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Vahdat-Lasemi F, Farhoudi L, Hosseinikhah SM, Santos RD, Sahebkar A. Angiopoietin-like protein inhibitors: Promising agents for the treatment of familial hypercholesterolemia and atherogenic dyslipidemia. Atherosclerosis 2025; 405:119235. [PMID: 40344904 DOI: 10.1016/j.atherosclerosis.2025.119235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 04/23/2025] [Accepted: 05/01/2025] [Indexed: 05/11/2025]
Abstract
BACKGROUND AND AIMS This review examines the physiological functions of Angiopoietin-like proteins (ANGPTLs) in lipid metabolism and the epidemiology of atherosclerotic cardiovascular disease (ASCVD), while discussing their potential as therapies for dyslipidemias. METHODS A review of contemporary literature on ANGPTLs was conducted. RESULTS ANGPTLs comprise eight secreted proteins that share structural similarities with the angiopoietin family and serve as key regulators of various physiological and biochemical functions. Notably, ANGPTL3, ANGPTL4, and ANGPTL8 act as physiological inhibitors of lipoprotein lipase (LPL), playing a crucial role in lipoprotein and triglyceride metabolism in response to the body's nutritional status. A deficiency in these proteins is linked to hypolipidemia, characterized by a decrease in all lipid fractions, and genetic studies indicate a reduced risk of ASCVD in individuals with loss-of-function variants in ANGPTL3 and ANGPTL4. Conversely, elevated levels of ANGPTL3, ANGPTL4, and ANGPTL8 seem to increase the risk of cardiovascular disease. The role of ANGPTLs in regulating lipid metabolism underscores their potential in targeted therapies for managing dyslipidemias and lowering ASCVD risk, particularly in patients with difficult-to-control dyslipidemia phenotypes, such as homozygous Familial Hypercholesterolemia and mixed dyslipidemia. CONCLUSIONS The development of ANGPTL inhibitors could provide an effective strategy for preventing ASCVD.
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Affiliation(s)
- Fatemeh Vahdat-Lasemi
- Department of Medical Biotechnology and Nanotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Leila Farhoudi
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyedeh Maryam Hosseinikhah
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Raul D Santos
- Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo, Brazil; Lipid Clinic Heart Institute (InCor) University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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2
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Gao WY, Chen PY, Hsu HJ, Liou JW, Wu CL, Wu MJ, Yen JH. Xanthohumol, a prenylated chalcone, regulates lipid metabolism by modulating the LXRα/RXR-ANGPTL3-LPL axis in hepatic cell lines and high-fat diet-fed zebrafish models. Biomed Pharmacother 2024; 174:116598. [PMID: 38615609 DOI: 10.1016/j.biopha.2024.116598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 04/08/2024] [Accepted: 04/11/2024] [Indexed: 04/16/2024] Open
Abstract
Angiopoietin-like 3 (ANGPTL3) acts as an inhibitor of lipoprotein lipase (LPL), impeding the breakdown of triglyceride-rich lipoproteins (TGRLs) in circulation. Targeting ANGPTL3 is considered a novel strategy for improving dyslipidemia and atherosclerotic cardiovascular diseases (ASCVD). Hops (Humulus lupulus L.) contain several bioactive prenylflavonoids, including xanthohumol (Xan), isoxanthohumol (Isoxan), 6-prenylnaringenin (6-PN), and 8-prenylnaringenin (8-PN), with the potential to manage lipid metabolism. The aim of this study was to investigate the lipid-lowering effects of Xan, the effective prenylated chalcone in attenuating ANGPTL3 transcriptional activity, both in vitro using hepatic cells and in vivo using zebrafish models, along with exploring the underlying mechanisms. Xan (10 and 20 μM) significantly reduced ANGPTL3 mRNA and protein expression in HepG2 and Huh7 cells, leading to a marked decrease in secreted ANGPTL3 proteins via hepatic cells. In animal studies, orally administered Xan significantly alleviated plasma triglyceride (TG) and cholesterol levels in zebrafish fed a high-fat diet. Furthermore, it reduced hepatic ANGPTL3 protein levels and increased LPL activity in zebrafish models, indicating its potential to modulate lipid profiles in circulation. Furthermore, molecular docking results predicted that Xan exhibits a higher binding affinity to interact with liver X receptor α (LXRα) and retinoic acid X receptor (RXR) than their respective agonists, T0901317 and 9-Cis-retinoic acid (9-Cis-RA). We observed that Xan suppressed hepatic ANGPTL3 expression by antagonizing the LXRα/RXR-mediated transcription. These findings suggest that Xan ameliorates dyslipidemia by modulating the LXRα/RXR-ANGPTL3-LPL axis. Xan represents a novel potential inhibitor of ANGPTL3 for the prevention or treatment of ASCVD.
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Affiliation(s)
- Wan-Yun Gao
- Institute of Medical Sciences, Tzu Chi University, Hualien 970374, Taiwan
| | - Pei-Yi Chen
- Laboratory of Medical Genetics, Genetic Counseling Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970374, Taiwan; Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 970374, Taiwan
| | - Hao-Jen Hsu
- Department of Biomedical Science and Engineering, Tzu Chi University, Hualien 970374, Taiwan
| | - Je-Wen Liou
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien 970374, Taiwan
| | - Chia-Ling Wu
- Laboratory of Medical Genetics, Genetic Counseling Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970374, Taiwan
| | - Ming-Jiuan Wu
- Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 717301, Taiwan
| | - Jui-Hung Yen
- Institute of Medical Sciences, Tzu Chi University, Hualien 970374, Taiwan; Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 970374, Taiwan.
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3
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Jia W, Li Y, Cheung KCP, Zheng X. Bile acid signaling in the regulation of whole body metabolic and immunological homeostasis. SCIENCE CHINA. LIFE SCIENCES 2024; 67:865-878. [PMID: 37515688 DOI: 10.1007/s11427-023-2353-0] [Citation(s) in RCA: 57] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 04/23/2023] [Indexed: 07/31/2023]
Abstract
Bile acids (BAs) play a crucial role in nutrient absorption and act as key regulators of lipid and glucose metabolism and immune homeostasis. Through the enterohepatic circulation, BAs are synthesized, metabolized, and reabsorbed, with a portion entering the vascular circulation and distributing systemically. This allows BAs to interact with receptors in all major organs, leading to organ-organ interactions that regulate both local and global metabolic processes, as well as the immune system. This review focuses on the whole-body effects of BA-mediated metabolic and immunological regulation, including in the brain, heart, liver, intestine, eyes, skin, adipose tissue, and muscle. Targeting BA synthesis and receptor signaling is a promising strategy for the development of novel therapies for various diseases throughout the body.
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Affiliation(s)
- Wei Jia
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
| | - Yitao Li
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Kenneth C P Cheung
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Xiaojiao Zheng
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
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Su X, Xu Q, Li Z, Ren Y, Jiao Q, Wang L, Wang Y. Role of the angiopoietin-like protein family in the progression of NAFLD. Heliyon 2024; 10:e27739. [PMID: 38560164 PMCID: PMC10980950 DOI: 10.1016/j.heliyon.2024.e27739] [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: 01/09/2024] [Revised: 03/05/2024] [Accepted: 03/06/2024] [Indexed: 04/04/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease, with a range of conditions including non-alcoholic fatty liver, non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Currently recognized as the liver component of the metabolic syndrome, NAFLD is intimately linked to metabolic diseases. Angiopoietin-like proteins (ANGPTLs) comprise a class of proteins that resemble angiopoietins structurally. It is closely related to obesity, insulin resistance and lipid metabolism, and may be the critical factor of metabolic syndrome. In recent years, many studies have found that there is a certain correlation between ANGPTLs and the occurrence and progression of NAFLD disease spectrum. This article reviews the possible mechanisms and roles of ANGPTL protein in the pathogenesis and progression of NAFLD.
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Affiliation(s)
- Xin Su
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, China
| | - Qinchen Xu
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, China
| | - Zigan Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, China
| | - Yidan Ren
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, Shandong Province, China
| | - Qinlian Jiao
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, Shandong Province, China
| | - Lina Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, China
| | - Yunshan Wang
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, Shandong Province, China
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Rossi I, Marodin G, Lupo MG, Adorni MP, Papotti B, Dall’Acqua S, Ferri N. Gene Silencing of Angiopoietin-like 3 (ANGPTL3) Induced De Novo Lipogenesis and Lipid Accumulation in Huh7 Cell Line. Int J Mol Sci 2024; 25:3708. [PMID: 38612519 PMCID: PMC11011473 DOI: 10.3390/ijms25073708] [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: 02/28/2024] [Revised: 03/21/2024] [Accepted: 03/22/2024] [Indexed: 04/14/2024] Open
Abstract
Angiopoietin-like 3 (ANGPTL3) is a hepatokine acting as a negative regulator of lipoprotein lipase (LPL). Vupanorsen, an ANGPTL3 directed antisense oligonucleotide, showed an unexpected increase in liver fat content in humans. Here, we investigated the molecular mechanism linking ANGPTL3 silencing to hepatocyte fat accumulation. Human hepatocarcinoma Huh7 cells were treated with small interfering RNA (siRNA) directed to ANGPTL3, human recombinant ANGPTL3 (recANGPTL3), or their combination. Using Western blot, Oil Red-O, biochemical assays, and ELISA, we analyzed the expression of genes and proteins involved in lipid metabolism. Oil Red-O staining demonstrated that lipid content increased after 48 h of ANGPTL3 silencing (5.89 ± 0.33 fold), incubation with recANGPTL3 (4.08 ± 0.35 fold), or their combination (8.56 ± 0.18 fold), compared to untreated cells. This effect was also confirmed in Huh7-LX2 spheroids. A total of 48 h of ANGPTL3 silencing induced the expression of genes involved in the de novo lipogenesis, such as fatty acid synthase, stearoyl-CoA desaturase, ATP citrate lyase, and Acetyl-Coenzyme A Carboxylase 1 together with the proprotein convertase subtilisin/kexin 9 (PCSK9). Time-course experiments revealed that 6 h post transfection with ANGPTL3-siRNA, the cholesterol esterification by Acyl-coenzyme A cholesterol acyltransferase (ACAT) was reduced, as well as total cholesterol content, while an opposite effect was observed at 48 h. Under the same experimental conditions, no differences in secreted apoB and PCSK9 were observed. Since PCSK9 was altered by the treatment, we tested a possible co-regulation between the two genes. The effect of ANGPTL3-siRNA on the expression of genes involved in the de novo lipogenesis was not counteracted by gene silencing of PCSK9. In conclusion, our in vitro study suggests that ANGPTL3 silencing determines lipid accumulation in Huh7 cells by inducing the de novo lipogenesis independently from PCSK9.
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Affiliation(s)
- Ilaria Rossi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (I.R.); (G.M.); (S.D.)
| | - Giorgia Marodin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (I.R.); (G.M.); (S.D.)
| | | | - Maria Pia Adorni
- Department of Medicine and Surgery, University of Parma, Via Volturno 39/F, 43125 Parma, Italy;
| | - Bianca Papotti
- Department of Food and Drug, University of Parma, Viale delle Scienze 27/A, 43124 Parma, Italy;
| | - Stefano Dall’Acqua
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy; (I.R.); (G.M.); (S.D.)
| | - Nicola Ferri
- Department of Medicine, University of Padova, 35128 Padova, Italy;
- Veneto Institute of Molecular Medicine (VIMM), Via Orus, 2, 35129 Padova, Italy
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Chen W, Zhong Y, Yuan Y, Zhu M, Hu W, Liu N, Xing D. New insights into the suppression of inflammation and lipid accumulation by JAZF1. Genes Dis 2023; 10:2457-2469. [PMID: 37554201 PMCID: PMC10404878 DOI: 10.1016/j.gendis.2022.10.029] [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: 07/14/2022] [Revised: 09/27/2022] [Accepted: 10/25/2022] [Indexed: 12/03/2022] Open
Abstract
Atherosclerosis is one of the leading causes of disease and death worldwide. The identification of new therapeutic targets and agents is critical. JAZF1 is expressed in many tissues and is found at particularly high levels in adipose tissue (AT). JAZF1 suppresses inflammation (including IL-1β, IL-4, IL-6, IL-8, IL-10, TNFα, IFN-γ, IAR-20, COL3A1, laminin, and MCP-1) by reducing NF-κB pathway activation and AT immune cell infiltration. JAZF1 reduces lipid accumulation by regulating the liver X receptor response element (LXRE) of the SREBP-1c promoter, the cAMP-response element (CRE) of HMGCR, and the TR4 axis. LXRE and CRE sites are present in many cytokine and lipid metabolism gene promoters, which suggests that JAZF1 regulates these genes through these sites. NF-κB is the center of the JAZF1-mediated inhibition of the inflammatory response. JAZF1 suppresses NF-κB expression by suppressing TAK1 expression. Interestingly, TAK1 inhibition also decreases lipid accumulation. A dual-targeting strategy of NF-κB and TAK1 could inhibit both inflammation and lipid accumulation. Dual-target compounds (including prodrugs) 1-5 exhibit nanomolar inhibition by targeting NF-κB and TAK1, EGFR, or COX-2. However, the NF-κB suppressing activity of these compounds is relatively low (IC50 > 300 nM). Compounds 6-14 suppress NF-κB expression with IC50 values ranging from 1.8 nM to 38.6 nM. HS-276 is a highly selective, orally bioavailable TAK1 inhibitor. Combined structural modifications of compounds using a prodrug strategy may enhance NF-κB inhibition. This review focused on the role and mechanism of JAZF1 in inflammation and lipid accumulation for the identification of new anti-atherosclerotic targets.
