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Miura-Takahashi E, Tashiro K, Shiga Y, Kawahira Y, Kato Y, Kuwano T, Sugihara M, Otsu Y, Kamimura H, Miura SI. Association between pre-treatment with statin and its inhibitory effect on the onset of coronary artery disease at the time of coronary computed tomography angiography: a new look at an old medication. Heart Vessels 2024; 39:845-856. [PMID: 38687349 DOI: 10.1007/s00380-024-02407-4] [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: 01/06/2024] [Accepted: 04/11/2024] [Indexed: 05/02/2024]
Abstract
Coronary artery stenosis is often advanced by the time coronary computed tomography angiography (CCTA). Statins are the most important anti-lipidemic medication for improving the prognosis of coronary artery disease (CAD) patients. Although lipid-lowering therapy using statins appears to have been established as a method for preventing CAD, there remains the problem that CAD cannot be completely suppressed. In this study, we investigated whether pre-treatment with statin could significantly inhibit the onset of CAD when patients received CCTA for screening of CAD. The subjects were 1164 patients who underwent CCTA as screening for CAD. CAD was diagnosed when 50% or more coronary stenosis was present in the coronary arteries. Patient backgrounds were investigated by age, gender, body mass index, coronary risk factors [family history of cardiovascular diseases, smoking history, hypertension (HTN), diabetes mellitus (DM), dyslipidemia, chronic kidney disease (CKD) or metabolic sydrome] and medications. Patients were classified into two groups according to the presence or absence of statin pre-administration during CCTA [statin (-) group (n = 804) and (+) group (n = 360)]. Compared with the statin (-) group, the statin (+) group was significantly older and had higher rates of family history, HTN, and DM. The statin (+) group had a significantly higher % CAD than the statin (-) group. Serum levels of low-density lipoprotein cholesterol (LDL-C) were significantly lower in the statin (+) group than in the statin (-) group. There was no significant difference in either high-density lipoprotein cholesterol levels or triglyceride levels between the two groups. Age, male gender, HTN, DM and pre-treatment with statin were all associated with CAD (+) in all patients. In addition, factors that contributed to CAD (+) in the statin (-) group were age, male gender, and DM, and factors that contributed to CAD (+) in the statin (+) group were age, smoking, HTN and % maximum dose of statin. At the time of CCTA, the statin (+) group had a high rate of CAD and coronary artery stenosis progressed despite a reduction of LDL-C levels. To prevent the onset of CAD, in addition to strict control of other coronary risk factors (HTN etc.), further LDL cholesterol-lowering therapy may be necessary.
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Affiliation(s)
- Erika Miura-Takahashi
- Department of Pharmacy, Fukuoka University Hospital, Fukuoka, Japan
- Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | - Kohei Tashiro
- Department of Cardiology, Fukuoka University Hospital, Fukuoka, Japan
- Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | - Yuhei Shiga
- Department of Cardiology, Fukuoka University Hospital, Fukuoka, Japan
- Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | - Yuto Kawahira
- Department of Cardiology, Fukuoka University Hospital, Fukuoka, Japan
- Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | - Yuta Kato
- Department of Cardiology, Fukuoka University Hospital, Fukuoka, Japan
- Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | - Takashi Kuwano
- Department of Cardiology, Fukuoka University Hospital, Fukuoka, Japan
- Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | - Makoto Sugihara
- Department of Cardiology, Fukuoka University Hospital, Fukuoka, Japan
- Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | - Yuki Otsu
- Department of Pharmacy, Fukuoka University Hospital, Fukuoka, Japan
- Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | | | - Shin-Ichiro Miura
- Department of Cardiology, Fukuoka University Hospital, Fukuoka, Japan.
- Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
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Lusiki Z, Blom D, Soko ND, Malema S, Jones E, Rayner B, Blackburn J, Sinxadi P, Dandara MT, Dandara C. Major Genetic Drivers of Statin Treatment Response in African Populations and Pharmacogenetics of Dyslipidemia Through a One Health Lens. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2024; 28:261-279. [PMID: 37956269 DOI: 10.1089/omi.2023.0122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
A One Health lens is increasingly significant to address the intertwined challenges in planetary health concerned with the health of humans, nonhuman animals, plants, and ecosystems. A One Health approach can benefit the public health systems in Africa that are overburdened by noncommunicable, infectious, and environmental diseases. Notably, the COVID-19 pandemic revealed the previously overlooked two-fold importance of pharmacogenetics (PGx), for individually tailored treatment of noncommunicable diseases and environmental pathogens. For example, dyslipidemia, a common cardiometabolic risk factor, has been identified as an independent COVID-19 severity risk factor. Observational data suggest that patients with COVID-19 infection receiving lipid-lowering therapy may have better outcomes. However, among African patients, the response to these drugs varies from patient to patient, pointing to the possible contribution of genetic variation in important pharmacogenes. The PGx of lipid-lowering therapies may underlie differences in treatment responses observed among dyslipidemia patients as well as patients comorbid with COVID-19 and dyslipidemia. Genetic variations in APOE, ABCB1, CETP, CYP2C9, CYP3A4, CYP3A5, HMGCR, LDLR, NPC1L1, and SLCO1B1 genes affect the pharmacogenomics of statins, and they have individually been linked to differential responses to dyslipidemia and COVID-19 treatment. African populations are underrepresented in PGx research. This leads to poor accounting of additional diverse genetic variants that could be important in understanding interindividual and between-population variations in therapeutic responses to dyslipidemia and COVID-19. This expert review examines and synthesizes the salient and priority PGx variations, as seen through a One Health lens in Africa, to improve and inform personalized medicine in both dyslipidemia and COVID-19.
