda
- Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Melbourne, VIC 3052, Australia
| | - Martin Pal
- Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Melbourne, VIC 3052, Australia
| | - Luis Filipe Costa-Machado
- Metabolic Syndrome Laboratory, Madrid Institute for Advanced Studies (IMDEA) Food, Madrid 28049, Spain
| | | | - Grant A Ramm
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; The University of Queensland, Brisbane, QLD, Australia
| | - Manuel Alejandro Fernandez-Rojo
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; The University of Queensland, Brisbane, QLD, Australia; Hepatic Regenerative Medicine Laboratory, Madrid Institute for Advanced Studies (IMDEA) Food, Madrid 28049, Spain.
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21
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Ma C, Feng K, Yang X, Yang Z, Wang Z, Shang Y, Fan G, Liu L, Yang S, Li X, Han J, Duan Y, Chen Y. Targeting macrophage liver X receptors by hydrogel-encapsulated T0901317 reduces atherosclerosis without effect on hepatic lipogenesis. Br J Pharmacol 2021; 178:1620-1638. [PMID: 33506494 DOI: 10.1111/bph.15387] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 01/11/2021] [Accepted: 01/11/2021] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND AND PURPOSE Targeting macrophage but not hepatocyte liver X receptors (LXRs) can reduce atherosclerosis without effect on hepatic lipogenesis. In this study, we encapsulated LXR ligands with D-Nap-GFFY to form a nanofibre hydrogel (D-Nap-GFFY-T0901317 or GFFY-T0901317) and determined its effect on atherosclerosis, hepatic lipogenesis and the underlying mechanisms involved. EXPERIMENTAL APPROACH D-Nap-GFFY-T0901317 was subcutaneously injected to proatherogenic diet-fed apoE-deficient (Apoe-/- ) mice, followed by determination of the development of atherosclerosis, liver steatosis and the involved mechanisms, with comparison of T0901317 oral administration. KEY RESULTS Subcutaneous injection of D-Nap-GFFY-T0901317 to Apoe-/- mice inhibited atherosclerosis at a comparable level as T0901317 oral administration without effect on hepatic lipogenesis. More importantly, D-Nap-GFFY-T0901317 regressed the advanced lesions. In arterial wall, D-Nap-GFFY-T0901317 reduced macrophage/foam cells, necrotic cores and calcification and increased collagen content. It activated expression of ABCA1/G1 and smooth muscle α-actin, while inhibiting expression of intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). D-Nap-GFFY-T0901317 also reduced serum pro-inflammatory cytokines and facilitated Kupffer cell M2 polarization. Mechanistically, D-Nap-GFFY-T0901317 was selectively taken up by macrophages but not hepatocytes, resulting in activation of macrophage ABCA1/G1 expression, while having no effect on lipogenic genes in hepatocytes. Moreover, the selective uptake of D-Nap-GFFY-T0901317 by macrophages was mainly completed in a scavenger receptor class A-dependent manner. CONCLUSION AND IMPLICATIONS Our study demonstrates that D-Nap-GFFY-T0901317 reduces atherosclerosis without effect on hepatic lipogenesis by targeting macrophage LXRs selectively, indicating its potential application for atherosclerosis treatment.
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Affiliation(s)
- Chuanrui Ma
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Ke Feng
- Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Xiaoxiao Yang
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Zhimou Yang
- Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Zhongyan Wang
- Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Yuna Shang
- Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Guanwei Fan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Lipei Liu
- Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Shu Yang
- Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Xiaoju Li
- Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Jihong Han
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.,Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Yajun Duan
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Yuanli Chen
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
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22
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Fernandes GW, Bocco BMLC. Hepatic Mediators of Lipid Metabolism and Ketogenesis: Focus on Fatty Liver and Diabetes. Curr Diabetes Rev 2021; 17:e110320187539. [PMID: 33143628 DOI: 10.2174/1573399816999201103141216] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 09/29/2020] [Accepted: 10/03/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Diabetes mellitus (DM) is a chronic disorder that it is caused by the absence of insulin secretion due to the inability of the pancreas to produce it (type 1 diabetes; T1DM), or due to defects of insulin signaling in the peripheral tissues, resulting in insulin resistance (type 2 diabetes; T2DM). Commonly, the occurrence of insulin resistance in T2DM patients reflects the high prevalence of obesity and non-alcoholic fatty liver disease (NAFLD) in these individuals. In fact, approximately 60% of T2DM patients are also diagnosed to have NAFLD, and this condition is strongly linked with insulin resistance and obesity. NAFLD is the hepatic manifestation of obesity and metabolic syndrome and includes a spectrum of pathological conditions, which range from simple steatosis (NAFL), non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. NAFLD manifestation is followed by a series of hepatic lipid deregulations and the main abnormalities are increased triglyceride levels, increased hepatic production of VLDL and a reduction in VLDL catabolism. During the progression of NAFLD, the production of ketone bodies progressively reduces while hepatic glucose synthesis and output increases. In fact, most of the fat that enters the liver can be disposed of through ketogenesis, preventing the development of NAFLD and hyperglycemia. OBJECTIVE This review will focus on the pathophysiological aspect of hepatic lipid metabolism deregulation, ketogenesis, and its relevance in the progression of NAFLD and T2DM. CONCLUSION A better understanding of the molecular mediators involved in lipid synthesis and ketogenesis can lead to new treatments for metabolic disorders in the liver, such as NAFLD.
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Affiliation(s)
- Gustavo W Fernandes
- Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago IL, United States
| | - Barbara M L C Bocco
- Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago IL, United States
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23
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Kang S, Kumanogoh A. The spectrum of macrophage activation by immunometabolism. Int Immunol 2020; 32:467-473. [PMID: 32179900 DOI: 10.1093/intimm/dxaa017] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 03/12/2020] [Indexed: 12/28/2022] Open
Abstract
Macrophages are heterogeneous and plastic, and play several diverse functions in immune responses. Emerging data provide evidence of multiple roles for metabolic pathways in the control of macrophage effector functions. The diverse functions of macrophages are categorized into two main subsets: classical activated macrophages (M1) and alternative activated macrophages (M2). M1 macrophages secrete pro-inflammatory cytokines and reactive oxygen species and migrate into inflamed sites as a part of host defenses. On the other hand, M2 macrophages are involved in immune homeostasis by producing anti-inflammatory cytokines and phagocytosing apoptotic cells. Metabolic reprogramming of environmental or cellular nutrients such as glucose, lipids and amino acids supports this diversity. Mechanistically, the mammalian target of rapamycin (mTOR) network plays important roles in the effector functions of macrophages by modulating cellular metabolism and regulating gene expression at the transcriptional and translational levels. In this review, we outline immunometabolism and provide insights into metabolic regulation by mTOR in macrophages.
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Affiliation(s)
- Sujin Kang
- Department of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita City, Osaka, Japan
| | - Atsushi Kumanogoh
- Department of Immunopathology, Immunology Frontier Research Center, Osaka University, Suita City, Osaka, Japan.,Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita City, Osaka, Japan
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24
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Libby AE, Jones B, Lopez-Santiago I, Rowland E, Levi M. Nuclear receptors in the kidney during health and disease. Mol Aspects Med 2020; 78:100935. [PMID: 33272705 DOI: 10.1016/j.mam.2020.100935] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 10/24/2020] [Accepted: 11/16/2020] [Indexed: 02/06/2023]
Abstract
Over the last 30 years, nuclear receptors (NRs) have been increasingly recognized as key modulators of systemic homeostasis and as contributing factors in many diseases. In the kidney, NRs play numerous important roles in maintaining homeostasis-many of which continue to be unraveled. As "master regulators", these important transcription factors integrate and coordinate many renal processes such as circadian responses, lipid metabolism, fatty acid oxidation, glucose handling, and inflammatory responses. The use of recently-developed genetic tools and small molecule modulators have allowed for detailed studies of how renal NRs contribute to kidney homeostasis. Importantly, while NRs are intimately involved in proper kidney function, they are also implicated in a variety of renal diseases such as diabetes, acute kidney injury, and other conditions such as aging. In the last 10 years, our understanding of renal disease etiology and progression has been greatly shaped by knowledge regarding how NRs are dysregulated in these conditions. Importantly, NRs have also become attractive therapeutic targets for attenuation of renal diseases, and their modulation for this purpose has been the subject of intense investigation. Here, we review the role in health and disease of six key renal NRs including the peroxisome proliferator-activated receptors (PPAR), estrogen-related receptors (ERR), the farnesoid X receptors (FXR), estrogen receptors (ER), liver X receptors (LXR), and vitamin D receptors (VDR) with an emphasis on recent findings over the last decade. These NRs have generated a wealth of data over the last 10 years that demonstrate their crucial role in maintaining normal renal homeostasis as well as their capacity to modulate disease progression.