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Affiliation(s)
- Wujun Chen
- Cancer Institute, Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China
| | - Yingjie Zhong
- Cancer Institute, Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China
| | - Yang Yuan
- Cancer Institute, Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China
| | - Meng Zhu
- Cancer Institute, Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China
| | - Wenchao Hu
- Cancer Institute, Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China
- Department of Endocrinology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong 266035, China
| | - Ning Liu
- Cancer Institute, Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China
| | - Dongming Xing
- Cancer Institute, Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China
- School of Life Sciences, Tsinghua University, Beijing 100084, China
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7
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Zuo Y, Zhang C, Zhou Y, Li H, Xiao W, Herzog RW, Xu J, Zhang J, Chen YE, Han R. Liver-specific in vivo base editing of Angptl3 via AAV delivery efficiently lowers blood lipid levels in mice. Cell Biosci 2023; 13:109. [PMID: 37322547 PMCID: PMC10273718 DOI: 10.1186/s13578-023-01036-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 04/18/2023] [Indexed: 06/17/2023] Open
Abstract
BACKGROUND Gene editing has emerged as an exciting therapeutic development platform for numerous genetic and nongenetic diseases. Targeting lipid-modulating genes such as angiopoietin-related protein 3 (ANGPTL3) with gene editing offers hope for a permanent solution to lower cardiovascular disease risks associated with hypercholesterolemia. RESULTS In this study, we developed a hepatocyte-specific base editing therapeutic approach delivered by dual adeno-associated virus (AAV) to enable hepatocyte-specific targeting of Angptl3 to lower blood lipid levels. Systemic AAV9-mediated delivery of AncBE4max, a cytosine base editor (CBE), targeting mouse Angptl3 resulted in the installation of a premature stop codon in Angptl3 with an average efficiency of 63.3 ± 2.3% in the bulk liver tissue. A near-complete knockout of the ANGPTL3 protein in the circulation were observed within 2-4 weeks following AAV administration. Furthermore, the serum levels of triglyceride (TG) and total cholesterol (TC) were decreased by approximately 58% and 61%, respectively, at 4 weeks after treatment. CONCLUSIONS These results highlight the promise of liver-targeted Angptl3 base editing for blood lipid control.
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Affiliation(s)
- Yuanbojiao Zuo
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Department of Surgery, The Ohio State University, Columbus, OH, 43210, USA
- Department of Pediatrics, Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, P.R. China
| | - Chen Zhang
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Department of Surgery, The Ohio State University, Columbus, OH, 43210, USA
| | - Yuan Zhou
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Department of Surgery, The Ohio State University, Columbus, OH, 43210, USA
| | - Haiwen Li
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Department of Surgery, The Ohio State University, Columbus, OH, 43210, USA
| | - Weidong Xiao
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Roland W Herzog
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Jie Xu
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI, USA
| | - Jifeng Zhang
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI, USA
| | - Y Eugene Chen
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI, USA
| | - Renzhi Han
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
- Department of Surgery, The Ohio State University, Columbus, OH, 43210, USA.
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Fritsche K, Ziková-Kloas A, Marx-Stoelting P, Braeuning A. Metabolism-Disrupting Chemicals Affecting the Liver: Screening, Testing, and Molecular Pathway Identification. Int J Mol Sci 2023; 24:ijms24032686. [PMID: 36769005 PMCID: PMC9916672 DOI: 10.3390/ijms24032686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/26/2023] [Accepted: 01/26/2023] [Indexed: 02/04/2023] Open
Abstract
The liver is the central metabolic organ of the body. The plethora of anabolic and catabolic pathways in the liver is tightly regulated by physiological signaling but may become imbalanced as a consequence of malnutrition or exposure to certain chemicals, so-called metabolic endocrine disrupters, or metabolism-disrupting chemicals (MDCs). Among different metabolism-related diseases, obesity and non-alcoholic fatty liver disease (NAFLD) constitute a growing health problem, which has been associated with a western lifestyle combining excessive caloric intake and reduced physical activity. In the past years, awareness of chemical exposure as an underlying cause of metabolic endocrine effects has continuously increased. Within this review, we have collected and summarized evidence that certain environmental MDCs are capable of contributing to metabolic diseases such as liver steatosis and cholestasis by different molecular mechanisms, thereby contributing to the metabolic syndrome. Despite the high relevance of metabolism-related diseases, standardized mechanistic assays for the identification and characterization of MDCs are missing. Therefore, the current state of candidate test systems to identify MDCs is presented, and their possible implementation into a testing strategy for MDCs is discussed.
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Affiliation(s)
- Kristin Fritsche
- German Federal Institute for Risk Assessment, Department Food Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany
| | - Andrea Ziková-Kloas
- German Federal Institute for Risk Assessment, Department Pesticides Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany
| | - Philip Marx-Stoelting
- German Federal Institute for Risk Assessment, Department Pesticides Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany
| | - Albert Braeuning
- German Federal Institute for Risk Assessment, Department Food Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany
- Correspondence: ; Tel.: +49-(0)30-18412-25100
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Shikida R, Kim M, Futohashi M, Nishihara K, Lee H, Suzuki Y, Baek Y, Masaki T, Ikuta K, Iwamoto E, Uemoto Y, Haga S, Terada F, Roh S. Physiological roles and regulation of hepatic angiopoietin-like protein 3 in Japanese Black cattle (Bos taurus) during the fattening period. J Anim Sci 2023; 101:skad198. [PMID: 37317898 PMCID: PMC10294557 DOI: 10.1093/jas/skad198] [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: 02/23/2023] [Accepted: 06/13/2023] [Indexed: 06/16/2023] Open
Abstract
Angiopoietin-like protein 3 (ANGPTL3) is expressed predominantly in the liver and plays a major role in regulating the circulating triglyceride and lipoprotein fraction concentrations by inhibiting lipoprotein lipase (LPL) activity. Given these physiological roles, ANGPTL3 may play an important role in metabolic changes related to fat accumulation during the fattening period in Japanese Black. This study aimed to reveal the physiological roles of hepatic ANGPTL3 in Japanese Black steers (Bos taurus) during the fattening period and investigate the regulatory effects of hepatic ANGPTL3. To investigate the gene expression and protein localization of ANGPTL3, 18 tissue samples were collected from tree male Holstein bull calves aged 7 wk. Biopsied liver tissues and blood samples were collected from 21 Japanese Black steers during the early (T1; 13 mo of age), middle (T2; 20 mo), and late fattening phases (T3; 28 mo). Relative mRNA expression, blood metabolite concentrations, hormone concentrations, growth, and carcass traits were analyzed. To identify the regulatory factors of hepatic ANGPTL3, primary bovine hepatocytes collected by two Holstein calves aged 7 wk were incubated with insulin, palmitate, oleate, propionate, acetate, or beta-hydroxybutyric acid (BHBA). The ANGPTL3 gene was most highly expressed in the liver, with minor expression in the renal cortex, lungs, reticulum, and jejunum in Holstein bull calves. In Japanese Black steers, relative ANGPTL3 mRNA expressions were less as fattening progressed, and blood triglyceride, total cholesterol, and nonesterified fatty acid (NEFA) concentrations increased. Relative ANGPTL8 and Liver X receptor alpha (LXRα) mRNA expressions decreased in late and middle fattening phases, respectively. Furthermore, relative ANGTPL3 mRNA expression was positively correlated with ANGPTL8 (r = 0.650; P < 0.01) and ANGPTL4 (r = 0.540; P < 0.05) in T3 and T1, respectively, and LXRα showed no correlation with ANGPTL3. Relative ANGTPL3 mRNA expression was negatively correlated with total cholesterol (r = -0.434; P < 0.05) and triglyceride (r = -0.645; P < 0.01) concentrations in T3 and T1, respectively; There was no significant correlation between ANGTPL3 and carcass traits. Relative ANGTPL3 mRNA expression in cultured bovine hepatocytes was downregulated in oleate treatment. Together, these findings suggest that ANGPTL3 downregulation in late fattening phases is associated with the changes in lipid metabolism.
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Affiliation(s)
- Rika Shikida
- Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan
| | - Minji Kim
- Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan
| | - Makoto Futohashi
- Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan
| | - Koki Nishihara
- Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan
| | - Huseong Lee
- Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan
| | - Yutaka Suzuki
- Research Faculty of Agriculture, Hokkaido University, Sapporo 060-8589, Japan
| | - Yeolchang Baek
- Animal Nutrition and Physiology Team, National Institute of Animal Science, Rural Development Administration, Wanju 55365, Korea
| | - Tatsunori Masaki
- Hyogo Prefectural Technology Center of Agriculture, Forestry and Fisheries, Kasai, Hyogo 679-0198, Japan
| | - Kentaro Ikuta
- Hyogo Prefectural Technology Center of Agriculture, Forestry and Fisheries, Kasai, Hyogo 679-0198, Japan
| | - Eiji Iwamoto
- Hyogo Prefectural Technology Center of Agriculture, Forestry and Fisheries, Kasai, Hyogo 679-0198, Japan
| | - Yoshinobu Uemoto
- Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan
| | - Satoshi Haga
- Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan
| | - Fuminori Terada
- Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan
| | - Sanggun Roh
- Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan
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10
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Abstract
PURPOSE OF REVIEW This review aims to summarize the most recently published literature highlighting the potential of pharmacological inhibition of ANGPTL3 in treating patients suffering from dyslipidemias. The rational for this strategy will be discussed considering evidence describing the role of ANGPTL3 in lipid metabolism and the consequences of its deficiency in humans. RECENT FINDINGS Recent trials have demonstrated the efficacy and safety of ANGPTL3 inhibition in treating homozygous familial hypercholesterolemia even in those patients carrying biallelic null/null variants, thus supporting the notion that the LDL-lowering effect of ANGPLT3 inhibition is LDLR-independent. The use of ANGPTL3 inhibition strategies has expanded its indications in hypertrygliceridemic patients with functional lipoprotein lipase activity. Contemporarily, the pharmacological research is exploring novel approaches to ANGPTL3 inhibition such as the use of a small interfering RNA targeting the ANGPTL3 transcript in the liver, a protein-based vaccine against ANGPTL3, and a CRISP-Cas-9 method for a liver-selective knock-out of ANGPTL3 gene. First, we will describe the molecular function of ANGPTL3 in lipoprotein metabolism. Then, we will revise the clinical characteristics of individuals carrying loss-of-function mutations of ANGPTL3, a rare condition known as familial hypobetalipoproteinemia type 2 (FHBL2) that represents a unique human model of ANGPTL3 deficiency. Finally, we will examine the lipid-lowering potential of pharmacological inhibition of ANGPTL3 based on the results of clinical trials employing Evinacumab, the first approved fully humanized monoclonal antibody against ANGPTL3. The future perspectives for ANGPTL3 inhibition will also be revised.
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11
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Bini S, D'Erasmo L, Astiarraga B, Minicocci I, Palumbo M, Pecce V, Polito L, Di Costanzo A, Haeusler RA, Arca M, Ferrannini E, Camastra S. Differential effects of bariatric surgery on plasma levels of ANGPTL3 and ANGPTL4. Nutr Metab Cardiovasc Dis 2022; 32:2647-2654. [PMID: 36163215 PMCID: PMC10018753 DOI: 10.1016/j.numecd.2022.08.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 08/12/2022] [Accepted: 08/23/2022] [Indexed: 01/21/2023]
Abstract
BACKGROUND AND AIM Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) are regulators of triglyceride storage and utilization. Bariatric surgery (BS) leads to profound changes in adipose tissue composition and energy metabolism. We evaluated the impact of BS on plasma levels of ANGPTL3 and ANGPTL4. METHODS AND RESULTS Twenty-seven subjects affected by morbid obesity with or without type 2 diabetes (T2D) underwent Roux-en-Y gastric bypass (RYGB) and 18 patients with advanced T2D received Biliopancreatic Diversion (BPD). Fasting ANGPTL proteins levels, insulin sensitivity (evaluated by euglycemic hyperinsulinemic clamp), total bile acids (TBA) and free fatty acids (FFA) were measured at baseline and 1 year after surgery. Both surgical procedures resulted in the loss of fat mass, improved glucose control, and a ∼2-fold increase of insulin sensitivity. ANGPTL4 levels decreased significantly with both RYGB (26.6 ± 0.6 to 24.4 ± 0.3 ng/mL, p = 0.001) and BPD (27.9 ± 1.5 to 24.0 ± 0.5 ng/mL, p = 0.003). In contrast, ANGPTL3 concentrations did not change after RYGB but rose following BPD (225 ± 20 to 300 ± 15 ng/mL, p = 0.003). By multiple regression analysis, changes after BS in ANGPTL4 were independently associated with changes in blood glucose, (p = 0.0169) whereas changes in ANGPTL3 were associated with variations in FFA (p = 0.008) and insulin sensitivity (p = 0.043). CONCLUSION Circulating ANGPTL4 is reduced by BS, probably due to the loss of fat mass and improved insulin sensitivity. Conversely, ANGPTL3 levels increased after BPD, but not after RYGB, presumably because of the metabolic changes induced by the malabsorptive effect of BPD.
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Affiliation(s)
- Simone Bini
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
| | - Laura D'Erasmo
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy
| | - Brenno Astiarraga
- Department of Clinical and Experimental Medicine, University of Pisa, Italy; Pere Virgili Institute for Health Research (IISPV), Terragona, Spain
| | - Ilenia Minicocci
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy
| | - Maria Palumbo
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Valeria Pecce
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy
| | - Luca Polito
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy
| | - Alessia Di Costanzo
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy
| | - Rebecca A Haeusler
- Naomi Berrie Diabetes Center and Department of Pathology and Cell Biology, Columbia University, New York, USA
| | - Marcello Arca
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy
| | | | - Stefania Camastra
- Department of Clinical and Experimental Medicine, University of Pisa, Italy.