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Affiliation(s)
- Zizo Lusiki
- Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
- Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa
| | - Dirk Blom
- Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa
- Division of Lipidology and Cape Heart Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Nyarai D Soko
- Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
- Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa
| | - Smangele Malema
- Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa
| | - Erika Jones
- Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa
- Division of Nephrology and Hypertension, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Brian Rayner
- Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa
- Division of Nephrology and Hypertension, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Jonathan Blackburn
- Division of Chemical and Systems Biology, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa
| | - Phumla Sinxadi
- Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa
- Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Michelle T Dandara
- Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa
| | - Collet Dandara
- Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
- Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa
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Leierer J, Salib M, Evgeniou M, Rossignol P, Massy ZA, Kratochwill K, Mayer G, Fellström B, Girerd N, Zannad F, Perco P. Identification of endophenotypes supporting outcome prediction in hemodialysis patients based on mechanistic markers of statin treatment. Heliyon 2024; 10:e30709. [PMID: 38765135 PMCID: PMC11098839 DOI: 10.1016/j.heliyon.2024.e30709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 05/02/2024] [Indexed: 05/21/2024] Open
Abstract
Background Statins are widely used to reduce the risk of cardiovascular disease (CVD). Patients with end-stage renal disease (ESRD) on hemodialysis have significantly increased risk of developing CVD. Statin treatment in these patients however did not show a statistically significant benefit in large trials on a patient cohort level. Methods We generated gene expression profiles for statins to investigate the impact on cellular programs in human renal proximal tubular cells and mesangial cells in-vitro. We subsequently selected biomarkers from key statin-affected molecular pathways and assessed these biomarkers in plasma samples from the AURORA cohort, a double-blind, randomized, multi-center study of patients on hemodialysis or hemofiltration that have been treated with rosuvastatin. Patient clusters (phenotypes) were created based on the identified biomarkers using Latent Class Model clustering and the associations with outcome for the generated phenotypes were assessed using Cox proportional hazards regression models. The multivariable models were adjusted for clinical and biological covariates based on previously published data in AURORA. Results The impact of statin treatment on mesangial cells was larger as compared with tubular cells with a large overlap of differentially expressed genes identified for atorvastatin and rosuvastatin indicating a predominant drug class effect. Affected molecular pathways included TGFB-, TNF-, and MAPK-signaling and focal adhesion among others. Four patient clusters were identified based on the baseline plasma concentrations of the eight biomarkers. Phenotype 1 was characterized by low to medium levels of the hepatocyte growth factor (HGF) and high levels of interleukin 6 (IL6) or matrix metalloproteinase 2 (MMP2) and it was significantly associated with outcome showing increased risk of developing major adverse cardiovascular events (MACE) or cardiovascular death. Phenotype 2 had high HGF but low Fas cell surface death receptor (FAS) levels and it was associated with significantly better outcome at 1 year. Conclusions In this translational study, we identified patient subgroups based on mechanistic markers of statin therapy that are associated with disease outcome in patients on hemodialysis.
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Affiliation(s)
- Johannes Leierer
- Medical University of Innsbruck, Department of Internal Medicine IV, Innsbruck, Austria
| | - Madonna Salib
- Université de Lorraine, Inserm, Centre d’Investigations Cliniques- 1433, and Inserm U1116, CHRU Nancy, F-CRIN INI-CRCT, Nancy, France
| | - Michail Evgeniou
- Medical University of Vienna, Comprehensive Center for Pediatrics, Department of Pediatrics and Adolescent Medicine, Division of Pediatric Nephrology and Gastroenterology, Vienna, Austria
| | - Patrick Rossignol
- Université de Lorraine, Inserm, Centre d’Investigations Cliniques- 1433, and Inserm U1116, CHRU Nancy, F-CRIN INI-CRCT, Nancy, France
- Medical Specialties and Nephrology departments, Princess Grace Hospital, Monaco, Monaco
| | - Ziad A. Massy
- Association pour l'Utilisation du Rein Artificiel (AURA) Paris and Department of Nephrology, CHU Ambroise Paré, APHP, 92104, Boulogne Billancourt, and Centre for Research in Epidemiology and Population Health (CESP), University Paris-Saclay, University Versailles-Saint Quentin, Inserm UMRS, 1018, Clinical Epidemiology Team, Villejuif, France
| | - Klaus Kratochwill
- Medical University of Vienna, Comprehensive Center for Pediatrics, Department of Pediatrics and Adolescent Medicine, Division of Pediatric Nephrology and Gastroenterology, Vienna, Austria
| | - Gert Mayer
- Medical University of Innsbruck, Department of Internal Medicine IV, Innsbruck, Austria
| | - Bengt Fellström
- Uppsala University, Department of Medical Sciences, Uppsala, Sweden
| | - Nicolas Girerd
- Université de Lorraine, Inserm, Centre d’Investigations Cliniques- 1433, and Inserm U1116, CHRU Nancy, F-CRIN INI-CRCT, Nancy, France
| | - Faiez Zannad
- Université de Lorraine, Inserm, Centre d’Investigations Cliniques- 1433, and Inserm U1116, CHRU Nancy, F-CRIN INI-CRCT, Nancy, France
| | - Paul Perco
- Medical University of Innsbruck, Department of Internal Medicine IV, Innsbruck, Austria
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Tsujita K, Yokote K, Ako J, Tanigawa R, Tajima S, Suganami H. Efficacy and Safety of Pitavastatin/Ezetimibe Fixed-Dose Combination vs. Pitavastatin: Phase III, Double-Blind, Randomized Controlled Trial. J Atheroscler Thromb 2023; 30:1580-1600. [PMID: 36908150 PMCID: PMC10627746 DOI: 10.5551/jat.64006] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 01/23/2023] [Indexed: 03/13/2023] Open
Abstract
AIM We compared the efficacy and safety of pitavastatin/ezetimibe fixed-dose combination with those of pitavastatin monotherapy in patients with hypercholesterolemia. METHODS This trial was a multicenter, randomized, double-blind, active-controlled, parallel-group trial. A total of 293 patients were randomly assigned into four groups receiving 2 mg pitavastatin, 4 mg pitavastatin, 2 mg pitavastatin/10 mg ezetimibe (K-924 LD), and 4 mg pitavastatin/10 mg ezetimibe (K-924 HD) once daily for 12 weeks. RESULTS The percentage changes in low-density lipoprotein cholesterol (LDL-C), the primary endpoint, were -39.5% for 2 mg pitavastatin, -45.2% for 4 mg pitavastatin, -51.4% for K-924 LD, and -57.8% for K-924 HD. Compared with pitavastatin monotherapy, the pitavastatin/ezetimibe fixed-dose combination significantly reduced LDL-C, total cholesterol, and non-high-density lipoprotein cholesterol. Meanwhile, the cholesterol synthesis marker, lathosterol, was significantly decreased with pitavastatin monotherapy and the pitavastatin/ezetimibe fixed-dose combination, although the decrease was attenuated in the latter. On the other hand, the cholesterol absorption markers, beta-sitosterol and campesterol, were reduced with the fixed-dose combination but not with pitavastatin monotherapy. The incidence of adverse events and adverse drug reactions was not significantly different between the two groups receiving the fixed-dose combination and monotherapy. The mean values of laboratory tests that are related to liver function and myopathy increased but remained within the reference range in all groups. CONCLUSIONS The pitavastatin/ezetimibe fixed-dose combination showed an excellent LDL-C-reducing effect by the complementary pharmacological action of each component, and its safety profile was similar to that of pitavastatin monotherapy (ClinicalTrials.gov Identifier: NCT04289649).