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Affiliation(s)
- Andrew E Libby
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, 3900 Reservoir Rd, Washington, DC, 20007, USA.
| | - Bryce Jones
- Department of Pharmacology and Physiology, Georgetown University, 3900 Reservoir Rd, Washington, DC, 20007, USA.
| | - Isabel Lopez-Santiago
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, 3900 Reservoir Rd, Washington, DC, 20007, USA.
| | - Emma Rowland
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, 3900 Reservoir Rd, Washington, DC, 20007, USA.
| | - Moshe Levi
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, 3900 Reservoir Rd, Washington, DC, 20007, USA.
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25
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Tajbakhsh A, Farahani N, Gheibihayat SM, Mirkhabbaz AM, Savardashtaki A, Hamblin MR, Mirzaei H. Autoantigen-specific immune tolerance in pathological and physiological cell death: Nanotechnology comes into view. Int Immunopharmacol 2020; 90:107177. [PMID: 33249046 DOI: 10.1016/j.intimp.2020.107177] [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: 08/24/2020] [Revised: 10/26/2020] [Accepted: 11/02/2020] [Indexed: 02/06/2023]
Abstract
Apoptotic cells are tolerogenic and can present self-antigens in the absence of inflammation, to antigen-presenting cells by the process of efferocytosis, resulting in anergy and depletion of immune effector cells. This tolerance is essential to maintain immune homeostasis and prevent systemic autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Consequently, effective efferocytosis can result in the induction of immune tolerance mediated via triggering modulatory lymphocytes and anti-inflammatory responses. Furthermore, several distinct soluble factors, receptors and pathways have been found to be involved in the efferocytosis, which are able to regulate immune tolerance by lessening antigen presentation, inhibition of T-cell proliferation and induction of regulatory T-cells. Some newly developed nanotechnology-based approaches can induce antigen-specific immunological tolerance without any systemic immunosuppression. These strategies have been explored to reverse autoimmune responses induced against various protein antigens in different diseases. In this review, we describe some nanotechnology-based approaches for the maintenance of self-tolerance using the apoptotic cell clearance process (efferocytosis) that may be able to induce immune tolerance and treat autoimmune diseases.
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Affiliation(s)
- Amir Tajbakhsh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Najmeh Farahani
- Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sayed Mohammad Gheibihayat
- Department of Medical Genetics, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | | | - Amir Savardashtaki
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, Johannesburg 2028, South Africa.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, I.R., Iran.
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26
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Wang T, Zhao Y, You Z, Li X, Xiong M, Li H, Yan N. Endoplasmic Reticulum Stress Affects Cholesterol Homeostasis by Inhibiting LXRα Expression in Hepatocytes and Macrophages. Nutrients 2020; 12:nu12103088. [PMID: 33050595 PMCID: PMC7601278 DOI: 10.3390/nu12103088] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 09/30/2020] [Accepted: 10/05/2020] [Indexed: 02/06/2023] Open
Abstract
Atherosclerosis (AS) is the most common cardiovascular disease, and reverse cholesterol transport (RCT) plays an important role in maintaining cholesterol homeostasis. Both endoplasmic reticulum (ER) stress and LXRα can affect the metabolism of cholesterol. However, whether ER stress can modulate cholesterol metabolism by LXRα in hepatocytes and macrophages remains unclear. Therefore, in this study, we aimed to explore the relationship between ER stress induced by tunicamycin and LXRα in hepatocytes and macrophages and clarify their possible mechanisms and roles in AS. C57BL/6 mice and Huh-7 and THP-1 cells were treated with tunicamycin and LXR-623 (an agonist of LXRα) alone or in combination. Tunicamycin-induced ER stress caused liver injury; promoted the accumulation of cholesterol and triglycerides; inhibited the expression of LXRα, ABCA1 and ABCG1 in the livers of mice, thus reducing serum high-density lipoprotein (HDL)-C, low-density lipoprotein (LDL)-C, total cholesterol and triglyceride levels; however, LXR-623 could attenuate ER stress and reverse these changes. We also obtained the same results in Huh-7 and THP-1 cells. ER stress induced by tunicamycin could clearly be reversed by activating LXRα because it promoted cholesterol efflux by enhancing the expression of ABCA1 and ABCG1 in hepatocytes and macrophages, contributing to attenuation of the development of AS.
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27
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Abrams ME, Johnson KA, Perelman SS, Zhang LS, Endapally S, Mar KB, Thompson BM, McDonald JG, Schoggins JW, Radhakrishnan A, Alto NM. Oxysterols provide innate immunity to bacterial infection by mobilizing cell surface accessible cholesterol. Nat Microbiol 2020; 5:929-942. [PMID: 32284563 PMCID: PMC7442315 DOI: 10.1038/s41564-020-0701-5] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 03/04/2020] [Indexed: 11/09/2022]
Abstract
Cholesterol 25-hydroxylase (CH25H) is an interferon-stimulated gene that converts cholesterol to the oxysterol 25-hydroxycholesterol (25HC). Circulating 25HC modulates essential immunological processes including antiviral immunity, inflammasome activation and antibody class switching; and dysregulation of CH25H may contribute to chronic inflammatory disease and cancer. Although 25HC is a potent regulator of cholesterol storage, uptake, efflux and biosynthesis, how these metabolic activities reprogram the immunological state of target cells remains poorly understood. Here, we used recently designed toxin-based biosensors that discriminate between distinct pools of plasma membrane cholesterol to elucidate how 25HC prevents Listeria monocytogenes from traversing the plasma membrane of infected host cells. The 25HC-mediated activation of acyl-CoA:cholesterol acyltransferase (ACAT) triggered rapid internalization of a biochemically defined fraction of cholesterol, termed 'accessible' cholesterol, from the plasma membrane while having little effect on cholesterol in complexes with sphingomyelin. We show that evolutionarily distinct bacterial species, L. monocytogenes and Shigella flexneri, exploit the accessible pool of cholesterol for infection and that acute mobilization of this pool by oxysterols confers immunity to these pathogens. The significance of this signal-mediated membrane remodelling pathway probably extends beyond host defence systems, as several other biologically active oxysterols also mobilize accessible cholesterol through an ACAT-dependent mechanism.
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Affiliation(s)
- Michael E Abrams
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Kristen A Johnson
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Sofya S Perelman
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Microbiology, New York University School of Medicine, NY, NY, USA
| | - Li-Shu Zhang
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Shreya Endapally
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Katrina B Mar
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Bonne M Thompson
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Jeffrey G McDonald
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - John W Schoggins
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Arun Radhakrishnan
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Neal M Alto
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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28
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Anand PK. Lipids, inflammasomes, metabolism, and disease. Immunol Rev 2020; 297:108-122. [PMID: 32562313 DOI: 10.1111/imr.12891] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/19/2020] [Accepted: 05/27/2020] [Indexed: 12/19/2022]
Abstract
Inflammasomes are multi-protein complexes that regulate the cleavage of cysteine protease caspase-1, secretion of inflammatory cytokines, and induction of inflammatory cell death, pyroptosis. Several members of the nod-like receptor family assemble inflammasome in response to specific ligands. An exception to this is the NLRP3 inflammasome which is activated by structurally diverse entities. Recent studies have suggested that NLRP3 might be a sensor of cellular homeostasis, and any perturbation in distinct metabolic pathways results in the activation of this inflammasome. Lipid metabolism is exceedingly important in maintaining cellular homeostasis, and it is recognized that cells and tissues undergo extensive lipid remodeling during activation and disease. Some lipids are involved in instigating chronic inflammatory diseases, and new studies have highlighted critical upstream roles for lipids, particularly cholesterol, in regulating inflammasome activation implying key functions for inflammasomes in diseases with defective lipid metabolism. The focus of this review is to highlight how lipids regulate inflammasome activation and how this leads to the progression of inflammatory diseases. The key roles of cholesterol metabolism in the activation of inflammasomes have been comprehensively discussed. Besides, the roles of oxysterols, fatty acids, phospholipids, and lipid second messengers are also summarized in the context of inflammasomes. The overriding theme is that lipid metabolism has numerous but complex functions in inflammasome activation. A detailed understanding of this area will help us develop therapeutic interventions for diseases where dysregulated lipid metabolism is the underlying cause.