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12
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The Citrus Flavonoid Nobiletin Downregulates Angiopoietin-like Protein 3 (ANGPTL3) Expression and Exhibits Lipid-Modulating Effects in Hepatic Cells and Adult Zebrafish Models. Int J Mol Sci 2022; 23:ijms232012485. [PMID: 36293338 PMCID: PMC9604320 DOI: 10.3390/ijms232012485] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/11/2022] [Accepted: 10/13/2022] [Indexed: 11/22/2022] Open
Abstract
Nobiletin, a dietary citrus flavonoid, exerts biological activities against hyperlipidemia, obesity, and atherosclerotic cardiovascular diseases (ASCVDs). The aim of this study was to explore the lipid-lowering effects of nobiletin and the underlying molecular mechanisms in vitro in hepatic cells and in vivo in zebrafish models. Transcriptome and gene ontology (GO) analyses of differentially expressed genes (DEGs) by gene set enrichment analysis (GSEA) showed that a set of twenty-eight core enrichment DEGs associated with “GO BP regulation of lipid metabolic process” (GO: 0019216) were significantly downregulated in nobiletin-treated cells. Among these genes, angiopoietin-like 3 (ANGPTL3), an inhibitor of lipoprotein lipase (LPL) activity that regulates TG-rich lipoprotein (TGRL) metabolism in circulation, was the protein most markedly downregulated by nobiletin. Nobiletin (20 and 40 μM) significantly reduced the levels of ANGPTL3 mRNA and intracellular and secreted ANGPTL3 proteins in hepatic cell lines. Furthermore, alleviation of secreted ANGPTL3 production by nobiletin was found to reinstate LPL catalytic activity. Nobiletin significantly inhibited ANGPTL3 promoter activity and attenuated the transcription factor liver X receptor-α (LXRα)-mediated ANGPTL3 transcription. Molecular docking analysis predicted that nobiletin could bind to the ligand-binding domain of LXRα, thereby counteracting LXRα activation. In animal studies, orally administered nobiletin significantly alleviated the levels of plasma triglycerides (TGs) and cholesterol in zebrafish fed a high-fat diet. Moreover, nobiletin significantly reduced the amounts of hepatic ANGPTL3 protein in zebrafish. Our findings suggest that nobiletin may regulate the LXRα-ANGPTL3-LPL axis and exhibit lipid-modulating effects in vitro and in vivo. Thus, nobiletin is a potential ANGPTL3 inhibitor for the regulation of lipid metabolism to ameliorate dyslipidemia and ASCVDs.
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13
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Hu X, Fan J, Ma Q, Han L, Cao Z, Xu C, Luan J, Jing G, Nan Y, Wu T, Zhang Y, Wang H, Zhang Y, Ju D. A novel nanobody-heavy chain antibody against Angiopoietin-like protein 3 reduces plasma lipids and relieves nonalcoholic fatty liver disease. J Nanobiotechnology 2022; 20:237. [PMID: 35590366 PMCID: PMC9118633 DOI: 10.1186/s12951-022-01456-z] [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: 01/11/2022] [Accepted: 05/07/2022] [Indexed: 11/29/2022] Open
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is a metabolic disease mainly on account of hypercholesterolemia and may progress to cirrhosis and hepatocellular carcinoma. The discovery of effective therapy for NAFLD is an essential unmet need. Angiopoietin-like protein 3 (ANGPTL3), a critical lipid metabolism regulator, resulted in increased blood lipids and was elevated in NAFLD. Here, we developed a nanobody-heavy chain antibody (VHH-Fc) to inhibit ANGPTL3 for NAFLD treatment. Results In this study, we retrieved an anti-ANGPTL3 VHH and Fc fusion protein, C44-Fc, which exhibited high affinities to ANGPTL3 proteins and rescued ANGPLT3-mediated inhibition of lipoprotein lipase (LPL) activity. The C44-Fc bound a distinctive epitope within ANGPTL3 when compared with the approved evinacumab, and showed higher expression yield. Meanwhile, C44-Fc had significant reduction of the triglyceride (~ 44.2%), total cholesterol (~ 36.6%) and LDL-cholesterol (~ 54.4%) in hypercholesterolemic mice and ameliorated hepatic lipid accumulation and liver injury in NAFLD mice model. Conclusions We discovered a VHH-Fc fusion protein with high affinity to ANGPTL3, strong stability and also alleviated the progression of NAFLD, which might offer a promising therapy for NAFLD. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12951-022-01456-z.
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Affiliation(s)
- Xiaozhi Hu
- School of Pharmacy & Minhang Hospital, Shanghai Engineering Research Center of Immunotherapeutic, Fudan University, Shanghai, 201203, China
| | - Jiajun Fan
- School of Pharmacy & Minhang Hospital, Shanghai Engineering Research Center of Immunotherapeutic, Fudan University, Shanghai, 201203, China
| | - Qianqian Ma
- School of Pharmacy & Minhang Hospital, Shanghai Engineering Research Center of Immunotherapeutic, Fudan University, Shanghai, 201203, China.,National Children's Medical Center, Children's Hospital of Fudan University, Shanghai, 201203, China
| | - Lei Han
- School of Pharmacy & Minhang Hospital, Shanghai Engineering Research Center of Immunotherapeutic, Fudan University, Shanghai, 201203, China
| | - Zhonglian Cao
- School of Pharmacy & Minhang Hospital, Shanghai Engineering Research Center of Immunotherapeutic, Fudan University, Shanghai, 201203, China
| | - Caili Xu
- School of Pharmacy & Minhang Hospital, Shanghai Engineering Research Center of Immunotherapeutic, Fudan University, Shanghai, 201203, China
| | - Jingyun Luan
- School of Pharmacy & Minhang Hospital, Shanghai Engineering Research Center of Immunotherapeutic, Fudan University, Shanghai, 201203, China.,Ben May Department of Cancer Research, The University of Chicago, Chicago, IL, 60615, USA
| | - Guangjun Jing
- School of Pharmacy & Minhang Hospital, Shanghai Engineering Research Center of Immunotherapeutic, Fudan University, Shanghai, 201203, China
| | - Yanyang Nan
- School of Pharmacy & Minhang Hospital, Shanghai Engineering Research Center of Immunotherapeutic, Fudan University, Shanghai, 201203, China
| | - Tao Wu
- School of Pharmacy & Minhang Hospital, Shanghai Engineering Research Center of Immunotherapeutic, Fudan University, Shanghai, 201203, China
| | - Yuting Zhang
- School of Pharmacy & Minhang Hospital, Shanghai Engineering Research Center of Immunotherapeutic, Fudan University, Shanghai, 201203, China
| | - Hanqi Wang
- School of Pharmacy & Minhang Hospital, Shanghai Engineering Research Center of Immunotherapeutic, Fudan University, Shanghai, 201203, China
| | - Yuanzhen Zhang
- School of Pharmacy & Minhang Hospital, Shanghai Engineering Research Center of Immunotherapeutic, Fudan University, Shanghai, 201203, China
| | - Dianwen Ju
- School of Pharmacy & Minhang Hospital, Shanghai Engineering Research Center of Immunotherapeutic, Fudan University, Shanghai, 201203, China.
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14
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Identification and evaluation of a lipid-lowering small compound in preclinical models and in a Phase I trial. Cell Metab 2022; 34:667-680.e6. [PMID: 35427476 DOI: 10.1016/j.cmet.2022.03.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 12/12/2021] [Accepted: 03/16/2022] [Indexed: 12/13/2022]
Abstract
Developing non-statin-based small compounds to battle the global epidemic of hyperlipidemia remains challenging. Here, we report the discovery of DC371739, an indole-containing tetrahydroisoquinoline compound with promising lipid-lowering effects, both in vitro and in vivo, and with good tolerability in a Phase I clinical trial (NCT04927221). DC371739 significantly reduced the plasma levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides simultaneously in several animal models and showed preliminary positive results in the Phase I trial. Mechanistically, DC371739 acts in a distinct manner from other known lipid-lowering reagents. We show that it physically binds HNF-1α, impeding the transcription of both PCSK9 and ANGPTL3, two genes that are known to contribute to hypercholesterolemia and dyslipidemia. Moreover, the distinct mechanism of action of DC371739 allows its combination with atorvastatin treatment to additively improve dyslipidemia, while providing a potential alternative therapeutic strategy for individuals with statin intolerance.
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15
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Paragh G, Németh Á, Harangi M, Banach M, Fülöp P. Causes, clinical findings and therapeutic options in chylomicronemia syndrome, a special form of hypertriglyceridemia. Lipids Health Dis 2022; 21:21. [PMID: 35144640 PMCID: PMC8832680 DOI: 10.1186/s12944-022-01631-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 01/30/2022] [Indexed: 02/07/2023] Open
Abstract
The prevalence of hypertriglyceridemia has been increasing worldwide. Attention is drawn to the fact that the frequency of a special hypertriglyceridemia entity, named chylomicronemia syndrome, is variable among its different forms. The monogenic form, termed familial chylomicronemia syndrome, is rare, occuring in 1 in every 1 million persons. On the other hand, the prevalence of the polygenic form of chylomicronemia syndrome is around 1:600. On the basis of the genetical alterations, other factors, such as obesity, alcohol consumption, uncontrolled diabetes mellitus and certain drugs may significantly contribute to the development of the multifactorial form. In this review, we aimed to highlight the recent findings about the clinical and laboratory features, differential diagnosis, as well as the epidemiology of the monogenic and polygenic forms of chylomicronemias. Regarding the therapy, differentiation between the two types of the chylomicronemia syndrome is essential, as well. Thus, proper treatment options of chylomicronemia and hypertriglyceridemia will be also summarized, emphasizing the newest therapeutic approaches, as novel agents may offer solution for the effective treatment of these conditions.
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Affiliation(s)
- György Paragh
- Division of Metabolic Diseases, Department of Internal Medicine, University of Debrecen Faculty of Medicine, Nagyerdei krt. 98, Debrecen, H-4032, Hungary.
| | - Ákos Németh
- Division of Metabolic Diseases, Department of Internal Medicine, University of Debrecen Faculty of Medicine, Nagyerdei krt. 98, Debrecen, H-4032, Hungary
| | - Mariann Harangi
- Division of Metabolic Diseases, Department of Internal Medicine, University of Debrecen Faculty of Medicine, Nagyerdei krt. 98, Debrecen, H-4032, Hungary
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Lodz, Poland.,Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
| | - Péter Fülöp
- Division of Metabolic Diseases, Department of Internal Medicine, University of Debrecen Faculty of Medicine, Nagyerdei krt. 98, Debrecen, H-4032, Hungary
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16
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Chen MC, Lian SH, Hsu BG, Wang JH. Positive correlation of serum angiopoietin-like protein 3 levels with metabolic syndrome in patients with coronary artery disease. Tzu Chi Med J 2022; 34:75-81. [PMID: 35233360 PMCID: PMC8830538 DOI: 10.4103/tcmj.tcmj_49_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/11/2021] [Accepted: 06/16/2021] [Indexed: 11/04/2022] Open
Abstract
Objectives: Angiopoietin-like protein 3 (ANGPTL3) regulates triglyceride metabolism by reversibly inhibiting the lipoprotein lipase activity. Metabolic syndrome (MetS) is an independent risk factor for further cardiovascular disease. This study evaluated the relationship between the fasting serum ANGPTL3 levels and MetS in patients with coronary artery disease (CAD). Materials and Methods: Fasting blood samples were obtained from 90 patients with CAD. Serum ANGPTL3 levels were measured using a commercial enzyme-linked immunosorbent assay kit. MetS and its components were defined using the diagnostic criteria of the International Diabetes Federation. Results: Fifty-three patients (58.9%) had MetS. The hypertension (P = 0.001), diabetes (P < 0.001), body weight (P = 0.027), body mass index (P = 0.001), waist circumference (P < 0.001), systolic blood pressure (P = 0.001), fasting glucose (P < 0.001), triglycerides (P < 0.001), blood urea nitrogen (P = 0.044), C-reactive protein (P = 0.010), insulin (P = 0.040), homeostasis model assessment of insulin resistance (P = 0.002), and ANGPTL3 level (P = 0.001) of CAD patients who had MetS were higher, and the high-density lipoprotein cholesterol (P = 0.001) and estimated glomerular filtration rate (P = 0.016) were lower. A binary logistic regression analysis of the significant variables also revealed that the ANGPTL3 level (odds ratio: 1.023, 95% confidence interval: 1.008–1.038, P = 0.002) was an independent predictor of MetS in patients with CAD. Conclusion: The results of our study indicated that the fasting ANGPTL3 level was positively associated with MetS among patients with CAD.
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17
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Chen PY, Chao TY, Hsu HJ, Wang CY, Lin CY, Gao WY, Wu MJ, Yen JH. The Lipid-Modulating Effect of Tangeretin on the Inhibition of Angiopoietin-like 3 (ANGPTL3) Gene Expression through Regulation of LXRα Activation in Hepatic Cells. Int J Mol Sci 2021; 22:ijms22189853. [PMID: 34576019 PMCID: PMC8471037 DOI: 10.3390/ijms22189853] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/10/2021] [Accepted: 09/10/2021] [Indexed: 02/07/2023] Open
Abstract
The excessive accumulation of TG-rich lipoproteins (TGRLs) in plasma is associated with dyslipidemia and atherosclerotic cardiovascular diseases (ASCVDs). Tangeretin is a bioactive pentamethoxyflavone mainly found in citrus peels, and it has been reported to protect against hyperlipidemia, diabetes, and obesity. The aim of this study was to investigate the lipid-modulating effects and the underlying mechanisms of tangeretin action in hepatic cells. Transcriptome and bioinformatics analyses with the Gene Ontology (GO) database showed that tangeretin significantly regulated a set of 13 differentially expressed genes (DEGs) associated with the regulation of lipoprotein lipase (LPL) activity. Among these DEGs, angiopoietin-like 3 (ANGPTL3), an essential inhibitor of LPL catalytic activity that regulates TGRL metabolism in plasma, was markedly downregulated by tangeretin. We demonstrated that tangeretin significantly inhibited the mRNA expression of ANGPTL3 in HepG2 and Huh-7 cells. Tangeretin treatment of hepatic cells also reduced the levels of both intracellular and secreted ANGPTL3 proteins. Moreover, we found that inhibition of ANGPTL3 production by tangeretin augmented LPL activity. We further demonstrated that the transcriptional activity of the ANGPTL3 promoter was significantly attenuated by tangeretin, and we identified a DNA element located between the −250 and −121 positions that responded to tangeretin. Furthermore, we found that tangeretin did not alter the levels of the nuclear liver X receptor α (LXRα) protein, an essential transcription factor that binds to the tangeretin-responsive element, but it can counteract LXRα-mediated ANGPTL3 transcription. On the basis of molecular docking analysis, tangeretin was predicted to bind to the ligand-binding domain of LXRα, which would result in suppression of LXRα activation. Our findings support the hypothesis that tangeretin exerts a lipid-lowering effect by modulating the LXRα-ANGPTL3-LPL pathway, and thus, it can be used as a potential phytochemical for the prevention or treatment of dyslipidemia.