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Affiliation(s)
- Kenichi Tsujita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Koutaro Yokote
- Department of Endocrinology, Hematology, and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Junya Ako
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Ryohei Tanigawa
- Clinical Development Department, Kowa Company Ltd., Tokyo, Japan
| | - Sachiko Tajima
- Medical Affairs Department, Kowa Company, Ltd., Tokyo, Japan
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Itkonen A, Hakkola J, Rysä J. Adverse outcome pathway for pregnane X receptor-induced hypercholesterolemia. Arch Toxicol 2023; 97:2861-2877. [PMID: 37642746 PMCID: PMC10504106 DOI: 10.1007/s00204-023-03575-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 08/02/2023] [Indexed: 08/31/2023]
Abstract
Pharmaceuticals and environmental contaminants contribute to hypercholesterolemia. Several chemicals known to cause hypercholesterolemia, activate pregnane X receptor (PXR). PXR is a nuclear receptor, classically identified as a sensor of chemical environment and regulator of detoxification processes. Later, PXR activation has been shown to disrupt metabolic functions such as lipid metabolism and recent findings have shown PXR activation to promote hypercholesterolemia through multiple mechanisms. Hypercholesterolemia is a major causative risk factor for atherosclerosis and greatly promotes global health burden. Metabolic disruption by PXR activating chemicals leading to hypercholesterolemia represents a novel toxicity pathway of concern and requires further attention. Therefore, we constructed an adverse outcome pathway (AOP) by collecting the available knowledge considering the molecular mechanisms for PXR-mediated hypercholesterolemia. AOPs are tools of modern toxicology for systematizing mechanistic knowledge to assist health risk assessment of chemicals. AOPs are formalized and structured linear concepts describing a link between molecular initiating event (MIE) and adverse outcome (AO). MIE and AO are connected via key events (KE) through key event relationships (KER). We present a plausible route of how PXR activation (MIE) leads to hypercholesterolemia (AO) through direct regulation of cholesterol synthesis and via activation of sterol regulatory element binding protein 2-pathway.
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Affiliation(s)
- Anna Itkonen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland
| | - Jukka Hakkola
- Research Unit of Biomedicine and Internal Medicine, Biocenter Oulu, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Jaana Rysä
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland.
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André R, Pacheco R, Alves AC, Santos HM, Bourbon M, Serralheiro ML. The Hypocholesterolemic Potential of the Edible Algae Fucus vesiculosus: Proteomic and Quantitative PCR Analysis. Foods 2023; 12:2758. [PMID: 37509850 PMCID: PMC10379601 DOI: 10.3390/foods12142758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/29/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
A brown seaweed consumed worldwide, Fucus vesiculosus, has been used to prevent atherosclerosis and hypercholesterolemia, among other uses. However, the mechanisms of action that lead to these effects are not yet fully understood. This work aims to study the in vitro effect of an aqueous extract of F. vesiculosus, previously characterized as rich in phlorotannins and peptides, on the expression of different proteins involved in the synthesis and transport of cholesterol. A proteomic analysis, Western blot, and qRT-PCR analysis were performed to identify protein changes in HepG2 cells exposed to 0.25 mg/mL of the F. vesiculosus extract for 24 h. The proteomic results demonstrated that, in liver cells, the extract decreases the expression of four proteins involved in the cholesterol biosynthesis process (CYP51A1, DHCR24, HMGCS1 and HSD17B7). Additionally, a 12.76% and 18.40% decrease in the expression of two important transporters proteins of cholesterol, NPC1L1 and ABCG5, respectively, was also observed, as well as a 30% decrease in NPC1L1 mRNA levels in the cells exposed to the extract compared to control cells. Our study reveals some of the mechanisms underlying the actions of bioactive compounds from F. vesiculosus that may explain its previously reported hypocholesterolemic effect, future prospecting its use as a functional food.