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Affiliation(s)
- Paras K Anand
- Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, UK
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29
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Yang J, Liu L, Yang X, Duan Y, Zeng P, Yang S, Ma C, Li X, Han J, Chen Y. Combination of MEK1/2 inhibitor and LXR ligand synergistically inhibit atherosclerosis in LDLR deficient mice. Biochem Biophys Res Commun 2020; 522:512-517. [PMID: 31784089 DOI: 10.1016/j.bbrc.2019.11.115] [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: 11/03/2019] [Accepted: 11/18/2019] [Indexed: 11/20/2022]
Abstract
Combined LXR ligand (T0901317) and MEK1/2 inhibitor (U0126) not only reduces atherosclerosis in apoE deficient mice, but also blocks LXR ligand-induced fatty liver and hypertriglyceridemia. However, the atheroprotective function of combined T0901317 and U0126 should be further investigated in LDLR deficient (LDLR-/-) mice since deficiency of LDLR not apoE can occur to humans with a high frequency. Herein, we validated the effectiveness of this combinational therapy on the development of atherosclerosis in LDLR-/- mice to demonstrate its potential application in clinic. We found although T0901317 or U0126 alone reduced atherosclerotic plaques in en face and aortic root areas in HFD-fed LDLR-/- mice, their combination inhibited lesions in a synergistic manner. Combined U0126 and T0901317 had no effect on serum total cholesterol levels. T0901317 deceased HDL-cholesterol levels, which was restored by combined U0126. Meanwhile, U0126 alleviated T0901317-induced triglyceride accumulation, the major adverse effect of T0901317 which limits its clinical utility. Mechanistically, U0126 reduced fatty acid de novo synthesis by inhibiting hepatic fatty acid synthase (FASN) expression, thereby correcting T0901317-induced triglyceride overproduction. In conclusion, our study demonstrates that combination of MEK1/2 inhibitor and LXR ligand can synergistically reduce atherosclerosis in LDLR deficient mice without lipogenic side effects.
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Affiliation(s)
- Jie Yang
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Lipei Liu
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Xiaoxiao Yang
- Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Yajun Duan
- Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Peng Zeng
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Shu Yang
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Chuanrui Ma
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Xiaoju Li
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Jihong Han
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China; Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Yuanli Chen
- Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
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30
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Pastore M, Grimaudo S, Pipitone RM, Lori G, Raggi C, Petta S, Marra F. Role of Myeloid-Epithelial-Reproductive Tyrosine Kinase and Macrophage Polarization in the Progression of Atherosclerotic Lesions Associated With Nonalcoholic Fatty Liver Disease. Front Pharmacol 2019; 10:604. [PMID: 31191323 PMCID: PMC6548874 DOI: 10.3389/fphar.2019.00604] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 05/14/2019] [Indexed: 12/13/2022] Open
Abstract
Recent lines of evidence highlight the involvement of myeloid-epithelial-reproductive tyrosine kinase (MerTK) in metabolic disease associated with liver damage. MerTK is mainly expressed in anti-inflammatory M2 macrophages where it mediates transcriptional changes including suppression of proinflammatory cytokines and enhancement of inflammatory repressors. MerTK is regulated by metabolic pathways through nuclear sensors including LXRs, PPARs, and RXRs, in response to apoptotic bodies or to other sources of cholesterol. Nonalcoholic fatty liver disease (NAFLD) is one of the most serious public health problems worldwide. It is a clinicopathological syndrome closely related to obesity, insulin resistance, and oxidative stress. It includes a spectrum of conditions ranging from simple steatosis, characterized by hepatic fat accumulation with or without inflammation, to nonalcoholic steatohepatitis (NASH), defined by hepatic fat deposition with hepatocellular damage, inflammation, and accumulating fibrosis. Several studies support an association between NAFLD and the incidence of cardiovascular diseases including atherosclerosis, a major cause of death worldwide. This pathological condition consists in a chronic and progressive inflammatory process in the intimal layer of large- and medium-sized arteries. The complications of advanced atherosclerosis include chronic or acute ischemic damage in the tissue perfused by the affected artery, leading to cellular death. By identifying specific targets influencing lipid metabolism and cardiovascular-related diseases, the present review highlights the role of MerTK in NAFLD-associated atherosclerotic lesions as a potential innovative therapeutic target. Therapeutic advantages might derive from the use of compounds selective for nuclear receptors targeting PPARs rather than LXRs regulating macrophage lipid metabolism and macrophage mediated inflammation, by favoring the expression of MerTK, which mediates an immunoregulatory action with a reduction in inflammation and in atherosclerosis.
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Affiliation(s)
- Mirella Pastore
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Stefania Grimaudo
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Rosaria Maria Pipitone
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Giulia Lori
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Chiara Raggi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.,Humanitas Clinical and Research Center, Rozzano, Italy
| | - Salvatore Petta
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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31
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Byun S, Jung H, Chen J, Kim YC, Kim DH, Kong B, Guo G, Kemper B, Kemper JK. Phosphorylation of hepatic farnesoid X receptor by FGF19 signaling-activated Src maintains cholesterol levels and protects from atherosclerosis. J Biol Chem 2019; 294:8732-8744. [PMID: 30996006 DOI: 10.1074/jbc.ra119.008360] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 04/12/2019] [Indexed: 12/13/2022] Open
Abstract
The bile acid (BA) nuclear receptor, farnesoid X receptor (FXR/NR1H4), maintains metabolic homeostasis by transcriptional control of numerous genes, including an intestinal hormone, fibroblast growth factor-19 (FGF19; FGF15 in mice). Besides activation by BAs, the gene-regulatory function of FXR is also modulated by hormone or nutrient signaling-induced post-translational modifications. Recently, phosphorylation at Tyr-67 by the FGF15/19 signaling-activated nonreceptor tyrosine kinase Src was shown to be important for FXR function in BA homeostasis. Here, we examined the role of this FXR phosphorylation in cholesterol regulation. In both hepatic FXR-knockout and FXR-knockdown mice, reconstitution of FXR expression up-regulated cholesterol transport genes for its biliary excretion, including scavenger receptor class B member 1 (Scarb1) and ABC subfamily G member 8 (Abcg5/8), decreased hepatic and plasma cholesterol levels, and increased biliary and fecal cholesterol levels. Of note, these sterol-lowering effects were blunted by substitution of Phe for Tyr-67 in FXR. Moreover, consistent with Src's role in phosphorylating FXR, Src knockdown impaired cholesterol regulation in mice. In hypercholesterolemic apolipoprotein E-deficient mice, expression of FXR, but not Y67F-FXR, ameliorated atherosclerosis, whereas Src down-regulation exacerbated it. Feeding or treatment with an FXR agonist induced Abcg5/8 and Scarb1 expression in WT, but not FGF15-knockout, mice. Furthermore, FGF19 treatment increased occupancy of FXR at Abcg5/8 and Scarb1, expression of these genes, and cholesterol efflux from hepatocytes. These FGF19-mediated effects were blunted by the Y67F-FXR substitution or Src down-regulation or inhibition. We conclude that phosphorylation of hepatic FXR by FGF15/19-induced Src maintains cholesterol homeostasis and protects against atherosclerosis.