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Affiliation(s)
- Pei-Yi Chen
- Center of Medical Genetics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97004, Taiwan;
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan; (T.-Y.C.); (C.-Y.L.)
| | - Tzu-Ya Chao
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan; (T.-Y.C.); (C.-Y.L.)
| | - Hao-Jen Hsu
- Department of Life Science, Tzu Chi University, Hualien 97004, Taiwan;
| | - Chih-Yang Wang
- Program for Cancer Molecular Biology and Drug Discovery, Taipei Medical University, Taipei 11031, Taiwan;
- Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 11031, Taiwan
| | - Ching-Yen Lin
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan; (T.-Y.C.); (C.-Y.L.)
| | - Wan-Yun Gao
- Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan;
| | - Ming-Jiuan Wu
- Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan;
| | - Jui-Hung Yen
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan; (T.-Y.C.); (C.-Y.L.)
- Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan;
- Correspondence: or ; Tel.: +88-63-856-5301 (ext. 2683)
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18
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Heeren J, Scheja L. Metabolic-associated fatty liver disease and lipoprotein metabolism. Mol Metab 2021; 50:101238. [PMID: 33892169 PMCID: PMC8324684 DOI: 10.1016/j.molmet.2021.101238] [Citation(s) in RCA: 342] [Impact Index Per Article: 85.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 04/01/2021] [Accepted: 04/15/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease, or as recently proposed 'metabolic-associated fatty liver disease' (MAFLD), is characterized by pathological accumulation of triglycerides and other lipids in hepatocytes. This common disease can progress from simple steatosis to steatohepatitis, and eventually end-stage liver diseases. MAFLD is closely related to disturbances in systemic energy metabolism, including insulin resistance and atherogenic dyslipidemia. SCOPE OF REVIEW The liver is the central organ in lipid metabolism by secreting very low density lipoproteins (VLDL) and, on the other hand, by internalizing fatty acids and lipoproteins. This review article discusses recent research addressing hepatic lipid synthesis, VLDL production, and lipoprotein internalization as well as the lipid exchange between adipose tissue and the liver in the context of MAFLD. MAJOR CONCLUSIONS Liver steatosis in MAFLD is triggered by excessive hepatic triglyceride synthesis utilizing fatty acids derived from white adipose tissue (WAT), de novo lipogenesis (DNL) and endocytosed remnants of triglyceride-rich lipoproteins. In consequence of high hepatic lipid content, VLDL secretion is enhanced, which is the primary cause of complex dyslipidemia typical for subjects with MAFLD. Interventions reducing VLDL secretory capacity attenuate dyslipidemia while they exacerbate MAFLD, indicating that the balance of lipid storage versus secretion in hepatocytes is a critical parameter determining disease outcome. Proof of concept studies have shown that promoting lipid storage and energy combustion in adipose tissues reduces hepatic lipid load and thus ameliorates MAFLD. Moreover, hepatocellular triglyceride synthesis from DNL and WAT-derived fatty acids can be targeted to treat MAFLD. However, more research is needed to understand how individual transporters, enzymes, and their isoforms affect steatosis and dyslipidemia in vivo, and whether these two aspects of MAFLD can be selectively treated. Processing of cholesterol-enriched lipoproteins appears less important for steatosis. It may, however, modulate inflammation and consequently MAFLD progression.
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Affiliation(s)
- Joerg Heeren
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Ludger Scheja
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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19
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Angiopoietin-Like Protein 3 (ANGPTL3) Modulates Lipoprotein Metabolism and Dyslipidemia. Int J Mol Sci 2021; 22:ijms22147310. [PMID: 34298929 PMCID: PMC8304944 DOI: 10.3390/ijms22147310] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 07/04/2021] [Accepted: 07/05/2021] [Indexed: 12/11/2022] Open
Abstract
Dyslipidemia is characterized by increasing plasma levels of low-density lipoprotein-cholesterol (LDL-C), triglycerides (TGs) and TG-rich lipoproteins (TGRLs) and is a major risk factor for the development of atherosclerotic cardiovascular disorders (ASCVDs). It is important to understand the metabolic mechanisms underlying dyslipidemia to develop effective strategies against ASCVDs. Angiopoietin-like 3 (ANGPTL3), a member of the angiopoietin-like protein family exclusively synthesized in the liver, has been demonstrated to be a critical regulator of lipoprotein metabolism to inhibit lipoprotein lipase (LPL) activity. Genetic, biochemical, and clinical studies in animals and humans have shown that loss of function, inactivation, or downregulated expression of ANGPTL3 is associated with an obvious reduction in plasma levels of TGs, LDL-C, and high-density lipoprotein-cholesterol (HDL-C), atherosclerotic lesions, and the risk of cardiovascular events. Therefore, ANGPTL3 is considered an alternative target for lipid-lowering therapy. Emerging studies have focused on ANGPTL3 inhibition via antisense oligonucleotides (ASOs) and monoclonal antibody-based therapies, which have been carried out in mouse or monkey models and in human clinical studies for the management of dyslipidemia and ASCVDs. This review will summarize the current literature on the important role of ANGPTL3 in controlling lipoprotein metabolism and dyslipidemia, with an emphasis on anti-ANGPTL3 therapies as a potential strategy for the treatment of dyslipidemia and ASCVDs.
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20
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Chen YQ, Pottanat TG, Zhen EY, Siegel RW, Ehsani M, Qian YW, Konrad RJ. ApoA5 lowers triglyceride levels via suppression of ANGPTL3/8-mediated LPL inhibition. J Lipid Res 2021; 62:100068. [PMID: 33762177 PMCID: PMC8079461 DOI: 10.1016/j.jlr.2021.100068] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 03/07/2021] [Indexed: 02/06/2023] Open
Abstract
Triglyceride (TG) molecules represent the major storage form of fatty acids, and TG metabolism is essential to human health. However, the mechanistic details surrounding TG metabolism are complex and incompletely elucidated. Although it is known that angiopoietin-like protein 8 (ANGPTL8) increases TGs through an ANGPTL3/8 complex that inhibits LPL, the mechanism governing ApoA5, which lowers TGs, has remained elusive. Current hypotheses for how ApoA5 acts include direct stimulation of LPL, facilitation of TG-containing particle uptake, and regulation of hepatic TG secretion. Using immunoprecipitation-MS and Western blotting, biolayer interferometry, functional LPL enzymatic assays, and kinetic analyses of LPL activity, we show that ApoA5 associates with ANGPTL3/8 in human serum and most likely decreases TG by suppressing ANGPTL3/8-mediated LPL inhibition. We also demonstrate that ApoA5 has no direct effect on LPL, nor does it suppress the LPL-inhibitory activities of ANGPTL3, ANGPTL4, or ANGPTL4/8. Importantly, ApoA5 suppression of ANGPTL3/8-mediated LPL inhibition occurred at a molar ratio consistent with the circulating concentrations of ApoA5 and ANGPTL3/8. Because liver X receptor (LXR) agonists decrease ApoA5 expression and cause hypertriglyceridemia, we investigated the effect of the prototypical LXR agonist T0901317 on human primary hepatocytes. We observed that T0901317 modestly stimulated hepatocyte ApoA5 release, but markedly stimulated ANGPTL3/8 secretion. Interestingly, the addition of insulin to T0901317 attenuated ApoA5 secretion, but further increased ANGPTL3/8 secretion. Together, these results reveal a novel intersection of ApoA5 and ANGPTL3/8 in the regulation of TG metabolism and provide a possible explanation for LXR agonist-induced hypertriglyceridemia.
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Affiliation(s)
- Yan Q Chen
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Thomas G Pottanat
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA; Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN, USA
| | - Eugene Y Zhen
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Robert W Siegel
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Mariam Ehsani
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Yue-Wei Qian
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Robert J Konrad
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
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21
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ANGPLT3 in cardio-metabolic disorders. Mol Biol Rep 2021; 48:2729-2739. [PMID: 33677817 DOI: 10.1007/s11033-021-06248-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 02/22/2021] [Indexed: 01/15/2023]
Abstract
Dyslipidemia is associated with numerous health problems that include the combination of insulin resistance, hypertension and obesity, which is always grouped together asmetabolic syndrome. Given that metabolic syndrome leads to a high mortality and poses serious risks to human health worldwide, it is vital to explore the mechanisms whereby dyslipidemia modulates the risk and the severity of cardio-metabolic disorders. Recently, a specific secretory protein family, named angiopoietin-like protein (ANGPTL), is considered as one of the significant biomarkers which facilitate the development of angiogenesis. Among the eight proteins of ANGPTL family, ANGPTL3 has been demonstrated as an essential modulator of lipid catabolism within circulation by inhibiting the activity of lipoprotein lipase (LPL) and endothelial lipase (EL). Consistent with these notions, mice with ANGPTL3 gene-deficiency presented reduced circulating levels of low density lipoprotein cholesterol (LDL-C) and lower risk of atherosclerosis. On the other hand, participants carrying homozygous loss-of function (LOF) mutation in ANGPTL3 gene also displayed lower circulating LDL-C levels and atherosclerotic risk. In the current review, we summarized the recent understanding of ANGPTL3 in controlling the risk and the development of dyslipidemia and its related cardio-metabolic disorders. Moreover, we also provided the perspectives which potentially suggested that ANGPTL3 could be considered as a promising target in treating metabolic syndrome.
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22
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Liu C, Yi X, Lyu Y, Ren W, Zhou Y, Feng G, Wan W, Jiang XJ. Elevated Plasma Angiopoietinlike Protein 5 (ANGPTL5) Is More Positively Associated with Glucose Metabolism Disorders in Patients with Metabolic Syndrome. Med Sci Monit 2021; 27:e929626. [PMID: 33486501 PMCID: PMC7841967 DOI: 10.12659/msm.929626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Background Angiopoietinlike protein 5 (ANGPTL5) is an adipocytokine and has an important role in metabolic processes including lipid metabolism, obesity, and type 2 diabetes mellitus. On the basis of these roles, the present study aimed to investigate the level and role of plasma ANGPTL5 in metabolic syndrome (MS) patients. Material/Methods A total of 139 participants was enrolled in this study; 69 of them were diagnosed with MS. Plasma ANGPTL5 levels were measured by enzyme-linked immunosorbent assay. Sex, age, and other laboratory tests were compared statistically. Correlations between ANGPTL5 and biochemical parameters such as lipid levels and insulin resistance were all evaluated statistically. Results In patients with MS, plasma ANGPTL5 levels were higher than in those without MS (P<0.05). Moreover, after adjusting for the glucose profiles, positive correlations were found between plasma ANGPTL5 levels and body mass index (BMI), waist circumference, and waist-hip ratio (WHR); a weak negative correlation was found between ANGPTL5 concentration and high-density lipoprotein cholesterol. After controlling the lipid profiles, positive correlations were found between ANGPTL5 concentration and BMI, WHR, fasting plasma glucose, fasting insulin, glycated hemoglobin, and homeostatic model assessment (HOMA) of insulin resistance; a negative correlation was found between plasma ANGPTL5 concentration and HOMA of β-cell function. The area under the curve was approximately 0.912 in receiver operating characteristic curve analysis. Conclusions The findings in the present study showed that plasma ANGPTL5 was more positively correlated with glucose metabolism disorders than with lipid metabolism disorders in patients with MS, which suggested that ANGPTL5 might serve as a potential and useful clinical predictor of MS.
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Affiliation(s)
- Chang Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (mainland).,Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China (mainland).,Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China (mainland)
| | - Xin Yi
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (mainland).,Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China (mainland).,Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China (mainland)
| | - Yongnan Lyu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (mainland).,Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China (mainland).,Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China (mainland)
| | - Wei Ren
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (mainland)
| | - Yi Zhou
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (mainland).,Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China (mainland).,Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China (mainland)
| | - Gaoke Feng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (mainland).,Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China (mainland).,Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China (mainland)
| | - Weiguo Wan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (mainland).,Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China (mainland).,Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China (mainland)
| | - Xue-Jun Jiang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China (mainland).,Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China (mainland).,Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China (mainland)
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23
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Ruscica M, Zimetti F, Adorni MP, Sirtori CR, Lupo MG, Ferri N. Pharmacological aspects of ANGPTL3 and ANGPTL4 inhibitors: New therapeutic approaches for the treatment of atherogenic dyslipidemia. Pharmacol Res 2020; 153:104653. [PMID: 31931117 DOI: 10.1016/j.phrs.2020.104653] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 01/08/2020] [Accepted: 01/09/2020] [Indexed: 12/24/2022]
Abstract
Among the determinants of atherosclerotic cardiovascular disease (ASCVD), genetic and experimental evidence has provided data on a major role of angiopoietin-like proteins 3 and 4 (ANGPTL3 and ANGPTL4) in regulating the activity of lipoprotein lipase (LPL), antagonizing the hydrolysis of triglycerides (TG). Indeed, beyond low-density lipoprotein cholesterol (LDL-C), ASCVD risk is also dependent on a cluster of metabolic abnormalities characterized by elevated fasting and post-prandial levels of TG-rich lipoproteins and their remnants. In a head-to-head comparison between murine models for ANGPTL3 and ANGPTL4, the former was found to be a better pharmacological target for the treatment of hypertriglyceridemia. In humans, loss-of-function mutations of ANGPTL3 are associated with a marked reduction of plasma levels of VLDL, low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Carriers of loss-of-function mutations of ANGPTL4 show instead lower TG-rich lipoproteins and a modest but significant increase of HDL. The relevance of ANGPTL3 and ANGPTL4 as new therapeutic targets is proven by the development of monoclonal antibodies or antisense oligonucleotides. Studies in animal models, including non-human primates, have demonstrated that short-term treatment with monoclonal antibodies against ANGPTL3 and ANGPTL4 induces activation of LPL and a marked reduction of plasma TG-rich-lipoproteins, apparently without any major side effects. Inhibition of both targets also partially reduces LDL-C, independent of the LDL receptor. Similar evidence has been observed with the antisense oligonucleotide ANGPTL3-LRX. The genetic studies have paved the way for the development of new ANGPTL3 and 4 antagonists for the treatment of atherogenic dyslipidemias. Conclusive data of phase 2 and 3 clinical trials are still needed in order to define their safety and efficacy profile.