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Affiliation(s)
- Rebeca André
- BioISI-Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
| | - Rita Pacheco
- Department of Chemical Engineering, ISEL-Instituto Superior de Engenharia de Lisboa, Rua Conselheiro Emídio Navarro, 1, 1959-007 Lisboa, Portugal
- Centro de Química Estrutural, Institute of Molecular Sciences, Universidade de Lisboa, 1749-016 Lisboa, Portugal
| | - Ana Catarina Alves
- BioISI-Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
- Unidade de I&D, Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal
| | - Hugo M Santos
- LAQV@REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal
- PROTEOMASS Scientific Society, Madan Park, Rúa dos Inventores, 2825-182 Caparica, Portugal
| | - Mafalda Bourbon
- BioISI-Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
- Unidade de I&D, Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal
| | - Maria Luísa Serralheiro
- BioISI-Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
- Department of Chemistry and Biochemistry, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, C8 Bldg, 1749-016 Lisboa, Portugal
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Weaver OR, Krysa JA, Ye M, Vena JE, Eurich DT, Proctor SD. Nonfasting remnant cholesterol and cardiovascular disease risk prediction in Albertans: a prospective cohort study. CMAJ Open 2023; 11:E645-E653. [PMID: 37491049 PMCID: PMC10374248 DOI: 10.9778/cmajo.20210318] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/27/2023] Open
Abstract
BACKGROUND European studies have shown that nonfasting remnant cholesterol can be a strong predictor of cardiovascular disease risk and may contribute to identifying residual risk; however, Canadian data are lacking on nonfasting remnant cholesterol. In this study, we aimed to determine the relation between nonfasting remnant cholesterol, low-density lipoprotein (LDL) cholesterol and cardiovascular disease among people in Alberta. METHODS In this retrospective analysis, we used data from Alberta's Tomorrow Project, a large prospective cohort that enrolled Albertans aged 35-69 years (2000-2015). Participants with consent to data linkage, with complete nonfasting lipid data and without existing cardiovascular disease were included. The nonfasting remnant cholesterol and LDL cholesterol relation with a composite cardiovascular disease outcome of major incident cardiovascular diagnoses, ascertained by linking to Alberta Health databases, was determined by multivariable logistic regression, adjusting for age, sex, statin use, comorbidities, and LDL cholesterol or remnant cholesterol. RESULTS The final sample of 13 988 participants was 69.4% female, and the mean age was 61.8 (standard deviation [SD] 9.7) years. Follow-up time was approximately 15 years. Mean remnant cholesterol was significantly higher among individuals with versus without cardiovascular disease (0.87 [SD 0.40] mmol/L v. 0.78 [SD 0.38] mmol/L, standardized mean difference [SMD] -0.24), and mean LDL cholesterol was significantly lower (2.69 [SD 0.93] mmol/L v. 2.88 [SD 0.84] mmol/L, SMD 0.21). The odds of incident composite cardiovascular disease were significantly increased per mmol/L increase in remnant cholesterol (adjusted odds ratio [OR] 1.48, 95% confidence interval [CI] 1.27-1.73) but significantly decreased per mmol/L increase in LDL cholesterol (adjusted OR 0.73, 95% CI 0.68-0.79). INTERPRETATION In this large Albertan cohort of predominantly older females, nonfasting remnant cholesterol had a positive relation with cardiovascular disease incidence, whereas LDL cholesterol did not. These findings support the clinical utility of measuring non-fasting remnant cholesterol to detect cardiovascular disease risk.
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Affiliation(s)
- Olivia R Weaver
- School of Public Health (Weaver, Ye, Eurich) and Metabolic and Cardiovascular Diseases Laboratory (Krysa, Proctor), University of Alberta, Edmonton, Alta.; Alberta's Tomorrow Project (Vena), Cancer Research & Analytics, Cancer Care Alberta, Alberta Health Services, Calgary, Alta
| | - Jacqueline A Krysa
- School of Public Health (Weaver, Ye, Eurich) and Metabolic and Cardiovascular Diseases Laboratory (Krysa, Proctor), University of Alberta, Edmonton, Alta.; Alberta's Tomorrow Project (Vena), Cancer Research & Analytics, Cancer Care Alberta, Alberta Health Services, Calgary, Alta
| | - Ming Ye
- School of Public Health (Weaver, Ye, Eurich) and Metabolic and Cardiovascular Diseases Laboratory (Krysa, Proctor), University of Alberta, Edmonton, Alta.; Alberta's Tomorrow Project (Vena), Cancer Research & Analytics, Cancer Care Alberta, Alberta Health Services, Calgary, Alta
| | - Jennifer E Vena
- School of Public Health (Weaver, Ye, Eurich) and Metabolic and Cardiovascular Diseases Laboratory (Krysa, Proctor), University of Alberta, Edmonton, Alta.; Alberta's Tomorrow Project (Vena), Cancer Research & Analytics, Cancer Care Alberta, Alberta Health Services, Calgary, Alta
| | - Dean T Eurich
- School of Public Health (Weaver, Ye, Eurich) and Metabolic and Cardiovascular Diseases Laboratory (Krysa, Proctor), University of Alberta, Edmonton, Alta.; Alberta's Tomorrow Project (Vena), Cancer Research & Analytics, Cancer Care Alberta, Alberta Health Services, Calgary, Alta
| | - Spencer D Proctor
- School of Public Health (Weaver, Ye, Eurich) and Metabolic and Cardiovascular Diseases Laboratory (Krysa, Proctor), University of Alberta, Edmonton, Alta.; Alberta's Tomorrow Project (Vena), Cancer Research & Analytics, Cancer Care Alberta, Alberta Health Services, Calgary, Alta.
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Kim MH, Lee EJ, Kim SJ, Jung YJ, Park WJ, Park I. Macrophage inhibitory cytokine-1 aggravates diet-induced gallstone formation via increased ABCG5/ABCG8 expression. PLoS One 2023; 18:e0287146. [PMID: 37310967 DOI: 10.1371/journal.pone.0287146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 05/30/2023] [Indexed: 06/15/2023] Open
Abstract
Macrophage inhibitory cytokine 1 (MIC-1), which is overproduced in various human cancers and associated with cachexia, acts on the hypothalamus to suppress appetite and reduce body weight. We investigated the mechanisms through which MIC-1 affects bile acid metabolism and gallstone formation, which are poorly understood. Over 6 weeks, male C57BL/6 mice fed either standard chow or a lithogenic diet were intraperitoneally injected with phosphate-buffered saline (PBS) or MIC-1 (200 μg/kg/week). Among lithogenic diet-fed mice, MIC-1 treatment resulted in increased gallstone formation compared with PBS treatment. Compared with PBS treatment, MIC-1 treatment decreased hepatic cholesterol and bile acid levels and reduced expression of HMG-CoA reductase (HMGCR), the master cholesterol metabolism regulator sterol regulatory element-binding protein 2, cholesterol 7α-hydroxylase (CYP7A1), mitochondrial sterol 27-hydroxylase, and oxysterol 7α-hydroxylase. Compared with PBS treatment, MIC-1 treatment had no effect on small heterodimer partner, farnesoid X receptor, or pregnane X receptor expression, and extracellular signal-related kinase and c-Jun N-terminal kinase phosphorylation decreased, suggesting that these factors do not contribute to the MIC-1-induced reduction in CYP7A1 expression. Compared with PBS treatment, MIC-1 treatment increased AMP-activated protein kinase (AMPK) phosphorylation. Treatment with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) reduced CYP7A1 and HMGCR expression, whereas the AMPK inhibitor Compound C reversed MIC-1-induced reductions in CYP7A1 and HMGCR expression. Furthermore, in MIC-1-treated mice, total biliary cholesterol levels increased together with increased ATP-binding cassette subfamily G (ABCG)5 and ABCG8 expression. Compared with PBS treatment, MIC-1 treatment did not affect expression of liver X receptors α and β, liver receptor homolog 1, hepatocyte nuclear factor 4α, or NR1I3 (also known as constitutive androstane receptor), which are upstream of ABCG5/8; however, MIC-1 treatment increased ABCG5/8 expression and promoter activities. Our study indicates that MIC-1 influences gallstone formation by increasing AMPK phosphorylation, reducing CYP7A1 and HMGCR expression, and increasing ABCG5 and ABCG8 expression.