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Affiliation(s)
- Sangwon Byun
- From the Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois 61801 and
| | - Hyunkyung Jung
- From the Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois 61801 and
| | - Jinjing Chen
- From the Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois 61801 and
| | - Young-Chae Kim
- From the Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois 61801 and
| | - Dong-Hyun Kim
- From the Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois 61801 and
| | - Bo Kong
- the Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854
| | - Grace Guo
- the Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854
| | - Byron Kemper
- From the Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois 61801 and
| | - Jongsook Kim Kemper
- From the Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois 61801 and
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Zhao J, Chen H, Wei J, Jim Leu S, Lee T. CCN family member 1 deregulates cholesterol metabolism and aggravates atherosclerosis. Acta Physiol (Oxf) 2019; 225:e13209. [PMID: 30347516 DOI: 10.1111/apha.13209] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 09/26/2018] [Accepted: 10/01/2018] [Indexed: 12/25/2022]
Abstract
AIM CCN family member 1 (CCN1) is an extracellular matrix cytokine and appears in atherosclerotic lesions. However, we have no evidence to support the role of CCN1 in regulating cholesterol metabolism and atherosclerosis. METHODS Apolipoprotein E-deficient (apoE-/- ) mice were used as in vivo model. Oxidized low-density lipoprotein (oxLDL)-induced macrophage-foam cells were used as in vitro model. RT-PCR and western blot analysis were used for evaluating gene and protein expression, respectively. Conventional assay kits were used for assessing the levels of cholesterol, triglycerides, and cytokines. RESULTS We show predominant expression of CCN1 in foamy macrophages in atherosclerotic aortas of apoE-/- mice. In apoE-/- mice, CCN1 treatment worsened hyperlipidaemia, systemic inflammation, and the progression of atherosclerosis. In addition, CCN1 decreased the capacity of reverse cholesterol transport and downregulated the protein expression of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 in atherosclerotic aortas. Notably, CCN1 decreased the protein expression of cholesterol clearance-related proteins, including ABCG5, ABCG8, liver X receptor α (LXRα), cholesterol 7α-hydrolase and LDL receptor in liver, and exacerbated hepatic lipid accumulation. In macrophages, treatment with oxLDL increased CCN1 expression. Inhibition of CCN1 activity by neutralizing antibody or small interfering RNA attenuated the oxLDL-induced lipid accumulation. In contrast, cotreatment with CCN1 or overexpression of CCN1 augmented oxLDL-induced lipid accumulation by impairing apolipoprotein AI- and high-density lipoprotein-dependent cholesterol efflux, which was attributed to downregulation of LXRα-dependent expression of ABCA1 and ABCG1. CONCLUSION Our findings suggest that CCN1 plays a pivotal role in regulating cholesterol metabolism and the development of atherosclerosis.
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Affiliation(s)
- Jin‐Feng Zhao
- MRC Protein Phosphorylation and Ubiquitylation Unit University of Dundee Dundee UK
- Department of Physiology National Yang‐Ming University Taipei Taiwan
| | - Hsiang‐Ying Chen
- Department of Physiology National Yang‐Ming University Taipei Taiwan
| | - Jeng Wei
- Heart Center Cheng‐Hsin General Hospital Taipei Taiwan
| | - Shr‐Jeng Jim Leu
- Department of Biotechnology and Laboratory Science in Medicine National Yang‐Ming University Taipei Taiwan
| | - Tzong‐Shyuan Lee
- Graduate Institute and Department of Physiology, College of Medicine National Taiwan University Taipei Taiwan
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García-Ríos A, Camargo Garcia A, Perez-Jimenez F, Perez-Martinez P. Gut microbiota: A new protagonist in the risk of cardiovascular disease? CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS 2019; 31:178-185. [PMID: 30737071 DOI: 10.1016/j.arteri.2018.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 11/12/2018] [Accepted: 11/23/2018] [Indexed: 11/26/2022]
Abstract
Cardiovascular disease remains the first cause of mortality in Western countries. New strategies for prevention and control of cardiovascular disease are needed. At the same time, the incidence of risk factors that lead to the development of this disease, such as obesity, hypertension and diabetes, continues to rise. Therefore, the search for new markers or mediators is a priority in most cardiovascular prevention programs. The study of the intestinal microbiota is emerging because it is known that intestinal microorganisms act collectively as an integrated organ, regulating multiple biological functions that can modulate cardiovascular risk factors and the pathogenic mechanisms of this process. This review considers the current situation regarding the influence of gut microbiota on cardiovascular disease and particularly, its influence on the main traditional risk factors that lead to cardiovascular disease, such as obesity, diabetes, hypertension and lipids.
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Affiliation(s)
- Antonio García-Ríos
- Unidad de Lípidos y Arteriosclerosis, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Córdoba, España.
| | - Antonio Camargo Garcia
- Unidad de Lípidos y Arteriosclerosis, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Córdoba, España
| | - Francisco Perez-Jimenez
- Unidad de Lípidos y Arteriosclerosis, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Córdoba, España
| | - Pablo Perez-Martinez
- Unidad de Lípidos y Arteriosclerosis, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Córdoba, España
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Guo S, Lu J, Zhuo Y, Xiao M, Xue X, Zhong S, Shen X, Yin C, Li L, Chen Q, Zhu M, Chen B, Zhao M, Zheng L, Tao Y, Yin H. Endogenous cholesterol ester hydroperoxides modulate cholesterol levels and inhibit cholesterol uptake in hepatocytes and macrophages. Redox Biol 2018; 21:101069. [PMID: 30576926 PMCID: PMC6302155 DOI: 10.1016/j.redox.2018.101069] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 12/06/2018] [Indexed: 12/14/2022] Open
Abstract
Dysregulation of cholesterol metabolism represents one of the major risk factors for atherosclerotic cardiovascular disease (CVD). Oxidized cholesterol esters (oxCE) in low-density lipoprotein (LDL) have been implicated in CVD but the underlying mechanisms remain poorly defined. We use a targeted lipidomic approach to demonstrate that levels of oxCEs in human plasma are associated with different types of CVD and significantly elevated in patients with myocardial infarction. We synthesized a major endogenous cholesterol ester hydroperoxide (CEOOH), cholesteryl-13(cis, trans)-hydroperoxy-octadecadienoate (ch-13(c,t)-HpODE) and show that this endogenous compound significantly increases plasma cholesterol level in mice while decrease cholesterol levels in mouse liver and peritoneal macrophages, which is primarily due to the inhibition of cholesterol uptake in macrophages and liver. Further studies indicate that inhibition of cholesterol uptake by ch-13(c,t)-HpODE in macrophages is dependent on LXRα-IDOL-LDLR pathway, whereas inhibition on cholesterol levels in hepatocytes is dependent on LXRα and LDLR. Consistently, these effects on cholesterol levels by ch-13(c,t)-HpODE are diminished in LDLR or LXRα knockout mice. Together, our study provides evidence that elevated plasma cholesterol levels by CEOOHs are primarily due to the inhibition of cholesterol uptake in the liver and macrophages, which may play an important role in the pathogenesis of CVD.
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Affiliation(s)
- Shuyuan Guo
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China; University of Chinese Academy of Sciences, CAS, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China
| | - Jianhong Lu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China; University of Chinese Academy of Sciences, CAS, Beijing 100049, China
| | - Yujuan Zhuo
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China; University of Chinese Academy of Sciences, CAS, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China
| | - Mengqing Xiao
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China; University of Chinese Academy of Sciences, CAS, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China
| | - Xinli Xue
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China; University of Chinese Academy of Sciences, CAS, Beijing 100049, China
| | - Shanshan Zhong
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China; University of Chinese Academy of Sciences, CAS, Beijing 100049, China
| | - Xia Shen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China; University of Chinese Academy of Sciences, CAS, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China
| | - Chunzhao Yin
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China; University of Chinese Academy of Sciences, CAS, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China
| | - Luxiao Li
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China; University of Chinese Academy of Sciences, CAS, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China
| | - Qun Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China; University of Chinese Academy of Sciences, CAS, Beijing 100049, China
| | - Mingjiang Zhu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China
| | - Buxing Chen
- Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Mingming Zhao
- The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Peking University Health Science Center, Beijing, China
| | - Lemin Zheng
- The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Peking University Health Science Center, Beijing, China
| | - Yongzhen Tao
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China
| | - Huiyong Yin
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China; University of Chinese Academy of Sciences, CAS, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China; Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100000, China.