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Affiliation(s)
- Massimiliano Ruscica
- Dipartimento di Science Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
| | - Francesca Zimetti
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università di Parma, Parma, Italy
| | - Maria Pia Adorni
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università di Parma, Parma, Italy
| | - Cesare R Sirtori
- Dyslipidemia Center, A.S.S.T. Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Maria Giovanna Lupo
- Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Padua, Italy
| | - Nicola Ferri
- Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Padua, Italy
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24
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Li J, Li L, Guo D, Li S, Zeng Y, Liu C, Fu R, Huang M, Xie W. Triglyceride metabolism and angiopoietin-like proteins in lipoprotein lipase regulation. Clin Chim Acta 2020; 503:19-34. [PMID: 31923423 DOI: 10.1016/j.cca.2019.12.029] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 12/31/2019] [Accepted: 12/31/2019] [Indexed: 12/21/2022]
Abstract
Hypertriglyceridemia is a risk factor for a series of diseases, such as cardiovascular disease (CVD), diabetes and nonalcoholic fatty liver disease (NAFLD). Angiopoietin-like proteins (ANGPTLs) family, especially ANGPTL3, ANGPTL4 and ANGPTL8, which regulate lipoprotein lipase (LPL) activity, play pivotal roles in triglyceride (TG) metabolism and related diseases/complications. There are many transcriptional and post-transcriptional factors that participate in physiological and pathological regulation of ANGPTLs to affect triglyceride metabolism. This review is intended to focus on the similarity and difference in the expression, structural features, regulation profile of the three ANGPTLs and inhibitory models for LPL. Description of the regulatory factors of ANGPTLs and the properties in regulating the lipid metabolism involved in the underlying mechanisms in pathological effects on diseases will provide potential therapeutic approaches for the treatment of dyslipidemia related diseases.
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Affiliation(s)
- Jing Li
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang 421001, Hunan, China; 2016 Class of Clinical Medicine, University of South China, Hengyang 421001, Hunan, China
| | - Liang Li
- Department of Pathophysiology, University of South China, Hengyang 421001, Hunan, China
| | - DongMing Guo
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang 421001, Hunan, China
| | - SuYun Li
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang 421001, Hunan, China
| | - YuXin Zeng
- 2018 Class of Excellent Doctor, University of South China, Hengyang 421001, Hunan, China
| | - ChuHao Liu
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang 421001, Hunan, China; 2016 Class of Clinical Medicine, University of South China, Hengyang 421001, Hunan, China
| | - Ru Fu
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang 421001, Hunan, China; 2016 Class of Clinical Medicine, University of South China, Hengyang 421001, Hunan, China
| | - MengQian Huang
- 2015 Class of Clinical Medicine, Fuxing Hospital, Capital Medical University, Beijing 100038, China.
| | - Wei Xie
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang 421001, Hunan, China.
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25
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Jiang X, Yang F, Zhao Q, Tian D, Tang Y. Protective effects of pentadecapeptide derived from Cyclaina sinensis against cyclophosphamide-induced hepatotoxicity. Biochem Biophys Res Commun 2019; 520:392-398. [PMID: 31607481 DOI: 10.1016/j.bbrc.2019.10.051] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Accepted: 10/04/2019] [Indexed: 02/06/2023]
Abstract
Our study was aimed at investigating the hepatoprotective effects of pentadecapeptide (RVAPEEHPVEGRYLV) from Cyclaina sinensis (SCSP) against cyclophosphamide (CTX)-induced hepatotoxicity in mice. Our results show that SCSP can significantly alleviate CTX-induced hepatotoxicity by decreasing the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG) and malondialdehyde (MDA), and increasing the levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) in the liver. In addition, the levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) were also significantly decreased in the liver tissues when treated with SCSP. Moreover, the protein levels of the toll-like receptor 4 (TLR4)-mediated nuclear factor-kappa B (NF-κB) pathway and apoptosis-related proteins were also restored by SCSP treatment. Overall, our results suggest that SCSP can potentially improve the CTX-induced hepatotoxicity.
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Affiliation(s)
- Xiaoxia Jiang
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan, 316022, China
| | - Fei Yang
- Hangzhou Obstetrics & Gynecology Hospital, Hangzhou, 310008, China
| | - Qiaojun Zhao
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan, 316022, China
| | - Diying Tian
- College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, 310018, China
| | - Yunping Tang
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan, 316022, China.
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26
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Brandi J, Di Carlo C, Manfredi M, Federici F, Bazaj A, Rizzi E, Cornaglia G, Manna L, Marengo E, Cecconi D. Investigating the Proteomic Profile of HT-29 Colon Cancer Cells After Lactobacillus kefiri SGL 13 Exposure Using the SWATH Method. JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY 2019; 30:1690-1699. [PMID: 31309410 DOI: 10.1007/s13361-019-02268-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 04/18/2019] [Accepted: 06/09/2019] [Indexed: 06/10/2023]
Abstract
Despite some studies revealed that kefir acts on different cancers, such as colorectal cancer, the proteomic changes that occur in the colon cancer cells remain to be explored. In this study, the proteomic analysis was combined with determination of kefir characteristics (e.g., adhesion capacity, gastrointestinal and antibiotic resistances), in order to confirm its use as a probiotic. Therefore, a label-free strategy based on SWATH-MS was applied to investigate the proteomic profile of HT-29 cells after exposure for 24 h to a specific strain of Lactobacillus kefiri named SGL 13. We identified a total of 60 differentially expressed proteins in HT-29 cells, among which most are located into the extracellular exosome, playing important/crucial roles in translation and cell adhesion, as indicated by the enrichment analysis. The eIF2 and retinoid X receptor activation pathways appeared to be correlated with the anti-tumoral effect of SGL 13. Immunoblot analysis showed an increase in Bax and a decrease in caspase 3 and mutant p53, and ELISA assay revealed inhibition of IL-8 secretion from HT-29 cells stimulated with LPS upon SGL 13 treatment, suggesting pro-apoptotic and anti-inflammatory properties of kefir. In conclusion, the results of this study, the first of its kind using co-culture of kefir and colon cancer cells, demonstrate that L. kefiri SGL 13 possesses probiotic potency and contribute to elucidate the molecular mechanisms involved in the L. kefiri-colon cancer cell interactions.
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Affiliation(s)
- Jessica Brandi
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Strada le Grazie 15, 37134, Verona, Italy
| | - Claudia Di Carlo
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Strada le Grazie 15, 37134, Verona, Italy
| | - Marcello Manfredi
- ISALIT s.r.l., Novara, Italy
- Center for Translational Research on Autoimmune & Allergic Diseases-CAAD, Novara, Italy
- Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | | | - Alda Bazaj
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Eleonora Rizzi
- Sintal Dietetics s.r.l., Castelnuovo Vomano, Teramo, Italy
| | - Giuseppe Cornaglia
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Laura Manna
- Sintal Dietetics s.r.l., Castelnuovo Vomano, Teramo, Italy
| | - Emilio Marengo
- Center for Translational Research on Autoimmune & Allergic Diseases-CAAD, Novara, Italy
- Department of Sciences and Technological Innovation, University of Eastern Piedmont, Alessandria, Italy
| | - Daniela Cecconi
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Strada le Grazie 15, 37134, Verona, Italy.
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27
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Ding P, Chen Z, Chen H, Zhang Z, Liu Z, Yan X, Zhou H, Gu Q, Li C, Xu J. Structurally Selective Mechanism of Liver X Receptor Ligand: In Silico and In Vitro Studies. J Chem Inf Model 2019; 59:3277-3290. [DOI: 10.1021/acs.jcim.9b00292] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Affiliation(s)
- Peng Ding
- Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Circle at University City, Guangzhou 510006, China
| | - Ziyang Chen
- Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Circle at University City, Guangzhou 510006, China
| | - Hao Chen
- Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Circle at University City, Guangzhou 510006, China
| | - Zizhen Zhang
- Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Circle at University City, Guangzhou 510006, China
| | - Zhihong Liu
- Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Circle at University City, Guangzhou 510006, China
| | - Xin Yan
- Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Circle at University City, Guangzhou 510006, China
| | - Huihao Zhou
- Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Circle at University City, Guangzhou 510006, China
| | - Qiong Gu
- Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Circle at University City, Guangzhou 510006, China
| | - Chanjuan Li
- Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Circle at University City, Guangzhou 510006, China
| | - Jun Xu
- Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Circle at University City, Guangzhou 510006, China
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28
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Tarugi P, Bertolini S, Calandra S. Angiopoietin-like protein 3 (ANGPTL3) deficiency and familial combined hypolipidemia. J Biomed Res 2019; 33:73-81. [PMID: 29752428 PMCID: PMC6477171 DOI: 10.7555/jbr.32.20170114] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Three members of the angiopoietin-like (ANGPTL) protein family-ANGPTL3, ANGPTL4 and ANGPTL8- are important regulators of plasma lipoproteins. They inhibit the enzyme lipoprotein lipase, which plays a key role in the intravascular lipolysis of triglycerides present in some lipoprotein classes. This review focuses on the role of ANGPTL3 as emerged from the study of genetic variants of Angptl3 gene in mice and humans. Both loss of function genetic variants and inactivation of Angptl3 gene in mice are associated with a marked reduction of plasma levels of triglyceride and cholesterol and an increased activity of lipoprotein lipase and endothelial lipase. In humans with ANGPTL3 deficiency, caused by homozygous loss of function (LOF) variants of Angptl3 gene, the levels of all plasma lipoproteins are greatly reduced. This plasma lipid disorder referred to as familial combined hypolipidemia (FHBL2) does not appear to be associated with distinct pathological manifestations. Heterozygous carriers of LOF variants have reduced plasma levels of total cholesterol and triglycerides and are at lower risk of developing atherosclerotic cardiovascular disease, as compared to non-carriers. These observations have paved the way to the development of strategies to reduce the plasma level of atherogenic lipoproteins in man by the inactivation of ANGPTL3, using either a specific monoclonal antibody or anti-sense oligonucleotides.
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Affiliation(s)
- Patrizia Tarugi
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena 41125, Italy
| | - Stefano Bertolini
- Department of Internal Medicine, University of Genova, Genova 16148, Italy
| | - Sebastiano Calandra
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena 41125, Italy
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29
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Jiang S, Qiu GH, Zhu N, Hu ZY, Liao DF, Qin L. ANGPTL3: a novel biomarker and promising therapeutic target. J Drug Target 2019; 27:876-884. [PMID: 30615486 DOI: 10.1080/1061186x.2019.1566342] [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] [Indexed: 10/27/2022]
Abstract
Angiopoietin-like protein 3 (ANGPTL3) belongs to a multifunctional secreted protein that mainly expresses in the liver, and is regulated by numerous post-translational modifications, including multiple cleavage and glycosylation. Accumulating evidences have revealed that ANGPTL3 plays a critical role in both biological processes, such as lipid metabolism, angiogenesis and haematopoietic function and pathological changes, including atherosclerosis, carcinogenesis, nephrotic syndrome, diabetes, liver diseases and so on. Thus, ANGPTL3 may serve as a potential biomarker in these diseases. Furthermore, ANGPTL3 signalling pathways including LXR/ANGPTL3, thyroid hormone/ANGPTL3, insulin/ANGPTL3 and leptin/ANGPTL3 are also involved in physiological and pathological processes. Some biological ANGPTL3 inhibitors, chemical drugs and traditional Chinese medicine exert beneficial effects by targeting ANGPTL3 directly or indirectly. Therefore, elucidating the effects and underlying mechanisms of ANGPTL3 is essential to develop promising strategies in the diagnosis and treatment of related diseases.
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Affiliation(s)
- Shuang Jiang
- a School of Pharmacy , Hunan University of Chinese Medicine , Changsha , Hunan , China.,b Division of Stem Cell Regulation and Application , Hunan University of Chinese Medicine , Changsha , Hunan , China
| | - Guo-Hui Qiu
- a School of Pharmacy , Hunan University of Chinese Medicine , Changsha , Hunan , China.,c Department of Pharmacy , Hunan Provincial People's Hospital , Changsha , Hunan , China
| | - Neng Zhu
- d The First Affiliated Hospital , Hunan University of Chinese Medicine , Changsha , Hunan , China
| | - Zhe-Yu Hu
- e Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya Medical School , Central South University , Changsha , Hunan , China
| | - Duan-Fang Liao
- a School of Pharmacy , Hunan University of Chinese Medicine , Changsha , Hunan , China.,b Division of Stem Cell Regulation and Application , Hunan University of Chinese Medicine , Changsha , Hunan , China
| | - Li Qin
- a School of Pharmacy , Hunan University of Chinese Medicine , Changsha , Hunan , China.,b Division of Stem Cell Regulation and Application , Hunan University of Chinese Medicine , Changsha , Hunan , China
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30
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Goedeke L, Bates J, Vatner DF, Perry RJ, Wang T, Ramirez R, Li L, Ellis MW, Zhang D, Wong KE, Beysen C, Cline GW, Ray AS, Shulman GI. Acetyl-CoA Carboxylase Inhibition Reverses NAFLD and Hepatic Insulin Resistance but Promotes Hypertriglyceridemia in Rodents. Hepatology 2018; 68:2197-2211. [PMID: 29790582 PMCID: PMC6251774 DOI: 10.1002/hep.30097] [Citation(s) in RCA: 185] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Accepted: 04/30/2018] [Indexed: 12/13/2022]
Abstract
Pharmacologic inhibition of acetyl-CoA carboxylase (ACC) enzymes, ACC1 and ACC2, offers an attractive therapeutic strategy for nonalcoholic fatty liver disease (NAFLD) through simultaneous inhibition of fatty acid synthesis and stimulation of fatty acid oxidation. However, the effects of ACC inhibition on hepatic mitochondrial oxidation, anaplerosis, and ketogenesis in vivo are unknown. Here, we evaluated the effect of a liver-directed allosteric inhibitor of ACC1 and ACC2 (Compound 1) on these parameters, as well as glucose and lipid metabolism, in control and diet-induced rodent models of NAFLD. Oral administration of Compound 1 preferentially inhibited ACC enzymatic activity in the liver, reduced hepatic malonyl-CoA levels, and enhanced hepatic ketogenesis by 50%. Furthermore, administration for 6 days to high-fructose-fed rats resulted in a 20% reduction in hepatic de novo lipogenesis. Importantly, long-term treatment (21 days) significantly reduced high-fat sucrose diet-induced hepatic steatosis, protein kinase C epsilon activation, and hepatic insulin resistance. ACCi treatment was associated with a significant increase in plasma triglycerides (approximately 30% to 130%, depending on the length of fasting). ACCi-mediated hypertriglyceridemia could be attributed to approximately a 15% increase in hepatic very low-density lipoprotein production and approximately a 20% reduction in triglyceride clearance by lipoprotein lipase (P ≤ 0.05). At the molecular level, these changes were associated with increases in liver X receptor/sterol response element-binding protein-1 and decreases in peroxisome proliferator-activated receptor-α target activation and could be reversed with fenofibrate co-treatment in a high-fat diet mouse model. Conclusion: Collectively, these studies warrant further investigation into the therapeutic utility of liver-directed ACC inhibition for the treatment of NAFLD and hepatic insulin resistance.