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Affiliation(s)
- Min Hee Kim
- Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Eun-Ji Lee
- Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Su-Jeong Kim
- Department of Biochemistry, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Yun-Jae Jung
- Department of Microbiology, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, Incheon, Republic of Korea
- Department of Health Science and Technology, Gachon Advanced Institute for Health Science & Technology, Gachon University, Incheon, Republic of Korea
| | - Woo-Jae Park
- Department of Biochemistry, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Inkeun Park
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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9
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Yan J, Nie Y, Chen Z, Yao J, Zhang S, Chen Z. The IDI1/SREBP2 axis drives intrahepatic cholestasis and is a treatment target of San-Huang-Cai-Zhu formula identified by sequencing and experiments. Front Pharmacol 2023; 14:1093934. [PMID: 36843951 PMCID: PMC9944032 DOI: 10.3389/fphar.2023.1093934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 01/20/2023] [Indexed: 02/11/2023] Open
Abstract
San-Huang-Chai-Zhu formula (SHCZF), originates from Da-Huang-Xiao-Shi decoction (DHXSD) for the treatment of jaundice as recorded in the Chinese traditional Chinese medicine book Jin Gui Yao Lue. In the clinic, SHCZF has been used to treat cholestasis-related liver disease by improving intrahepatic cholestasis, but the treatment mechanism has not been elucidated. In this study, 24 Sprague-Dawley (SD) rats were randomly assigned to the normal, acute intrahepatic cholestasis (AIC), SHCZF, and ursodeoxycholic acid (UDCA) groups. In addition, 36 SD rats were divided into dynamic groups, namely, normal 24 h, AIC 24 h, normal 48 h, AIC 48 h, normal 72 h, and AIC 72 h groups. Alpha-naphthylisothiocyanate (ANIT) was used to induce an AIC rat model. Serum biochemical indices and hepatic pathology were detected. Part of the hepatic tissues was used for sequencing, and others were used for subsequent experiments. Sequencing data combined with bioinformatics analysis were used to screen target genes and identify the mechanisms of SHCZF in treating AIC rats. Quantitative real-time PCR (qRT-PCR) and Western blotting (WB) were used to detect the RNA/Protein expression levels of screened genes. Rats in the dynamic group were used to determine the sequence of cholestasis and liver injury. High-performance liquid chromatography (HPLC) was used to determine the representative bioingredients of SHCZF. Sequencing and bioinformatics analysis suggested that IDI1 and SREBP2 are hub target genes of SHCZF to ameliorate ANTI-induced intrahepatic cholestasis in rats. The treatment mechanism is associated with the regulation of lipoprotein receptor (LDLr) to reduce cholesterol intake and 3-Hydroxy-3-Methylglutaryl-CoA reductase (HMGCR), and 3-Hydroxy-3-Methylglutaryl-CoA synthase 1 (HMGCS1) to decrease cholesterol synthesis. Animal experiments showed that SHCZF significantly reduced the expression levels of the above genes and proinflammatory cytokine lipocalin 2 (LCN2), inflammatory cytokines interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), thereby improving intrahepatic cholestasis and inflammation and liver injury.