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Kim Y, Jeong J, Yang J, Joo SW, Hong J, Choi J. Graphene oxide nano-bio interaction induces inhibition of spermatogenesis and disturbance of fatty acid metabolism in the nematode Caenorhabditis elegans. Toxicology 2018; 410:83-95. [PMID: 30218681 DOI: 10.1016/j.tox.2018.09.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 08/02/2018] [Accepted: 09/09/2018] [Indexed: 01/10/2023]
Abstract
Graphene oxide (GO) has the potential for wide applications, which necessitates an intensive investigation of its potential hazard on human and environmental health. Even if previous studies show reproductive toxicity in the nematode Caenorhabditis elegans, the mechanisms of reproductive toxicity by GO are poorly understood. To understand the underlying mechanisms of GO-induced reproductive toxicity, we investigated the interaction between GO and C. elegans using Raman spectroscopy, sperm counts produced by spermatogenesis, progeny and analyzed the fatty acid metabolism using molecular techniques. GO-characteristic Raman spectral bands measured throughout C. elegans, brood size and Hoecst staining of dissected gonads clearly showed GO accumulation in the reproductive organs, reduced progeny and low sperm counts, which are possibly direct results of the reproductive toxicity from GO exposure. Interestingly, reduced fatty acid metabolites, such as stearic, oleic, palmitoleic, and palmitic acids, were found with GO exposure. We found that GO increased intestinal fat accumulation in wild type N2, fat-5(tm420), and fat-7(wa36) mutants, whereas it decreased fat storage in the fat-6(tm331) and nhr-49(nr2041) mutants. GO exposure affected C. elegans fat accumulation and consumption, which was possibly regulated by daf-16 and nhr-80 gene activity. Also, GO exposure suppressed the survival of long-lived fat-5(tm420) mutants, whereas it increased the survival of short-lived nhr-49(nr2041) mutants. Hence, our studies collectively indicated that GO accumulation in reproductive organs, suppression of spermatogenesis, and the alteration of fatty acid metabolism play critical roles in understanding mechanisms of toxicity in C. elegans.
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Affiliation(s)
- Yongsoon Kim
- School of Environmental Engineering, University of Seoul, 163 Seoulsiripdaero, Dongdaemun-gu, Seoul 02504, Republic of Korea
| | - Jaeseong Jeong
- School of Environmental Engineering, University of Seoul, 163 Seoulsiripdaero, Dongdaemun-gu, Seoul 02504, Republic of Korea
| | - Jisu Yang
- School of Environmental Engineering, University of Seoul, 163 Seoulsiripdaero, Dongdaemun-gu, Seoul 02504, Republic of Korea
| | - Sang-Woo Joo
- Department of Information Communication, Materials and Chemistry Convergence Technology, Soongsil University, 369 Sangdo-Ro, Dongjak-gu, Seoul 06978, Republic of Korea
| | - Jongki Hong
- College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Jinhee Choi
- School of Environmental Engineering, University of Seoul, 163 Seoulsiripdaero, Dongdaemun-gu, Seoul 02504, Republic of Korea.
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Krishna SM, Moxon JV, Jose RJ, Li J, Sahebkar A, Jaafari MR, Hatamipour M, Liu D, Golledge J. Anionic nanoliposomes reduced atherosclerosis progression in Low Density Lipoprotein Receptor (LDLR) deficient mice fed a high fat diet. J Cell Physiol 2018; 233:6951-6964. [PMID: 29741759 DOI: 10.1002/jcp.26610] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 03/22/2018] [Indexed: 12/28/2022]
Abstract
Atherosclerosis is a systemic disease characterized by the deposition of cholesterol and inflammatory cells within the arterial wall. Removal of cholesterol from the vessel wall may have an impact on the size and composition of atherosclerotic lesions. Anionic phospholipids or liposome vesicles composed of a lipid bilayer such as nanoliposomes have been suggested as treatments for dyslipidemia. In this study, we investigated the effect of anionic nanoliposomes on atherosclerosis in a mouse model. Low-density lipoprotein receptor knockout mice (Ldlr-/- ) were fed with an atherosclerosis promoting high fat and cholesterol (HFC) diet for 12 weeks. Anionic nanoliposomes including hydrogenated soy phosphatidylcholine (HSPC) and distearoyl phosphatidylglycerol (DSPG) (molar ratio: 1:3) were injected intravenously into HFC-fed Ldlr-/- mice once a week for 4 weeks. Mice receiving nanoliposomes had significantly reduced atherosclerosis within the aortic arch as assessed by Sudan IV staining area (p = 0.007), and reduced intima/media ratio (p = 0.030) and greater collagen deposition within atherosclerosis plaques within the brachiocephalic artery (p = 0.007), compared to control mice. Administration of nanoliposomes enhanced markers of reverse cholesterol transport (RCT) and increased markers of plaque stability in HFC-fed Ldlr-/- mice. Reduced cholesterol accumulation was observed in the liver along with the up-regulation of the major genes involved in the efflux of cholesterol such as hepatic ATP-binding cassette transporters (ABC) including Abc-a1, Abc-g1, Abc-g5, and Abc-g8, Scavenger receptor class B, member 1 (Scarb1), and Liver X receptor alpha (Lxr)-α. Lecithin Cholesterol Acyltransferase activity within the plasma was also increased in mice receiving nanoliposomes. Anionic nanoliposome administration reduced atherosclerosis in HFC-fed Ldlr-/- mice by promoting RCT and upregulating the ABC-A1/ABC-G1 pathway.
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Affiliation(s)
- Smriti M Krishna
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia
| | - Joseph V Moxon
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia
| | - Roby J Jose
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia
| | - Jiaze Li
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud R Jaafari
- Nanotechnology Research Centre, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahdi Hatamipour
- Nanotechnology Research Centre, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Dawie Liu
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia
| | - Jonathan Golledge
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia.,Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Queensland, Australia
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Feng T, Liu P, Wang X, Luo J, Zuo X, Jiang X, Liu C, Li Y, Li N, Chen M, Zhu N, Han X, Liu C, Xu Y, Si S. SIRT1 activator E1231 protects from experimental atherosclerosis and lowers plasma cholesterol and triglycerides by enhancing ABCA1 expression. Atherosclerosis 2018; 274:172-181. [PMID: 29787963 DOI: 10.1016/j.atherosclerosis.2018.04.039] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 04/18/2018] [Accepted: 04/27/2018] [Indexed: 01/09/2023]
Abstract
BACKGROUND AND AIMS Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent protein deacetylase. Recent studies have demonstrated that enhancing SIRT1 expression or activity may modulate cholesterol and lipid metabolism. However, pharmacological and molecular regulators for SIRT1 are scarce. Here, we aimed to find novel small molecule modulators of SIRT1 to regulate cholesterol and lipid metabolism. METHODS A high-throughput screening assay was established to identify SIRT1 activators. Surface plasmon resonance and immunoprecipitation were performed to confirm the interaction of E1231 with SIRT1. Cholesterol assay was performed to demonstrate the in vitro effect of E1231. The in vivo effect of E1231 was evaluated in experimental models. RESULTS E1231, a piperazine 1,4-diamide compound, was identified as a SIRT1 activator with EC50 value of 0.83 μM. E1231 interacted with recombinant human SIRT1 protein and deacetylated liver X receptor-alpha (LXRα). E1231 increased ATP-binding cassette transporter A1 (ABCA1) expression in RAW 264.7 cells dependent on SIRT1 and LXRα. E1231 promoted cholesterol efflux and inhibited lipid accumulation in RAW 264.7 cells via SIRT1 and ABCA1. In the golden hamster hyperlipidemia model, E1231 treatment decreased total cholesterol and triglyceride levels in both serum and the liver, while increased cholesterol content in feces. Moreover, E1231 increased ABCA1 and SIRT1 protein expression in the liver. In ApoE-/- mice, E1231 treatment reduced atherosclerotic plaque development compared with untreated ApoE-/- mice. CONCLUSIONS We identified a novel SIRT1 activator E1231 and elucidated its beneficial effects on lipid and cholesterol metabolism. Our study suggests that E1231 might be developed as a novel drug for treating atherosclerosis.
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Affiliation(s)
- Tingting Feng
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China; Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China
| | - Peng Liu
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Xiao Wang
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Jinque Luo
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Xuan Zuo
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Xinhai Jiang
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Chang Liu
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Yongzhen Li
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Ni Li
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, CAMS & PUMC, Beijing, 100050, China
| | - Minghua Chen
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Ningyu Zhu
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Xiaowan Han
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Chao Liu
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China
| | - Yanni Xu
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China.
| | - Shuyi Si
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China.