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Affiliation(s)
- Leigh Goedeke
- Department of Internal Medicine, Yale University School of Medicine, New Haven CT, 06520
| | | | - Daniel F. Vatner
- Department of Internal Medicine, Yale University School of Medicine, New Haven CT, 06520
| | - Rachel J. Perry
- Department of Internal Medicine, Yale University School of Medicine, New Haven CT, 06520
| | - Ting Wang
- Gilead Sciences Inc., Foster City CA 94404
| | | | - Li Li
- Gilead Sciences Inc., Foster City CA 94404
| | - Matthew W. Ellis
- Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven CT 06520
| | - Dongyan Zhang
- Department of Internal Medicine, Yale University School of Medicine, New Haven CT, 06520
| | | | | | - Gary W. Cline
- Department of Internal Medicine, Yale University School of Medicine, New Haven CT, 06520
| | | | - Gerald I. Shulman
- Department of Internal Medicine, Yale University School of Medicine, New Haven CT, 06520,Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven CT 06520,Howard Hughes Medical Institute, Yale University School of Medicine, New Haven CT 06520
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31
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Angiopoietin-Like 3 (ANGPTL3) and Atherosclerosis: Lipid and Non-Lipid Related Effects. J Cardiovasc Dev Dis 2018; 5:jcdd5030039. [PMID: 30011918 PMCID: PMC6162638 DOI: 10.3390/jcdd5030039] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 07/10/2018] [Accepted: 07/11/2018] [Indexed: 01/13/2023] Open
Abstract
Genetic and clinical studies have demonstrated that loss-of-function variants in the angiopoietin-like 3 (ANGPTL3) gene are associated with decreased plasma levels of triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), which leads to a significant reduction in cardiovascular risk. For this reason, ANGPTL3 is considered an important new pharmacological target for the treatment of cardiovascular diseases (CVDs) together with more conventional lipid lowering therapies, such as statins and anti proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies. Experimental evidence demonstrates that anti-ANGPTL3 therapies have an important anti-atherosclerotic effect. Results from phase I clinical trials with a monoclonal anti-ANGPTL3 antibody (evinacumab) and anti-sense oligonucleotide (ASO) clearly show a significant lipid lowering effect. In addition, from the analysis of the protein structure of ANGPTL3, it has been hypothesized that, beyond its inhibitory activity on lipoprotein and endothelial lipases, this molecule may have a pro-inflammatory, pro-angiogenic effect and a negative effect on cholesterol efflux, implying additional pro-atherosclerotic properties. In the future, data from phase II clinical trials and additional experimental evidence will help to define the efficacy and the additional anti-atherosclerotic properties of anti-ANGPTL3 therapies beyond the already available lipid lowering therapies.
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Su X, Peng DQ. New insights into ANGPLT3 in controlling lipoprotein metabolism and risk of cardiovascular diseases. Lipids Health Dis 2018; 17:12. [PMID: 29334984 PMCID: PMC5769531 DOI: 10.1186/s12944-018-0659-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 01/05/2018] [Indexed: 02/07/2023] Open
Abstract
Dyslipidemia, characterized by elevation of plasma low density lipoprotein cholesterol (LDL-C), triglyceride (TG) and reduction of plasma high density lipoprotein cholesterol (HDL-C), has been verified as a causal risk factor for cardiovascular diseases (CVD), leading to a high mortality rate in general population. It is important to understand the molecular metabolism underlying dyslipidemia in order to reduce the risk and to develop effective therapeutic approaches against CVD. ANGPTL3 (human) or Angptl3 (mouse), one member of the angiopoietin-like protein (ANGPTL) family, has been identified as an important regulator of lipid metabolism by inhibiting LPL and EL activity. Results have demonstrated that inactivation of Angptl3 in mice could obviously reduce the level of TG, LDL-C and the atherosclerotic lesion size, leading to a lower risk for dyslipidemia and CVD. Additionally, in humans, carriers with homozygous LOF mutations in ANGPTL3 have lower plasma LDL-C, TG levels and lower risk of atherosclerosis compared to the non-carriers. Here, we collect the latest data and results, giving a new insight into the important role of ANGPTL3 in controlling lipoprotein metabolism. Finally, we introduce two update reports on the antisense oligonucleotide and monoclonal antibody-based inactivation of ANGPTL3 in human clinical trials, to identify that ANGPTL3 could be a novel and effective target for the treatment of dyslipidemia and CVD.
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Affiliation(s)
- Xin Su
- Department of Cardiovascular Medicine, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Dao-Quan Peng
- Department of Cardiovascular Medicine, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
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Ren R, Yang Z, Zhao A, Huang Y, Lin S, Gong J, Chen J, Zhu P, Huang F, Lin W. Sulfated polysaccharide from Enteromorpha prolifera increases hydrogen sulfide production and attenuates non-alcoholic fatty liver disease in high-fat diet rats. Food Funct 2018; 9:4376-4383. [DOI: 10.1039/c8fo00518d] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
EP upregulates hepatic CBS expression, thus increasing serum H2S level, which reduces serum TG level and ameliorates NAFLD induced by a high-fat diet.
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Affiliation(s)
- Rendong Ren
- School of Public Health
- Fujian Medical University
- Fuzhou
- China
| | - Zheng Yang
- School of Public Health
- Fujian Medical University
- Fuzhou
- China
| | - Aili Zhao
- School of Public Health
- Fujian Medical University
- Fuzhou
- China
| | - Yuyang Huang
- School of Clinical Medicine
- Fujian Medical University
- Fuzhou
- China
| | - Shiying Lin
- School of Public Health
- Fujian Medical University
- Fuzhou
- China
| | - Junjie Gong
- School of Public Health
- Fujian Medical University
- Fuzhou
- China
| | - Jie Chen
- School of Public Health
- Fujian Medical University
- Fuzhou
- China
| | - Pingping Zhu
- School of Public Health
- Fujian Medical University
- Fuzhou
- China
| | - Fang Huang
- School of Public Health
- Fujian Medical University
- Fuzhou
- China
| | - Wenting Lin
- School of Public Health
- Fujian Medical University
- Fuzhou
- China
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Abstract
Triglycerides and cholesterol circulate in the bloodstream as part of various lipoprotein particles. Three members of the angiopoietin-like (ANGPTL) protein family - ANGPTL3, ANGPTL4 and ANGPTL8 - have emerged as important regulators of plasma lipoprotein levels by inhibiting the enzyme lipoprotein lipase. Here, I review the role of ANGPTL3 in lipoprotein metabolism. In contrast to ANGPTL4 and ANGPTL8, ANGPTL3 is exclusively produced in the liver and can therefore be classified as a true hepatokine. ANGPTL3 cooperates with ANGPTL8 to inhibit lipoprotein lipase and is mostly active after feeding, whereas ANGPTL4 is mostly active after fasting. Inactivation of ANGPTL3 in mice reduces plasma triglyceride and free fatty acid levels and suppresses atherosclerosis. In humans, homozygous loss-of-function mutations in ANGPTL3 lead to low plasma levels of low-density lipoproteins, high-density lipoproteins and triglycerides, a condition referred to as familial combined hypolipidaemia. Heterozygous carriers of loss-of-function mutations in ANGPTL3 have a lower risk of coronary artery disease than non-carriers. At present, researchers are investigating antisense oligonucleotide and monoclonal antibody-based inactivation of ANGPTL3 in human clinical trials for the therapeutic management of dyslipidaemia and atherosclerosis. Thus, ANGPTL3 is an important liver-derived regulator of lipoprotein metabolism that holds considerable promise as a target for atherosclerosis.
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Affiliation(s)
- Sander Kersten
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Stippeneng 4, 6708 WE Wageningen, The Netherlands
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35
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Kick EK, Busch BB, Martin R, Stevens WC, Bollu V, Xie Y, Boren BC, Nyman MC, Nanao MH, Nguyen L, Plonowski A, Schulman IG, Yan G, Zhang H, Hou X, Valente MN, Narayanan R, Behnia K, Rodrigues AD, Brock B, Smalley J, Cantor GH, Lupisella J, Sleph P, Grimm D, Ostrowski J, Wexler RR, Kirchgessner T, Mohan R. Discovery of Highly Potent Liver X Receptor β Agonists. ACS Med Chem Lett 2016; 7:1207-1212. [PMID: 27994765 PMCID: PMC5150697 DOI: 10.1021/acsmedchemlett.6b00234] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Accepted: 09/27/2016] [Indexed: 12/13/2022] Open
Abstract
![]()
Introducing a uniquely substituted
phenyl sulfone into a series
of biphenyl imidazole liver X receptor (LXR) agonists afforded a dramatic
potency improvement for induction of ATP binding cassette transporters,
ABCA1 and ABCG1, in human whole blood. The agonist series demonstrated
robust LXRβ activity (>70%) with low partial LXRα agonist
activity (<25%) in cell assays, providing a window between desired
blood cell ABCG1 gene induction in cynomolgus monkeys and modest elevation
of plasma triglycerides for agonist 15. The addition
of polarity to the phenyl sulfone also reduced binding to the plasma
protein, human α-1-acid glycoprotein. Agonist 15 was selected for clinical development based on the favorable combination
of in vitro properties, excellent pharmacokinetic
parameters, and a favorable lipid profile.
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Affiliation(s)
| | - Brett B. Busch
- Exelixis Inc., 210 East Grand
Avenue, South San Francisco, California 94080, United States
| | - Richard Martin
- Exelixis Inc., 210 East Grand
Avenue, South San Francisco, California 94080, United States
| | - William C. Stevens
- Exelixis Inc., 210 East Grand
Avenue, South San Francisco, California 94080, United States
| | - Venkataiah Bollu
- Exelixis Inc., 210 East Grand
Avenue, South San Francisco, California 94080, United States
| | - Yinong Xie
- Exelixis Inc., 210 East Grand
Avenue, South San Francisco, California 94080, United States
| | - Brant C. Boren
- Exelixis Inc., 210 East Grand
Avenue, South San Francisco, California 94080, United States
| | - Michael C. Nyman
- Exelixis Inc., 210 East Grand
Avenue, South San Francisco, California 94080, United States
| | - Max H. Nanao
- Exelixis Inc., 210 East Grand
Avenue, South San Francisco, California 94080, United States
| | - Lam Nguyen
- Exelixis Inc., 210 East Grand
Avenue, South San Francisco, California 94080, United States
| | - Artur Plonowski
- Exelixis Inc., 210 East Grand
Avenue, South San Francisco, California 94080, United States
| | - Ira G. Schulman
- Exelixis Inc., 210 East Grand
Avenue, South San Francisco, California 94080, United States
| | - Grace Yan
- Exelixis Inc., 210 East Grand
Avenue, South San Francisco, California 94080, United States
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Raju Mohan
- Exelixis Inc., 210 East Grand
Avenue, South San Francisco, California 94080, United States
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Fasting and Feeding Signals Control the Oscillatory Expression of Angptl8 to Modulate Lipid Metabolism. Sci Rep 2016; 6:36926. [PMID: 27845381 PMCID: PMC5109406 DOI: 10.1038/srep36926] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 10/24/2016] [Indexed: 12/27/2022] Open
Abstract
Emerging evidence implies a key role of angiopoietin-like protein 8 (Angptl8) in the metabolic transition between fasting and feeding, whereas much less is known about the mechanism of its own expression. Here we show that hepatic Angptl8 is rhythmically expressed, which involving the liver X receptor alpha (LXRα) and glucocorticoid receptor (GR) modulation during feeding and fasting periods, respectively. In addition, Angptl8 mRNA is very unstable, which contributes to the nature of its daily rhythmicity by rapidly responding to fasting/feeding transition. To explore its pathological function in dexamethasone (DEX)-induced fatty liver, we reversed its suppression by glucocorticoids through adenoviral delivery of Angptl8 gene in mouse liver. Surprisingly, hepatic overexpression of Angptl8 dramatically elevated plasma triglyceride (TG) and non-esterified fatty acid (NEFA) levels in DEX-treated mice, suggesting a metabolic interaction between Angptl8 and glucocorticoid signaling. Moreover, intracellular hepatic Angptl8 is implicated in the regulation of lipid homeostasis by the experiments with ectopic expression of a nonsecreted Angptl8 mutant (Δ25-Angptl8). Altogether, our data demonstrate the molecular mechanism of the diurnal rhythm of Angptl8 expression regulated by glucocorticoid signaling and LXRα pathway, and provide new evidence to understand the role of Angptl8 in maintaining plasma TG homeostasis.