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Affiliation(s)
- Junbin Yan
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Chinese Medicine, Hangzhou, China,The Second Affiliated Hospital of Zhejiang Chinese Medical University, The Xin Hua Hospital of Zhejiang Province, Hangzhou, China
| | - Yunmeng Nie
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zheng Chen
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Chinese Medicine, Hangzhou, China,Key Laboratory of Integrative Chinese and Western Medicine for the Diagnosis and Treatment of Circulatory Diseases of Zhejiang Province, Hangzhou, China
| | - Jiaming Yao
- Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, China
| | - Shuo Zhang
- The Second Affiliated Hospital of Zhejiang Chinese Medical University, The Xin Hua Hospital of Zhejiang Province, Hangzhou, China,*Correspondence: Shuo Zhang, ; Zhiyun Chen,
| | - Zhiyun Chen
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Chinese Medicine, Hangzhou, China,Key Laboratory of Integrative Chinese and Western Medicine for the Diagnosis and Treatment of Circulatory Diseases of Zhejiang Province, Hangzhou, China,*Correspondence: Shuo Zhang, ; Zhiyun Chen,
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10
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Shoji T, Akiyama Y, Fujii H, Harada-Shiba M, Ishibashi Y, Ishida T, Ishigaki Y, Kabata D, Kihara Y, Kotani K, Kurisu S, Masuda D, Matoba T, Matsuki K, Matsumura T, Mori K, Nakagami T, Nakazato M, Taniuchi S, Ueno H, Yamashita S, Yoshida H, Yoshida H. Association of Kidney Function with Serum Levels of Cholesterol Absorption and Synthesis Markers: The CACHE Study CKD Analysis. J Atheroscler Thromb 2022; 29:1835-1848. [PMID: 35249905 PMCID: PMC9881540 DOI: 10.5551/jat.63311] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 01/06/2022] [Indexed: 02/04/2023] Open
Abstract
AIM Serum levels of cholesterol absorption and synthesis markers are known to be associated with cardiovascular risk. Individuals with reduced kidney function or chronic kidney disease (CKD) are at an increased risk for cardiovascular disease. Hence, we examined the relationship between estimated glomerular filtration rate (eGFR) and serum markers of cholesterol absorption and synthesis. METHODS The CACHE (Cholesterol Absorption and Cholesterol synthesis in High-risk patiEnts) Consortium, comprised of 13 research groups in Japan possessing data of lathosterol (Latho, synthesis marker) and campesterol (Campe, absorption marker) measured via gas chromatography, compiled the clinical data using the REDCap system. Among the 3597 records, data from 2944 individuals were utilized for five analyses including this CKD analysis. RESULTS This study analyzed data from 2200 individuals including 522 hemodialysis patients; 42.3% were female, the median age was 58 years, and the median eGFR was 68.9 mL/min/1.73 m2. Latho, Campe, and Campe/Latho ratio were significantly different when compared across CKD stages. When the associations of eGFR with these markers were assessed with multivariable nonlinear regression models, Latho, Campe, and Campe/Latho ratio showed positive, inverse, and inverse associations with eGFR. These associations were significantly modified by sex, the presence/absence of diabetes mellitus, and the presence/absence of statin use. CONCLUSION We showed that individuals with lower eGFR have lower cholesterol synthesis marker levels and higher cholesterol absorption marker levels in this large sample.
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Affiliation(s)
- Tetsuo Shoji
- Department of Vascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
- Vascular Science Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yusuke Akiyama
- Division of Cardiovascular Medicine, Oita Prefectural Hospital, Oita, Japan
| | - Hisako Fujii
- Department of Health and Medical Innovation, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Mariko Harada-Shiba
- Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
| | - Yutaka Ishibashi
- Department of General Medicine, Shimane University Faculty of Medicine, Izumo, Japan
- Jinjukai Education & Training Center for Healthcare Professionals, Shimane, Japan
| | - Tatsuro Ishida
- Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yasushi Ishigaki
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Daijiro Kabata
- Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yasuki Kihara
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuhiko Kotani
- Division of Community and Family Medicine, Jichi Medical University, Shimotsuke-City, Japan
| | - Satoshi Kurisu
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | | | - Tetsuya Matoba
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kota Matsuki
- Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, Japan
| | - Takeshi Matsumura
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Kenta Mori
- Department of General Internal Medicine, Kobe University Hospital, Kobe, Japan
| | - Tomoko Nakagami
- Division of Diabetology and Metabolism, Department of Internal Medicine, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan
| | - Masamitsu Nakazato
- Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Satsuki Taniuchi
- Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hiroaki Ueno
- Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | | | - Hisako Yoshida
- Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hiroshi Yoshida
- Department of Laboratory Medicine, The Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan
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11
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Liao J, Yang L, Zhou L, Zhao H, Qi X, Cui Y, Ouyang D. The NPC1L1 Gene Exerts a Notable Impact on the Reduction of Low-Density Lipoprotein Cholesterol in Response to Hyzetimibe: A Factorial-Designed Clinical Trial. Front Pharmacol 2022; 13:755469. [PMID: 35359877 PMCID: PMC8963242 DOI: 10.3389/fphar.2022.755469] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 02/09/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Hyzetimibe is a novel inhibitor of cholesterol that specifically targets the NPC1L1 gene. Significant inter-individual variability suggests the existence of an abundance of poor responders and non-responders. In addition, the current literature is inconsistent and controversial regarding the potential impact of the Niemann-Pick C1-Like 1 (NPC1L1) gene on low-density lipoprotein cholesterol (LDL-C) reduction. In light of these concerns, we performed a high-quality clinical trial to investigate the specific characteristics of NPC1L1 gene variation on LDL-C reduction. Methods: This was a multicenter, randomized, double-blind, placebo-controlled, clinical trial with a factorial design. Qualified patients were randomly assigned to one of six treatments: placebo, hyzetimibe (10 or 20 mg), atorvastatin, and atorvastatin plus hyzetimibe (10 or 20 mg). Fasting blood samples were collected and genotyped, and the concentrations of LDL-C and the targeted drug trough were determined to investigate the association between the NPC1L1 gene expression and the reduction of LDL-C. Results: In total, 727 individuals were initially recruited; of these, 444 were eligible to begin the trial. We identified one SNP (g1679C > G) that exerted significantly different impacts on LDL-C levels. As monotherapy, CC carriers experienced significantly higher reductions in the mean LDL-C (−23.99%) than either the GG (−16.45%, p < 0.01) or GC (−13.02%, p < 0.01) carriers in the hyzetimibe (20 mg) group. In contrast, when co-administered with atorvastatin, GC carriers experienced greater LDL-C reduction than non-GC carriers (-52.23% vs. −45.03%) in the hyzetimibe (20 mg) plus atorvastatin group. Furthermore, the proportions of individuals experiencing a reduction in LDL-C by >50% increased as the dose of hyzetimibe increased from 16.1% to 65.4%. Conclusion: The g1679C > G SNP in the NPC1L1 gene is critical and exerts a differential impact on the response to hyzetimibe treatment. Heterozygotic patients respond with poor efficacy when treated by monotherapy but show good responses in terms of LDL-C reduction when hyzetimibe was co-administered with atorvastatin. To treat hypercholesterolemia in a precise manner with hyzetimibe, it is necessary to identify genotype patients for the g1679C > G SNP. We also highlight the potential necessity for identifying the appropriate subjects to be treated with ezetimibe. Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [CTR20150351]