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Bhat OM, Kumar PU, Rao KR, Ahmad A, Dhawan V. Terminalia arjuna prevents Interleukin-18-induced atherosclerosis via modulation of NF-κB/PPAR-γ-mediated pathway in Apo E-/- mice. Inflammopharmacology 2018; 26:583-598. [PMID: 28547701 DOI: 10.1007/s10787-017-0357-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Accepted: 04/29/2017] [Indexed: 12/23/2022]
Abstract
AIM OF THE STUDY Terminalia arjuna is a medicinal plant well known as a cardiotonic in Ayurvedic system of medicine. We hypothesized that aqueous stem bark extract of T. arjuna (TAE) may inhibit IL-18-induced atherosclerosis via NF-κB/PPAR-γ-mediated pathway in Apo E-/- mice. MATERIALS AND METHODS 12-week-old, male Apo E-/- mice divided into four groups (n = 6/group) fed with normal chow-diet were employed: GP I: phosphate buffer saline (PBS) (2 month); GP II: rIL-18 (1 month) followed by PBS (1 month); GP III: rIL-18 (1 month) followed by TAE (1 month); GP IV: rIL-18 (1 month) followed by atorvastatin (1 month). RESULTS IL-18 treatment induced a significant increase (p < 0.001) in pro-inflammatory marker (IL-18) (170 ± 9.16 vs. 1178.66 ± 8.08, pg/ml), and downregulated cholesterol efflux gene (PPAR-γ) by ~0.6-fold vs. 1.00 in IL-18-treated mice as compared to the control animals, respectively. TAE treatment to both groups caused a significant reduction in IL-18 to 281.66 ± 9.60 vs. 1178.66 ± 8.08 (pg/ml), upregulated cholesterol efflux gene by ~1.5- vs. 0.6-fold in TAE-treated group, decreased atherogenic lipids, and percentage atherosclerotic lesion area, demonstrating comparable effects with atorvastatin. CONCLUSION Our data demonstrate that TAE protects against IL-18-induced atherosclerosis via NF-κB/PPAR-γ-mediated pathway.
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Affiliation(s)
- Owais Mohammad Bhat
- Department of Pharmcology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
| | - P Uday Kumar
- Department of Histopathology, National Institute of Nutrition (NIN), Hyderabad, India
| | - K Rajender Rao
- National Centre for Laboratory Animal Sciences (NCLAS), National Institute of Nutrition (NIN), Hyderabad, India
| | - Ashfaq Ahmad
- Department of Pharmcology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
| | - Veena Dhawan
- Department of Experimental Medicine and Biotechnology, Research Block-B, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India.
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Zhen X, Xie C, Jiang Y, Ai X, Xing B, Pu K. Semiconducting Photothermal Nanoagonist for Remote-Controlled Specific Cancer Therapy. NANO LETTERS 2018; 18:1498-1505. [PMID: 29342359 DOI: 10.1021/acs.nanolett.7b05292] [Citation(s) in RCA: 145] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
Nanomedicine have shown success in cancer therapy, but the pharmacological actions of most nanomedicine are often nonspecific to cancer cells because of utilization of the therapeutic agents that induce cell apoptosis from inner organelles. We herein report the development of semiconducting photothermal nanoagonists that can remotely and specifically initiate the apoptosis of cancer cells from cell membrane. The organic nanoagonists comprise semiconducting polymer nanoparticles (SPNs) and capsaicin (Cap) as the photothermally responsive nanocarrier and the agonist for activation of transient receptor potential cation channel subfamily V member 1 (TRPV1), respectively. Under multiple NIR laser irradiation at the time scale of seconds, the nanoagonists can repeatedly and locally release Cap to multiply activate TRPV1 channels on the cellular membrane; the cumulative effect is the overinflux of ions in mitochondria followed by the induction of cell apoptosis specifically for TRPV1-postive cancer cells. Multiple transient activation of TRPV1 channels is essential to induce such a cell death both in vitro and in vivo because both free Cap and simple Cap-encapsulated nanoparticles fail to do so. The photothermally triggered release also ensures a high local concentration of the TRPV1 agonist at tumor site, permitting specific cancer cell therapy at a low systemic administration dosage. Our study thus demonstrates the first example of ion-channel-specific and remote-controlled drug-delivery system for cancer cell therapy.
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Affiliation(s)
- Xu Zhen
- School of Chemical and Biomedical Engineering, Nanyang Technological University , 70 Nanyang Drive, 637457 Singapore
| | - Chen Xie
- School of Chemical and Biomedical Engineering, Nanyang Technological University , 70 Nanyang Drive, 637457 Singapore
| | - Yuyan Jiang
- School of Chemical and Biomedical Engineering, Nanyang Technological University , 70 Nanyang Drive, 637457 Singapore
| | - Xiangzhao Ai
- Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University , 637371 Singapore
| | - Bengang Xing
- Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University , 637371 Singapore
| | - Kanyi Pu
- School of Chemical and Biomedical Engineering, Nanyang Technological University , 70 Nanyang Drive, 637457 Singapore
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Liu M, Yang W, Liu S, Hock D, Zhang B, Huo RY, Tong X, Yan H. LXRα is expressed at higher levels in healthy people compared to atherosclerosis patients and its over-expression polarizes macrophages towards an anti-inflammatory MΦ2 phenotype. Clin Exp Hypertens 2018; 40:213-217. [PMID: 29420090 DOI: 10.1080/10641963.2017.1288740] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Mengyuan Liu
- Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin, 300060 China
- Tianjin Huanhu Hospital, Tianjin Dementia Institute, Tianjin, 300060 China
| | - Weijian Yang
- Graduate School of Tianjin Medical University, Tianjin, China
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, China
| | - Shuling Liu
- Department of Neurology, Tianjin Huanhu Hospital, Tianjin, 300060 China
| | - Duncan Hock
- Medicine School, University of South Florida, Tampa, 33620-9951 United States
| | - Bohao Zhang
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, China
| | - Ruth Ya Huo
- School of Medicine, University of New South Wales, Sydney, 2052 Australia
| | - Xiaoguang Tong
- Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin, 300060 China
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, China
| | - Hua Yan
- Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin, 300060 China
- Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, China
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Yamauchi Y, Rogers MA. Sterol Metabolism and Transport in Atherosclerosis and Cancer. Front Endocrinol (Lausanne) 2018; 9:509. [PMID: 30283400 PMCID: PMC6157400 DOI: 10.3389/fendo.2018.00509] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 08/14/2018] [Indexed: 01/22/2023] Open
Abstract
Cholesterol is a vital lipid molecule for mammalian cells, regulating fluidity of biological membranes, and serving as an essential constituent of lipid rafts. Mammalian cells acquire cholesterol from extracellular lipoproteins and from de novo synthesis. Cholesterol biosynthesis generates various precursor sterols. Cholesterol undergoes metabolic conversion into oxygenated sterols (oxysterols), bile acids, and steroid hormones. Cholesterol intermediates and metabolites have diverse and important cellular functions. A network of molecular machineries including transcription factors, protein modifiers, sterol transporters/carriers, and sterol sensors regulate sterol homeostasis in mammalian cells and tissues. Dysfunction in metabolism and transport of cholesterol, sterol intermediates, and oxysterols occurs in various pathophysiological settings such as atherosclerosis, cancers, and neurodegenerative diseases. Here we review the cholesterol, intermediate sterol, and oxysterol regulatory mechanisms and intracellular transport machineries, and discuss the roles of sterols and sterol metabolism in human diseases.
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Affiliation(s)
- Yoshio Yamauchi
- Nutri-Life Science Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan
- AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan
- *Correspondence: Yoshio Yamauchi
| | - Maximillian A. Rogers
- Division of Cardiovascular Medicine, Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
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Nomura S, Endo-Umeda K, Fujii S, Makishima M, Hashimoto Y, Ishikawa M. Structural development of tetrachlorophthalimides as liver X receptor β (LXRβ)-selective agonists with improved aqueous solubility. Bioorg Med Chem Lett 2017; 28:796-801. [PMID: 29398545 DOI: 10.1016/j.bmcl.2017.12.024] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 12/08/2017] [Accepted: 12/11/2017] [Indexed: 10/18/2022]
Abstract
LXRβ-selective agonists are promising candidates to improve atherosclerosis without increasing plasma or hepatic TG levels. We have reported a series of tetrachlorophthalimide analogs as an LXRβ-selective agonist. However, they exhibited poor aqueous solubility probably due to its high hydrophobicity and highly rigid and plane structure. In this report, we present further structural development of tetrachloro(styrylphenyl)phthalimides as the LXRβ-selective agonists with improved aqueous solubility.