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Zhao D, Yang LY, Wang XH, Yuan SS, Yu CG, Wang ZW, Lang JN, Feng YM. Different relationship between ANGPTL3 and HDL components in female non-diabetic subjects and type-2 diabetic patients. Cardiovasc Diabetol 2016; 15:132. [PMID: 27620179 PMCID: PMC5020513 DOI: 10.1186/s12933-016-0450-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 09/03/2016] [Indexed: 01/03/2023] Open
Abstract
Background Angiopoietin-like protein 3 (ANGPTL3) is a major lipoprotein regulator and shows positive correlation with high-density lipoprotein-cholesterol (HDL-c) in population studies and ANGPTL3 mutated subjects. However, no study has looked its correlation with HDL components nor with HDL function in patients with type 2 diabetes mellitus (T2DM). Methods We studied 298 non-diabetic subjects and 300 T2DM patients who were randomly recruited in the tertiary referral centre. Plasma levels of ANGPTL3 were quantified by ELISA. Plasma samples were fractionated to obtain HDLs. HDL components including apolipoprotein A-I (apoA-I), triglyceride, serum amyloid A (SAA), phospholipid and Sphingosine-1-phosphate were measured. HDLs were isolated from female controls and T2DM patients by ultracentrifugation to assess cholesterol efflux against HDLs. A Pearson unadjusted correlation analysis and a linear regression analysis adjusting for age, body mass index and lipid lowering drugs were performed in male or female non-diabetic participants or diabetic patients, respectively. Results We demonstrated that plasma level of ANGPTL3 was lower in female T2DM patients than female controls although no difference of ANGPTL3 levels was detected between male controls and T2DM patients. After adjusting for confounding factors, one SD increase of ANGPTL3 (164.6 ng/ml) associated with increase of 2.57 mg/dL cholesterol and 1.14 μg/mL apoA-I but decrease of 47.07 μg/L of SAA in HDL particles of non-diabetic females (p < 0.05 for cholesterol and SAA; p < 0.0001 for apoA-I). By contrast, 1-SD increase of ANGPTL3 (159.9 ng/ml) associated with increase of 1.69 mg/dl cholesterol and 1.25 μg/mL apoA-I but decrease of 11.70 μg/L of SAA in HDL particles of female diabetic patients (p < 0.05 for cholesterol; p < 0.0001 for apoA-I; p = 0.676 for SAA). Moreover, one SD increase of ANGPTL3 associated with increase of 2.11 % cholesterol efflux against HDLs in non-diabetic females (p = 0.071) but decrease of 1.46 % in female T2DM patients (p = 0.13) after adjusting for confounding factors. Conclusions ANGPTL3 is specifically correlated with HDL-c, apoA-I, SAA and HDL function in female non-diabetic participants. The decrease of ANGPTL3 level in female T2DM patients might contribute to its weak association to HDL components and function. ANGPTL3 could be considered as a novel therapeutic target for HDL metabolism for treating diabetes. Electronic supplementary material The online version of this article (doi:10.1186/s12933-016-0450-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Dong Zhao
- Beijing Key Laboratory of Diabetes Prevention and Research, Department of Endocrinology, Lu He Hospital, Capital Medical University, Beijing, 101149, China
| | - Long-Yan Yang
- Beijing Key Laboratory of Diabetes Prevention and Research, Department of Endocrinology, Lu He Hospital, Capital Medical University, Beijing, 101149, China
| | - Xu-Hong Wang
- Beijing Key Laboratory of Diabetes Prevention and Research, Department of Endocrinology, Lu He Hospital, Capital Medical University, Beijing, 101149, China
| | - Sha-Sha Yuan
- Beijing Key Laboratory of Diabetes Prevention and Research, Department of Endocrinology, Lu He Hospital, Capital Medical University, Beijing, 101149, China
| | - Cai-Guo Yu
- Beijing Key Laboratory of Diabetes Prevention and Research, Department of Endocrinology, Lu He Hospital, Capital Medical University, Beijing, 101149, China
| | - Zong-Wei Wang
- Beijing Key Laboratory of Diabetes Prevention and Research, Department of Endocrinology, Lu He Hospital, Capital Medical University, Beijing, 101149, China
| | - Jia-Nan Lang
- Beijing Key Laboratory of Diabetes Prevention and Research, Department of Endocrinology, Lu He Hospital, Capital Medical University, Beijing, 101149, China
| | - Ying-Mei Feng
- Beijing Key Laboratory of Diabetes Prevention and Research, Department of Endocrinology, Lu He Hospital, Capital Medical University, Beijing, 101149, China. .,Stem Cell Institute, University of Leuven, 3000, Louvain, Belgium.
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38
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Kirchgessner TG, Sleph P, Ostrowski J, Lupisella J, Ryan CS, Liu X, Fernando G, Grimm D, Shipkova P, Zhang R, Garcia R, Zhu J, He A, Malone H, Martin R, Behnia K, Wang Z, Barrett YC, Garmise RJ, Yuan L, Zhang J, Gandhi MD, Wastall P, Li T, Du S, Salvador L, Mohan R, Cantor GH, Kick E, Lee J, Frost RJA. Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils. Cell Metab 2016; 24:223-33. [PMID: 27508871 DOI: 10.1016/j.cmet.2016.07.016] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 06/21/2016] [Accepted: 07/21/2016] [Indexed: 01/20/2023]
Abstract
The development of LXR agonists for the treatment of coronary artery disease has been challenged by undesirable properties in animal models. Here we show the effects of an LXR agonist on lipid and lipoprotein metabolism and neutrophils in human subjects. BMS-852927, a novel LXRβ-selective compound, had favorable profiles in animal models with a wide therapeutic index in cynomolgus monkeys and mice. In healthy subjects and hypercholesterolemic patients, reverse cholesterol transport pathways were induced similarly to that in animal models. However, increased plasma and hepatic TG, plasma LDL-C, apoB, apoE, and CETP and decreased circulating neutrophils were also evident. Furthermore, similar increases in LDL-C were observed in normocholesterolemic subjects and statin-treated patients. The primate model markedly underestimated human lipogenic responses and did not predict human neutrophil effects. These studies demonstrate both beneficial and adverse LXR agonist clinical responses and emphasize the importance of further translational research in this area.
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Affiliation(s)
| | - Paul Sleph
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Jacek Ostrowski
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - John Lupisella
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Carol S Ryan
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Xiaoqin Liu
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Gayani Fernando
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Denise Grimm
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Petia Shipkova
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Rongan Zhang
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Ricardo Garcia
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Jun Zhu
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Aiqing He
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Harold Malone
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | | | - Kamelia Behnia
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Zhaoqing Wang
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Yu Chen Barrett
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Robert J Garmise
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Long Yuan
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Jane Zhang
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Mohit D Gandhi
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Philip Wastall
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Tong Li
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Shuyan Du
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Lisa Salvador
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Raju Mohan
- Exelixis, Inc., South San Francisco, CA 94080, USA
| | - Glenn H Cantor
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Ellen Kick
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - John Lee
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
| | - Robert J A Frost
- Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA
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Taoka H, Yokoyama Y, Morimoto K, Kitamura N, Tanigaki T, Takashina Y, Tsubota K, Watanabe M. Role of bile acids in the regulation of the metabolic pathways. World J Diabetes 2016; 7:260-270. [PMID: 27433295 PMCID: PMC4937164 DOI: 10.4239/wjd.v7.i13.260] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 11/24/2015] [Accepted: 05/27/2016] [Indexed: 02/05/2023] Open
Abstract
Recent studies have revealed that bile acids (BAs) are not only facilitators of dietary lipid absorption but also important signaling molecules exerting multiple physiological functions. Some major signaling pathways involving the nuclear BAs receptor farnesoid X receptor and the G protein-coupled BAs receptor TGR5/M-BAR have been identified to be the targets of BAs. BAs regulate their own homeostasis via signaling pathways. BAs also affect diverse metabolic pathways including glucose metabolism, lipid metabolism and energy expenditure. This paper suggests the mechanism of controlling metabolism via BA signaling and demonstrates that BA signaling is an attractive therapeutic target of the metabolic syndrome.
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Abstract
Angiopoietin-like protein 3 (ANGPTL3) is a secretory protein regulating plasma lipid levels via affecting lipoprotein lipase- and endothelial lipase-mediated hydrolysis of triglycerides and phospholipids. ANGPTL3-deficiency due to loss-of-function mutations in the ANGPTL3 gene causes familial combined hypobetalipoproteinemia (FHBL2, OMIM # 605019), a phenotype characterized by low concentration of all major lipoprotein classes in circulation. ANGPTL3 is therefore a potential therapeutic target to treat combined hyperlipidemia, a major risk factor for atherosclerotic coronary heart disease. This review focuses on the mechanisms behind ANGPTL3-deficiency induced FHBL2.
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Affiliation(s)
- Anna Tikka
- National Institute for Health and Welfare. Genomics and Biomarkers Unit, Biomedicum, Haartmaninkatu 8, 00250, Helsinki, Finland.
| | - Matti Jauhiainen
- National Institute for Health and Welfare. Genomics and Biomarkers Unit, Biomedicum, Haartmaninkatu 8, 00250, Helsinki, Finland
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Minicocci I, Tikka A, Poggiogalle E, Metso J, Montali A, Ceci F, Labbadia G, Fontana M, Di Costanzo A, Maranghi M, Rosano A, Ehnholm C, Donini LM, Jauhiainen M, Arca M. Effects of angiopoietin-like protein 3 deficiency on postprandial lipid and lipoprotein metabolism. J Lipid Res 2016; 57:1097-107. [PMID: 27040449 DOI: 10.1194/jlr.p066183] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2016] [Indexed: 12/29/2022] Open
Abstract
The consequences of angiopoietin-like protein 3 (ANGPTL3) deficiency on postprandial lipid and lipoprotein metabolism has not been investigated in humans. We studied 7 homozygous (undetectable circulating ANGPTL3 levels) and 31 heterozygous (50% of circulating ANGPTL3 levels) subjects with familial combined hypolipidemia (FHBL2) due to inactivating ANGPTL3 mutations in comparison with 35 controls. All subjects were evaluated at fasting and during 6 h after a high fat meal. Postprandial lipid and lipoprotein changes were quantified by calculating the areas under the curve (AUCs) using the 6 h concentration data. Plasma changes of β-hydroxybutyric acid (β-HBA) were measured as marker of hepatic oxidation of fatty acids. Compared with controls, homozygotes showed lower incremental AUCs (iAUCs) of total TG (-69%, P < 0.001), TG-rich lipoproteins (-90%, P < 0.001), apoB-48 (-78%, P = 0.032), and larger absolute increase of FFA (128%, P < 00.1). Also, heterozygotes displayed attenuated postprandial lipemia, but the difference was significant only for the iAUC of apoB-48 (-28%; P < 0.05). During the postprandial period, homozygotes, but not heterozygotes, showed a lower increase of β-HBA. Our findings demonstrate that complete ANGPTL3 deficiency associates with highly reduced postprandial lipemia probably due to faster catabolism of intestinally derived lipoproteins, larger expansion of the postprandial FFA pool, and decreased influx of dietary-derived fatty acids into the liver. These results add information on mechanisms underlying hypolipidemia in FHBL2.
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Affiliation(s)
- Ilenia Minicocci
- Departments of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Anna Tikka
- National Institute for Health and Welfare, Genomics and Biomarkers Unit, Biomedicum, Helsinki, Finland
| | | | - Jari Metso
- National Institute for Health and Welfare, Genomics and Biomarkers Unit, Biomedicum, Helsinki, Finland
| | - Anna Montali
- Departments of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Fabrizio Ceci
- Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy
| | - Giancarlo Labbadia
- Departments of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Mario Fontana
- Departments of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Alessia Di Costanzo
- Departments of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Marianna Maranghi
- Departments of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Aldo Rosano
- ISFOL, Department of Employment and Social Policies, Rome, Italy
| | - Christian Ehnholm
- National Institute for Health and Welfare, Genomics and Biomarkers Unit, Biomedicum, Helsinki, Finland
| | | | - Matti Jauhiainen
- National Institute for Health and Welfare, Genomics and Biomarkers Unit, Biomedicum, Helsinki, Finland
| | - Marcello Arca
- Departments of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
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Sun L, Zhang S, Yu C, Pan Z, Liu Y, Zhao J, Wang X, Yun F, Zhao H, Yan S, Yuan Y, Wang D, Ding X, Liu G, Li W, Zhao X, Liu Z, Li Y. Hydrogen sulfide reduces serum triglyceride by activating liver autophagy via the AMPK-mTOR pathway. Am J Physiol Endocrinol Metab 2015; 309:E925-35. [PMID: 26442880 DOI: 10.1152/ajpendo.00294.2015] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 09/23/2015] [Indexed: 12/31/2022]
Abstract
Autophagy plays an important role in liver triglyceride (TG) metabolism. Inhibition of autophagy could reduce the clearance of TG in the liver. Hydrogen sulfide (H2S) is a potent stimulator of autophagic flux. Recent studies showed H2S is protective against hypertriglyceridemia (HTG) and noalcoholic fatty liver disease (NAFLD), while the mechanism remains to be explored. Here, we tested the hypothesis that H2S reduces serum TG level and ameliorates NAFLD by stimulating liver autophagic flux by the AMPK-mTOR pathway. The level of serum H2S in patients with HTG was lower than that of control subjects. Sodium hydrosulfide (NaHS, H2S donor) markedly reduced serum TG levels of male C57BL/6 mice fed a high-fat diet (HFD), which was abolished by coadministration of chloroquine (CQ), an inhibitor of autophagic flux. In HFD mice, administration of NaSH increased the LC3BII-to-LC3BI ratio and decreased the p62 protein level. Meanwhile, NaSH increased the phosphorylation of AMPK and thus reduced the phosphorylation of mTOR in a Western blot study. In cultured LO2 cells, high-fat treatment reduced the ratio of LC3BII to LC3BI and the phosphorylation of AMPK, which were reversed by the coadministration of NaSH. Knockdown of AMPK by siRNA in LO2 cells blocked the autophagic enhancing effects of NaSH. The same qualitative effect was observed in AMPKα2(-/-) mice. These results for the first time demonstrated that H2S could reduce serum TG level and ameliorate NAFLD by activating liver autophagy via the AMPK-mTOR pathway.