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Affiliation(s)
- Jianwei Liao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacology, Central South University, Changsha, China
| | - Liyun Yang
- Zhejiang Hisun Pharmaceutical Co. Ltd, Taizhou, China
| | - Luping Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacology, Central South University, Changsha, China
| | - Hongbin Zhao
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha, China
| | - Xiao Qi
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha, China
| | - Yimin Cui
- Peking University First Hospital, Beijing, China
- *Correspondence: Yimin Cui, ; Dongsheng Ouyang,
| | - Dongsheng Ouyang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacology, Central South University, Changsha, China
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha, China
- *Correspondence: Yimin Cui, ; Dongsheng Ouyang,
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12
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Dai X, He L, Hu N, Guo C, Zhou M, Zhao X, Wang C, Gong L, Ma C, Xue X, Li Y. Polygoni Multiflori Radix Praeparata Ethanol Extract Exerts a Protective Effect Against High-Fat Diet Induced Non-Alcoholic Fatty Liver Disease in Mice by Remodeling Intestinal Microbial Structure and Maintaining Metabolic Homeostasis of Bile Acids. Front Pharmacol 2021; 12:734670. [PMID: 34867343 PMCID: PMC8634718 DOI: 10.3389/fphar.2021.734670] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 10/20/2021] [Indexed: 12/12/2022] Open
Abstract
In the prescription of Traditional Chinese Medicine for lipid metabolism, Polygoni Multiflori Radix Preparata (ZhiHeShouWu, RPMP) was widely used. In recent years, RPMP ethanol extract has been reported for the treatment of non-alcoholic fatty liver disease (NAFLD). However, the role of RPMP ethanol extract in the treatment of NAFLD has not been fully elucidated. Therefore, we examined the optimal therapeutic dose of RPMP ethanol extracts. Afterward, a mouse model of non-alcoholic fatty liver induced by a high-fat diet (HFD) was treated with RPMP ethanol extract to further evaluate the mechanism of action of RPMP ethanol extract treatment. And the serum lipid metabolism indexes and liver function indexes showed that the RPMP ethanol extract in the 1.35 g/kg dose group exhibited better therapeutic effects than the 2.70 g/kg dose group. Meanwhile, RPMP ethanol extract can regulate the biochemical indicators of serum and liver to normal levels, and effectively reduce liver steatosis and lipid deposition. RPMP ethanol extract treatment restored HFD-induced disruption of the compositional structure of the intestinal microbial (IM) and bile acids (BAs) pools. And restore the reduced expression of intestinal barrier-related genes caused by HFD administration, which also effectively regulates the expression of genes related to the metabolism of BAs in mice. Thus, RPMP ethanol extract can effectively improve the abnormal lipid metabolism and hepatic lipid accumulation caused by HFD, which may be related to the regulation of IM composition, maintenance of intestinal barrier function, and normal cholesterol metabolism in the body.
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Affiliation(s)
- Xuyang Dai
- School of Pharmacy, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Linfeng He
- School of Pharmacy, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Naihua Hu
- School of Pharmacy, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chaocheng Guo
- School of Pharmacy, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Mengting Zhou
- School of Pharmacy, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xingtao Zhao
- School of Pharmacy, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cheng Wang
- School of Pharmacy, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lihong Gong
- School of Pharmacy, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cheng Ma
- School of Pharmacy, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xinyan Xue
- School of Pharmacy, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yunxia Li
- School of Pharmacy, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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13
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Schade DS, Gonzales K, Kaminsky N, Adolphe A, Shey L, Eaton RP. Resolving the Egg and Cholesterol Intake Controversy: New Clinical Insights Into Cholesterol Regulation by the Liver and Intestine. Endocr Pract 2021; 28:102-109. [PMID: 34547473 DOI: 10.1016/j.eprac.2021.09.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 08/19/2021] [Accepted: 09/09/2021] [Indexed: 11/17/2022]
Abstract
OBJECTIVE Cardiovascular disease is the number one cause of death. Achieving American Heart Association low-density lipoprotein (LDL) cholesterol treatment goals is very difficult for many patients. The importance of a low cholesterol diet is controversial and not emphasized by most physicians. Of critical importance is determining whether each individual is a "hyper- or hypo-absorber" of dietary cholesterol. Furthermore, the quantity of each individual's baseline daily dietary cholesterol and saturated fat intake is important in assessing the effect of added egg yolk cholesterol and saturated fat on blood LDL cholesterol. METHODS Gut cholesterol is absorbed via a specific enteric receptor (the Niemann- Pick-like receptor). Dietary cholesterol contributes one fourth of the absorbed cholesterol, while the remaining gut cholesterol is derived from secreted bile cholesterol. This dietary quantity of cholesterol is significant when other determinants are constant. For some individuals, dietary cholesterol has no adverse effects and in others, a significant elevation in blood LDL cholesterol may occur. RESULTS There are no readily available blood tests to determine the effect of egg yolk cholesterol and saturated fat on an individual's plasma LDL cholesterol. However, a one month trial of a low cholesterol and saturated fat diet will provide the needed information to make clinical decisions. CONCLUSION This article delineates the mechanisms that are altered by genetic and environmental factors that determine the net effects of dietary cholesterol and saturated fat on circulating LDL cholesterol. It then makes a practical clinical recommendation based on these mechanisms.