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Affiliation(s)
- Sayaka Nomura
- Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Kaori Endo-Umeda
- Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Shinya Fujii
- Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Makoto Makishima
- Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Yuichi Hashimoto
- Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Minoru Ishikawa
- Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
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P-407-induced Mouse Model of Dose-controlled Hyperlipidemia and Atherosclerosis: 25 Years Later. J Cardiovasc Pharmacol 2017; 70:339-352. [DOI: 10.1097/fjc.0000000000000522] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Peng L, Lv CS, Zhao Y, Chen SD, Huang Y, Lu DW, Huang SQ, Yang ZB, Qian LC, Wen L. QiShenYiQi pill attenuates atherosclerosis by promoting regulatory T cells, inhibiting T helper 17 cells and accelerating cholesterol excretion. Oncotarget 2017; 8:82196-82206. [PMID: 29137256 PMCID: PMC5669882 DOI: 10.18632/oncotarget.19072] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 06/05/2017] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE The aim of this study was to explore potential immunoregulatory mechanisms underlying the suppressive effect on atherosclerosis of QiShenYiQi pill (QSYQ). METHODS AND RESULTS Male ApoE-/- mice were maintained on a Western-type diet and QSYQ treatment for eight weeks. Determination of atherosclerosis demonstrated that QSYQ attenuated plaque formation and decreased the level of blood low-density lipoproteins-cholesterol. QSYQ treatment did not affect body weight but reduced the ratio of liver weight and body weight. Western blots of liver showed that QSYQ increased the expression of liver X receptor alpha and ATP-binding cassette sub-family G member 5. Western blots of atherosclerotic aorta revealed that QSYQ inhibited the expression of cluster of differentiation 36, promoted the expression of forkhead box P3 and decreased interleukin-17A expression. Western blots of spleen showed that QSYQ decreased the expression of mothers against decapentaplegic homolog 2/3 and forkhead box P3, as well as attenuated the expression of spleen interleukin-6, RAR-related orphan receptor gamma and interleukin-17A. CONCLUSIONS QSYQ exerted an anti-atherosclerosis effect by promoting regulatory T cells in atherosclerotic lesion, inhibiting T helper 17 cells in plaque and spleen and accelerating liver cholesterol excretion.
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Affiliation(s)
- Li Peng
- Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, China
| | - Chong-Shan Lv
- Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, China
| | - Yun Zhao
- Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, China
| | - Shao-Dong Chen
- Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, China
| | - Yang Huang
- Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, China
| | - Da-Wei Lu
- Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, China
| | - Shu-Qiong Huang
- Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, China
| | - Zong-Bao Yang
- Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, China
| | - Lin-Chao Qian
- Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, China
| | - Lei Wen
- Department of Traditional Chinese Medicine, Medical College, Xiamen University, Xiamen 361102, China
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Bakry OA, El Farargy SM, El Kady NNED, Dawy HFA. Immunohistochemical Expression of Cyclo-oxygenase 2 and Liver X Receptor-α in Acne Vulgaris. J Clin Diagn Res 2017; 11:WC01-WC07. [PMID: 29207817 DOI: 10.7860/jcdr/2017/28754.10577] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 07/20/2017] [Indexed: 11/24/2022]
Abstract
Introduction Acne Vulgaris (AV) is a common inflammatory disease of pilosebaceous units. Liver X Receptor-α (LXR-α) is a ligand activated transcription factor. It controls transcription of genes involved in lipid and fatty acid synthesis. Cyclo-oxygenase 2 (COX2) is a rate limiting enzyme in prostaglandin synthesis. It plays important role in inflammation. Aim To evaluate the immunohistochemical expression of LXR-α and COX2 in acne vulgaris skin biopsies to explore their possible pathogenic role in this disease. Materials and Methods Sixty five subjects were included (45 cases with AV and 20 age and gender-matched healthy controls). Skin biopsies were taken from lesional and perilesional skin of cases and from site-matched areas of control subjects. The evaluation of LXR-α and COX2 was done using immunohistochemical technique. Data were collected, tabulated and statistically analysed using a personal computer with "(SPSS) version 11" program. Chi-square test was used to study the association between qualitative variables. Mann-Whitney test was used for comparison between quantitative variables. Student's t-test was used for comparison between two groups having quantitative variables. Spearman's coefficient was used to study the correlation between two different variables. Differences were considered statistically significant with p<0.05. Results COX2 was upregulated in lesional skin compared with peilesional and control skin both in epidermis and pilosebaceous units (p<0.001 for all). Higher epidermal COX2% was significantly associated with papulopustular acne (p=0.009) and higher acne score (p=0.018). Higher pilosebaceous units COX2% was significantly associated with papulopustular acne (p=0.04). LXR-α was upregulated in lesional skin compared with peilesional and control skin both in epidermis and pilosebaceous units (p<0.001 for all). Higher LXR-α % in epidermis and pilosebaceous units was significantly associated with papulopustular acne (p=0.01 for both) and higher acne score (p=0.03 for both). Significant positive correlation was detected between COX2% and LXR-α % in epidermis (p=0.001, r=0.87) and pilosebaceous units (p=0.001, r=0.65). Conclusion Both LXR-α and COX-2 play a role in the pathogenesis of acne vulgaris through their effects on cellular proliferation, inflammation and lipid synthesis. Research for new therapeutic modalities based on their inhibition is needed. More understanding of the interaction between LXR-α, COX2 and acne lesions may lead to effective interference, possibly directed toward specific cell types or steps within inflammatory pathways.
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Affiliation(s)
- Ola Ahmed Bakry
- Assistant Professor, Department of Dermatology, Andrology and STDs, Faculty of Medicine, Menoufiya University, Shibeen El Koom, Egypt
| | - Shawky Mahmoud El Farargy
- Professor, Department of Dermatology, Andrology and STDs, Faculty of Medicine, Menoufiya University, Shibeen El Koom, Egypt
| | - Noha Nour El Din El Kady
- Lecturer, Department of Pathology, Faculty of Medicine, Menoufiya University, Shibeen El Koom, Egypt
| | - Hend Farag Abu Dawy
- Dermatology Specialist, Faculty of Medicine, Menoufiya University, Shibeen El Koom, Egypt
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Gatticchi L, Cerra B, Scarpelli P, Macchioni L, Sebastiani B, Gioiello A, Roberti R. Selected cholesterol biosynthesis inhibitors produce accumulation of the intermediate FF-MAS that targets nucleus and activates LXRα in HepG2 cells. Biochim Biophys Acta Mol Cell Biol Lipids 2017; 1862:842-852. [DOI: 10.1016/j.bbalip.2017.05.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 05/07/2017] [Indexed: 01/23/2023]
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Kanaki M, Tiniakou I, Thymiakou E, Kardassis D. Physical and functional interactions between nuclear receptor LXRα and the forkhead box transcription factor FOXA2 regulate the response of the human lipoprotein lipase gene to oxysterols in hepatic cells. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2017; 1860:848-860. [PMID: 28576574 DOI: 10.1016/j.bbagrm.2017.05.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 05/17/2017] [Accepted: 05/29/2017] [Indexed: 11/30/2022]
Abstract
Lipoprotein lipase (LPL) catalyzes the hydrolysis of triglycerides from triglyceride-rich lipoproteins such as VLDL and chylomicrons in the circulation. Mutations in LPL or its activator apolipoprotein C-II cause hypertriglyceridemia in humans and animal models. The levels of LPL in the liver are low but they can be strongly induced by a high cholesterol diet or by synthetic ligands of Liver X Receptors (LXRs). However, the mechanism by which LXRs activate the human LPL gene is unknown. In the present study we show that LXR agonists increased the mRNA and protein levels as well as the promoter activity of human LPL in HepG2 cells. A promoter deletion analysis defined the proximal -109/-28 region, which contains a functional FOXA2 element, as essential for transactivation by ligand-activated LXRα/RXRα heterodimers. Silencing of endogenous FOXA2 in HepG2 cells by siRNAs or by treatment with insulin compromised the induction of the LPL gene by LXR agonists whereas mutations in the FOXA2 site abolished the synergistic transactivation of the LPL promoter by LXRα/RXRα and FOXA2. Physical and functional interactions between LXRα and FOXA2 were established in vitro and ex vivo. In summary, the present study revealed a novel mechanism of human LPL gene induction by oxysterols in the liver with is based on physical and functional interactions between transcription factors LXRα and FOXA2. This mechanism, which may not be restricted to the LPL gene, is critically important for a better understanding of the regulation of cholesterol and triglyceride metabolism in the liver under healthy or pathological states.