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Affiliation(s)
- Li Sun
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Song Zhang
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Chengyuan Yu
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Zhenwei Pan
- Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Yang Liu
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Jing Zhao
- Key Laboratory of Cardiac Diseases and Heart Failure, Harbin Medical University, Harbin, Heilongjiang Province, China; and
| | - Xiaoyu Wang
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Fengxiang Yun
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Hongwei Zhao
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Sen Yan
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Yue Yuan
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Dingyu Wang
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Xue Ding
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Guangzhong Liu
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Wenpeng Li
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Xuezhu Zhao
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Zhaorui Liu
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Yue Li
- Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China; Key Laboratory of Cardiac Diseases and Heart Failure, Harbin Medical University, Harbin, Heilongjiang Province, China; and
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Lee J, Hong SW, Park SE, Rhee EJ, Park CY, Oh KW, Park SW, Lee WY. AMP-activated protein kinase suppresses the expression of LXR/SREBP-1 signaling-induced ANGPTL8 in HepG2 cells. Mol Cell Endocrinol 2015; 414:148-55. [PMID: 26254015 DOI: 10.1016/j.mce.2015.07.031] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Revised: 07/14/2015] [Accepted: 07/31/2015] [Indexed: 02/08/2023]
Abstract
ANGPTL8 is a liver-derived secretory protein that leads to elevated serum triglyceride and the level of circulating ANGPTL8 is strongly associated with obesity and diabetes. Here we investigated the mechanisms of activation and inhibition of ANGPTL8 expression in hepatocytes. The expression of ANGPTL8 was significantly increased in HepG2 cells exposed to palmitic acid, tunicamycin, or T0901317, and was reversed in cells treated with AICAR. Palmitic acid, tunicamycin, and T0901317 increased LXRα and SREBP-1c mRNA expression. The inhibitory effect of AICAR on the expression of T0901317-induced ANGPTL8 was most strongly evident in cells that were transfected with SREBP-1 siRNA. AICAR increased phosphorylation of PPARα and the effect of AICAR was not observed in cells treated with PPARα inhibitor. Metformin had a similar effect on ANGPTL8 expression to that of AICAR. These data suggest that AMPK can suppress the expression of LXR/SREBP-1 signal-induced ANGPTL8 in HepG2 cells.
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Affiliation(s)
- Jinmi Lee
- Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 110-746, South Korea
| | - Seok-Woo Hong
- Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 110-746, South Korea
| | - Se Eun Park
- Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 110-746, South Korea
| | - Eun-Jung Rhee
- Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 110-746, South Korea
| | - Cheol-Young Park
- Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 110-746, South Korea
| | - Ki-Won Oh
- Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 110-746, South Korea
| | - Sung-Woo Park
- Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 110-746, South Korea
| | - Won-Young Lee
- Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 110-746, South Korea.
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Wang Y, Gusarova V, Banfi S, Gromada J, Cohen JC, Hobbs HH. Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. J Lipid Res 2015; 56:1296-307. [PMID: 25954050 DOI: 10.1194/jlr.m054882] [Citation(s) in RCA: 154] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Indexed: 02/01/2023] Open
Abstract
Humans and mice lacking angiopoietin-like protein 3 (ANGPTL3) have pan-hypolipidemia. ANGPTL3 inhibits two intravascular lipases, LPL and endothelial lipase, and the low plasma TG and HDL-cholesterol levels in ANGPTL3 deficiency reflect increased activity of these enzymes. The mechanism responsible for the low LDL-cholesterol levels associated with ANGPTL3 deficiency is not known. Here we used an anti-ANGPTL3 monoclonal antibody (REGN1500) to inactivate ANGPTL3 in mice with genetic deficiencies in key proteins involved in clearance of ApoB-containing lipoproteins. REGN1500 treatment consistently reduced plasma cholesterol levels in mice in which Apoe, Ldlr, Lrp1, and Sdc1 were inactivated singly or in combination, but did not alter clearance of rabbit (125)I-βVLDL or mouse (125)I-LDL. Despite a 61% reduction in VLDL-TG production, VLDL-ApoB-100 production was unchanged in REGN1500-treated animals. Hepatic TG content, fatty acid synthesis, and fatty acid oxidation were similar in REGN1500 and control antibody-treated animals. Taken together, our findings indicate that inactivation of ANGPTL3 does not affect the number of ApoB-containing lipoproteins secreted by the liver but alters the particles that are made such that they are cleared more rapidly from the circulation via a noncanonical pathway(s). The increased clearance of lipolytic remnants results in decreased production of LDL in ANGPTL3-deficient animals.
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Affiliation(s)
- Yan Wang
- Departments of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX
| | | | - Serena Banfi
- Departments of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX
| | | | - Jonathan C Cohen
- Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Helen H Hobbs
- Departments of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX
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Kirchgessner TG, Martin R, Sleph P, Grimm D, Liu X, Lupisella J, Smalley J, Narayanan R, Xie Y, Ostrowski J, Cantor GH, Mohan R, Kick E. Pharmacological characterization of a novel liver X receptor agonist with partial LXRα activity and a favorable window in nonhuman primates. J Pharmacol Exp Ther 2015; 352:305-14. [PMID: 25467132 DOI: 10.1124/jpet.114.219923] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Liver X Receptors (LXRs) α and β are nuclear hormone receptors that regulate multiple genes involved in reverse cholesterol transport (RCT) and are potential drug targets for atherosclerosis. However, full pan agonists also activate lipogenic genes, resulting in elevated plasma and hepatic lipids. We report the pharmacology of BMS-779788 [2-(2-(1-(2-chlorophenyl)-1-methylethyl)-1-(3'-(methylsulfonyl)-4-biphenylyl)-1H-imidazol-4-yl)-2-propanol], a potent partial LXR agonist with LXRβ selectivity, which has an improved therapeutic window in the cynomolgus monkey compared with a full pan agonist. BMS-779788 induced LXR target genes in blood in vivo with an EC50 = 610 nM, a value similar to its in vitro blood gene induction potency. BMS-779788 was 29- and 12-fold less potent than the full agonist T0901317 in elevating plasma triglyceride and LDL cholesterol, respectively, with similar results for plasma cholesteryl ester transfer protein and apolipoprotein B. However, ABCA1 and ABCG1 mRNA inductions in blood, which are critical for RCT, were comparable. Increased liver triglyceride was observed after 7-day treatment with BMS-779788 at the highest dose tested and was nearly identical to the dose response for plasma triglyceride, consistent with the central role of liver LXR in these lipogenic effects. Dose-dependent increases in biliary cholesterol and decreases in phospholipid and bile acid occurred in BMS-779788-treated animals, similar to LXR agonist effects reported in mouse. In summary, BMS-779788, a partial LXRβ selective agonist, has decreased lipogenic potential compared with a full pan agonist in cynomolgus monkeys, with similar potency in the induction of genes known to stimulate RCT. This provides support in nonhuman primates for improving LXR agonist therapeutic windows by limiting LXRα activity.
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Affiliation(s)
- Todd G Kirchgessner
- Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.)
| | - Richard Martin
- Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.)
| | - Paul Sleph
- Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.)
| | - Denise Grimm
- Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.)
| | - Xiaoqin Liu
- Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.)
| | - John Lupisella
- Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.)
| | - James Smalley
- Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.)
| | - Rangaraj Narayanan
- Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.)
| | - Yinong Xie
- Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.)
| | - Jacek Ostrowski
- Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.)
| | - Glenn H Cantor
- Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.)
| | - Raju Mohan
- Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.)
| | - Ellen Kick
- Bristol-Myers Squibb Research and Development, Bristol-Myers Squibb, Inc., Princeton, New Jersey (T.G.K., P.S., D.G., X.L., J.L., J.S., R.N., J.O., G.H.C., E.K.); and Exelixis, Inc., South San Francisco, California (R.Ma., Y.X., R.Mo.)
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Li Y, Teng C. Angiopoietin-like proteins 3, 4 and 8: regulating lipid metabolism and providing new hope for metabolic syndrome. J Drug Target 2014; 22:679-87. [PMID: 24960069 DOI: 10.3109/1061186x.2014.928715] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Angiopoietin-like proteins (ANGPTLs) are a group of eight proteins that share structural similarity to the members of the angiopoietin protein family. ANGPTL3 plays a vital role in the regulation of the plasma levels of triglyceride and cholesterol, mainly via reversible inhibition of the lipoprotein lipase activity. ANGPTL4, which functions as a homo-oligomer different from ANGPTL3 and ANGPTL8, not only regulates the plasma levels of triglyceride and prevents the uptake of dietary lipids into adipose tissues but also inhibits intravascular lipolysis. ANGPTL8 (also called betatrophin) has been identified as an important factor in regulating the triglyceride levels and adipose tissue mass as well as in replenishing the adipose tissue triglyceride store. ANGPTL8 acts together with ANGPTL3 to regulate the lipid metabolism, and ANGPTL8 promotes cleavage of ANGPTL3 to augment the activity of ANGPTL3. In addition, ANGPTL8 promotes proliferation of pancreatic β-cells and enhances insulin secretion. The properties of ANGPTLs in regulating the lipid metabolism suggest their application in the target therapy for metabolic syndrome. As ANGPTLs are regulated by several factors and may be involved in certain specific pathways of lipid metabolism, designing drugs that target ANGPTLs or factors regulating ANGPTLs may be an efficient approach to treat metabolic syndrome.
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Affiliation(s)
- Yunchao Li
- Laboratory of Animal Development Biology, College of Life Science, Northeast Forestry University, Ministry of Education , Harbin , China
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A Comparison of the Potential Unfavorable Effects of Oxycholesterol and Oxyphytosterol in Mice: Different Effects, on Cerebral 24S-Hydroxychoelsterol and Serum Triacylglycerols Levels. Biosci Biotechnol Biochem 2014; 72:3128-33. [DOI: 10.1271/bbb.80256] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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48
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Parikh M, Patel K, Soni S, Gandhi T. Liver X Receptor: A Cardinal Target for Atherosclerosis and Beyond. J Atheroscler Thromb 2014. [DOI: 10.5551/jat.19778] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
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Ding L, Pang S, Sun Y, Tian Y, Yu L, Dang N. Coordinated Actions of FXR and LXR in Metabolism: From Pathogenesis to Pharmacological Targets for Type 2 Diabetes. Int J Endocrinol 2014; 2014:751859. [PMID: 24872814 PMCID: PMC4020365 DOI: 10.1155/2014/751859] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Accepted: 04/09/2014] [Indexed: 12/13/2022] Open
Abstract
Type 2 diabetes (T2D) is the most prevalent metabolic disease, and many people are suffering from its complications driven by hyperglycaemia and dyslipidaemia. Nuclear receptors (NRs) are ligand-inducible transcription factors that mediate changes to metabolic pathways within the body. As metabolic regulators, the farnesoid X receptor (FXR) and the liver X receptor (LXR) play key roles in the pathogenesis of T2D, which remains to be clarified in detail. Here we review the recent progress concerning the physiological and pathophysiological roles of FXRs and LXRs in the regulation of bile acid, lipid and glucose metabolism and the implications in T2D, taking into account that these two nuclear receptors are potential pharmaceutical targets for the treatment of T2D and its complications.
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Affiliation(s)
- Lin Ding
- Endocrinology Department, Jinan Central Hospital Affiliated to Shandong University, No. 105 Jiefang Road, Jinan, Shandong 250013, China
| | - Shuguang Pang
- Endocrinology Department, Jinan Central Hospital Affiliated to Shandong University, No. 105 Jiefang Road, Jinan, Shandong 250013, China
- *Shuguang Pang:
| | - Yongmei Sun
- Endocrinology Department, Jinan Central Hospital Affiliated to Shandong University, No. 105 Jiefang Road, Jinan, Shandong 250013, China
| | - Yuling Tian
- Endocrinology Department, Jinan Central Hospital Affiliated to Shandong University, No. 105 Jiefang Road, Jinan, Shandong 250013, China
| | - Li Yu
- Endocrinology Department, Jinan Central Hospital Affiliated to Shandong University, No. 105 Jiefang Road, Jinan, Shandong 250013, China
| | - Ningning Dang
- Endocrinology Department, Jinan Central Hospital Affiliated to Shandong University, No. 105 Jiefang Road, Jinan, Shandong 250013, China
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Mattijssen F, Alex S, Swarts HJ, Groen AK, van Schothorst EM, Kersten S. Angptl4 serves as an endogenous inhibitor of intestinal lipid digestion. Mol Metab 2013; 3:135-44. [PMID: 24634819 DOI: 10.1016/j.molmet.2013.11.004] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 11/08/2013] [Accepted: 11/13/2013] [Indexed: 02/07/2023] Open
Abstract
Dietary triglycerides are hydrolyzed in the small intestine principally by pancreatic lipase. Following uptake by enterocytes and secretion as chylomicrons, dietary lipids are cleared from the bloodstream via lipoprotein lipase. Whereas lipoprotein lipase is inhibited by several proteins including Angiopoietin-like 4 (Angptl4), no endogenous regulator of pancreatic lipase has yet been identified. Here we present evidence that Angptl4 is an endogenous inhibitor of dietary lipid digestion. Angptl4-/- mice were heavier compared to their wild-type counterparts without any difference in food intake, energy expenditure or locomotor activity. However, Angptl4-/- mice showed decreased lipid content in the stools and increased accumulation of dietary triglycerides in the small intestine, which coincided with elevated luminal lipase activity in Angptl4-/- mice. Furthermore, recombinant Angptl4 reduced the activity of pancreatic lipase as well as the lipase activity in human ileostomy output. In conclusion, our data suggest that Angptl4 is an endogenous inhibitor of intestinal lipase activity.
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Affiliation(s)
- Frits Mattijssen
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Bomenweg 2, 6703 HD Wageningen, The Netherlands
| | - Sheril Alex
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Bomenweg 2, 6703 HD Wageningen, The Netherlands
| | - Hans J Swarts
- Human and Animal Physiology, Department of Animal Sciences, Wageningen University, 6700 EV Wageningen, The Netherlands
| | - Albert K Groen
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands
| | - Evert M van Schothorst
- Human and Animal Physiology, Department of Animal Sciences, Wageningen University, 6700 EV Wageningen, The Netherlands
| | - Sander Kersten
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Bomenweg 2, 6703 HD Wageningen, The Netherlands
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