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Affiliation(s)
- Maria Kanaki
- Laboratory of Biochemistry, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion 71003, Greece
| | - Ioanna Tiniakou
- Laboratory of Biochemistry, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion 71003, Greece
| | - Efstathia Thymiakou
- Laboratory of Biochemistry, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion 71003, Greece
| | - Dimitris Kardassis
- Laboratory of Biochemistry, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion 71003, Greece,.
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Bhat OM, Uday Kumar P, Harishankar N, Ravichandaran L, Bhatia A, Dhawan V. Interleukin-18-induced cell adhesion molecule expression is associated with feedback regulation by PPAR-γ and NF-κB in Apo E-/- mice. Mol Cell Biochem 2017; 428:119-128. [PMID: 28176248 DOI: 10.1007/s11010-016-2922-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 12/21/2016] [Indexed: 10/20/2022]
Abstract
Focal recruitment of monocytes and lymphocytes is one of the earliest detectable cellular responses in atherosclerotic lesion formation. Endothelium may regulate leukocyte recruitment by expressing specific adhesion molecules. Interleukin-18 is a proinflammatory cytokine that plays an important role in vascular pathologies. The present study highlights the modulation of adhesion molecules and PPAR-γ by IL-18 and proposes a novel feedback mechanism by which PPAR-γ may regulate IL-18 expression. Three groups of normal chow diet-fed, male Apo E-/- mice, aged 12 weeks (n = 6/group) were employed: Gp I, phosphate-buffered saline (PBS) (2 mo): Gp II, recombinant IL-18 (rIL-18) (1 mo) followed by PBS (1 mo); Gp III, rIL-18 (1 mo) followed by pyrrolidine dithiocarbamate (PDTC) (1 mo). Significantly augmented mRNA expression of ICAM-1 (~5.7-fold), VCAM-1 (~3.6-fold), and NF-κB (~7-fold) was observed in Gp II mice as compared to Gp I, whereas PPAR-γ expression was not altered. PDTC treatment caused a significant downregulation of ICAM-1 (~4.2-fold), VCAM-1(~2-fold), and NF-κB (~4.5-fold) and upregulation of PPAR-γ expression (~5-fold) in Gp III mice. A similar trend was observed in protein expression. In vivo imaging results demonstrated a marked increase in probe (CF750 dye conjugated to VCAM-1 antibody) fluorescence intensity for VCAM-1 expression in Gp II mice, whereas it was moderately decreased in Gp III. PPAR-γ was found to significantly downregulate both IL-18 levels and IL-18-induced adhesion molecules. The underlying mechanism was found to be via inhibition of NF-κB activity by PDTC, thereby leading to decreased adherence of monocytes to the activated endothelial cells and a step to halt the progression and development of atherosclerotic lesions.
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Affiliation(s)
- Owais Mohammad Bhat
- Department of Experimental Medicine and Biotechnology, Research Block-B, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India
- Department of Pharmacology and Toxicology, Virginia Common Wealth University, Richmond, VA, USA
| | - P Uday Kumar
- Department of Histopathology, National Centre for Laboratory Animal Sciences (NCLAS), National Institute of Nutrition (NIN), Hyderabad, India
| | - N Harishankar
- Department of Histopathology, National Centre for Laboratory Animal Sciences (NCLAS), National Institute of Nutrition (NIN), Hyderabad, India
| | - L Ravichandaran
- Department of Histopathology, National Centre for Laboratory Animal Sciences (NCLAS), National Institute of Nutrition (NIN), Hyderabad, India
| | - A Bhatia
- Department of Experimental Medicine and Biotechnology, Research Block-B, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India
| | - Veena Dhawan
- Department of Experimental Medicine and Biotechnology, Research Block-B, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India.
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Patel R, Magomedova L, Tsai R, Angers S, Orellana A, Cummins CL. Separating the Anti-Inflammatory and Diabetogenic Effects of Glucocorticoids Through LXRβ Antagonism. Endocrinology 2017; 158:1034-1047. [PMID: 28324010 DOI: 10.1210/en.2017-00094] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Accepted: 01/23/2017] [Indexed: 11/19/2022]
Abstract
Synthetic glucocorticoids (GCs), including dexamethasone (DEX), are powerful anti-inflammatory drugs. Long-term use of GCs, however, can result in metabolic side effects such as hyperglycemia, hepatosteatosis, and insulin resistance. The GC receptor (GR) and liver X receptors (LXRα and LXRβ) regulate overlapping genes involved in gluconeogenesis and inflammation. We have previously shown that Lxrβ-/- mice are resistant to the diabetogenic effects of DEX but still sensitive to its immunosuppressive actions. To determine whether this finding could be exploited for therapeutic intervention, we treated mice with GSK2033, a pan-LXR antagonist, alone or combined with DEX. GSK2033 suppressed GC-induced gluconeogenic gene expression without affecting immune-responsive GR target genes. The suppressive effect of GSK2033 on DEX-induced gluconeogenic genes was specific to LXRβ, was liver cell autonomous, and occurred in a target gene-specific manner. Compared with DEX treatment alone, the coadministration of GSK2033 with DEX decreased the recruitment of GR and its accessory factors MED1 and C/EBPβ to the phosphoenolpyruvate carboxykinase promoter. However, GSK2033 had no effect on DEX-mediated suppression of inflammatory genes expressed in the liver or in mouse primary macrophages stimulated with lipopolysaccharides. In conclusion, our study provides evidence that the gluconeogenic and immunosuppressive actions of GR activation can be mechanistically dissociated by pharmacological antagonism of LXRβ. Treatment with an LXRβ antagonist could allow the safer use of existing GC drugs in patients requiring chronic dosing of anti-inflammatory agents for the treatment of diseases such as rheumatoid arthritis and inflammatory bowel disease.
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Affiliation(s)
- Rucha Patel
- Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada
| | - Lilia Magomedova
- Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada
| | - Ricky Tsai
- Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada
| | - Stéphane Angers
- Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada
| | - Arturo Orellana
- Department of Chemistry, York University, Toronto, Ontario M3J 1P3, Canada
| | - Carolyn L Cummins
- Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada
- Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario M5G 2C4, Canada
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Hormone and receptor interplay in the regulation of mosquito lipid metabolism. Proc Natl Acad Sci U S A 2017; 114:E2709-E2718. [PMID: 28292900 DOI: 10.1073/pnas.1619326114] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Mosquitoes transmit devastating human diseases because they need vertebrate blood for egg development. Metabolism in female mosquitoes is tightly coupled with blood meal-mediated reproduction, which requires an extremely high level of energy consumption. Functional analysis has shown that major genes encoding for enzymes involved in lipid metabolism (LM) in the mosquito fat bodies are down-regulated at the end of the juvenile hormone (JH)-controlled posteclosion (PE) phase but exhibit significant elevation in their transcript levels during the post-blood meal phase (PBM), which is regulated mainly by 20-hydroxyecdysone (20E). Reductions in the transcript levels of genes encoding triacylglycerol (TAG) catabolism and β-oxidation enzymes were observed to correlate with a dramatic accumulation of lipids in the PE phase; in contrast, these transcripts were elevated significantly and lipid stores were diminished during the PBM phase. The RNAi depletion of Methoprene-tolerant (Met) and ecdysone receptor (EcR), receptors for JH and 20E, respectively, reversed the LM gene expression and the levels of lipid stores and metabolites, demonstrating the critical roles of these hormones in LM regulation. Hepatocyte nuclear factor 4 (HNF4) RNAi-silenced mosquitoes exhibited down-regulation of the gene transcripts encoding TAG catabolism and β-oxidation enzymes and an inability to use lipids effectively, as manifested by TAG accumulation. The luciferase reporter assay showed direct regulation of LM-related genes by HNF4. Moreover, HNF4 gene expression was down-regulated by Met and activated by EcR and Target of rapamycin, providing a link between nutritional and hormonal regulation of LM in female mosquitoes.
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