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Affiliation(s)
- David S Schade
- Division of Endocrinology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
| | - Kristen Gonzales
- Division of Endocrinology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
| | - Neil Kaminsky
- Division of Endocrinology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
| | - Allen Adolphe
- Division of Internal Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
| | - Lynda Shey
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Diabetes Comprehensive Care Center, Albuquerque, New Mexico
| | - Robert Philip Eaton
- Division of Endocrinology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
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14
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Takashima Y, Ishikawa K, Miyawaki R, Ogawa M, Ishii T, Misaka T, Kobayashi S. Modulatory Effect of Theaflavins on Apical Sodium-Dependent Bile Acid Transporter (ASBT) Activity. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:9585-9596. [PMID: 34346218 DOI: 10.1021/acs.jafc.1c03483] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Inhibiting apical sodium-dependent bile acid transporter (ASBT) has been identified as a potential strategy to reduce plasma cholesterol levels. Thus, in this study, we aimed to identify polyphenols that inhibited ASBT activity and to elucidate their mechanism. ASBT is responsible for most of the taurocholic acid (TC) uptake in Caco-2 cells. Of the 39 polyphenols examined, theaflavin (TF)-3-gallate (TF2A) and theaflavin-3'-gallate (TF2B) have been found to significantly reduce TC uptake in Caco-2 cells to 37.4 ± 2.8 and 33.8 ± 4.0%, respectively, of that in the untreated cells. The results from the TC uptake assay using N-acetylcysteine suggested that the inhibitory effect of TF2A and TF2B was attributed to the oxidization of their benzotropolone rings and their covalent bonding with ASBT's cysteine. TC uptake was reduced in the COS-7 cells expressing recombinant ASBT whose cysteine residues were mutated to alanine. Finally, the substrate concentration-dependent TC uptake assay showed that TFs competitively inhibited TC uptake.
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Affiliation(s)
- Yuki Takashima
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8654, Japan
| | - Kazuki Ishikawa
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8654, Japan
| | - Rina Miyawaki
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8654, Japan
| | - Mana Ogawa
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8654, Japan
| | - Takeshi Ishii
- Department of Nutrition, Kobe Gakuin University, Kobe 651-2180, Japan
| | - Takumi Misaka
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8654, Japan
| | - Shoko Kobayashi
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8654, Japan
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15
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Abstract
BACKGROUND Statins are one of the most prescribed classes of drugs worldwide. Atorvastatin, the most prescribed statin, is currently used to treat conditions such as hypercholesterolaemia and dyslipidaemia. By reducing the level of cholesterol, which is the precursor of the steroidogenesis pathway, atorvastatin may cause a reduction in levels of testosterone and other androgens. Testosterone and other androgens play important roles in biological functions. A potential reduction in androgen levels, caused by atorvastatin might cause negative effects in most settings. In contrast, in the setting of polycystic ovary syndrome (PCOS), reducing excessive levels of androgens with atorvastatin could be beneficial. OBJECTIVES Primary objective To quantify the magnitude of the effect of atorvastatin on total testosterone in both males and females, compared to placebo or no treatment. Secondary objectives To quantify the magnitude of the effects of atorvastatin on free testosterone, sex hormone binding globin (SHBG), androstenedione, dehydroepiandrosterone sulphate (DHEAS) concentrations, free androgen index (FAI), and withdrawal due to adverse effects (WDAEs) in both males and females, compared to placebo or no treatment. SEARCH METHODS The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to 9 November 2020: the Cochrane Hypertension Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; ;two international trials registries, and the websites of the US Food and Drug Administration, the European Patent Office and the Pfizer pharmaceutical corporation. These searches had no language restrictions. We also contacted authors of relevant articles regarding further published and unpublished work. SELECTION CRITERIA RCTs of daily atorvastatin for at least three weeks, compared with placebo or no treatment, and assessing change in testosterone levels in males or females. DATA COLLECTION AND ANALYSIS Two review authors independently screened the citations, extracted the data and assessed the risk of bias of the included studies. We used the mean difference (MD) with associated 95% confidence intervals (CI) to report the effect size of continuous outcomes,and the risk ratio (RR) to report effect sizes of the sole dichotomous outcome (WDAEs). We used a fixed-effect meta-analytic model to combine effect estimates across studies, and risk ratio to report effect size of the dichotomous outcomes. We used GRADE to assess the certainty of the evidence. MAIN RESULTS We included six RCTs involving 265 participants who completed the study and their data was reported. Participants in two of the studies were male with normal lipid profile or mild dyslipidaemia (N = 140); the mean age of participants was 68 years. Participants in four of the studies were female with PCOS (N = 125); the mean age of participants was 32 years. We found no significant difference in testosterone levels in males between atorvastatin and placebo, MD -0.20 nmol/L (95% CI -0.77 to 0.37). In females, atorvastatin may reduce total testosterone by -0.27 nmol/L (95% CI -0.50 to -0.04), FAI by -2.59 nmol/L (95% CI -3.62 to -1.57), androstenedione by -1.37 nmol/L (95% CI -2.26 to -0.49), and DHEAS by -0.63 μmol/l (95% CI -1.12 to -0.15). Furthermore, compared to placebo, atorvastatin increased SHBG concentrations in females by 3.11 nmol/L (95% CI 0.23 to 5.99). We identified no studies in healthy females (i.e. females with normal testosterone levels) or children (under age 18). Importantly, no study reported on free testosterone levels. AUTHORS' CONCLUSIONS We found no significant difference between atorvastatin and placebo on the levels of total testosterone in males. In females with PCOS, atorvastatin lowered the total testosterone, FAI, androstenedione, and DHEAS. The certainty of evidence ranged from low to very low for both comparisons. More RCTs studying the effect of atorvastatin on testosterone are needed.
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Affiliation(s)
- Muhammad Ismail Shawish
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada
| | - Bahador Bagheri
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | - Vijaya M Musini
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada
| | - Stephen P Adams
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada
| | - James M Wright
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada
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16
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He Y, Chhetri SB, Arvanitis M, Srinivasan K, Aguet F, Ardlie KG, Barbeira AN, Bonazzola R, Im HK, Brown CD, Battle A. sn-spMF: matrix factorization informs tissue-specific genetic regulation of gene expression. Genome Biol 2020; 21:235. [PMID: 32912314 PMCID: PMC7488540 DOI: 10.1186/s13059-020-02129-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 08/04/2020] [Indexed: 01/09/2023] Open
Abstract
Genetic regulation of gene expression, revealed by expression quantitative trait loci (eQTLs), exhibits complex patterns of tissue-specific effects. Characterization of these patterns may allow us to better understand mechanisms of gene regulation and disease etiology. We develop a constrained matrix factorization model, sn-spMF, to learn patterns of tissue-sharing and apply it to 49 human tissues from the Genotype-Tissue Expression (GTEx) project. The learned factors reflect tissues with known biological similarity and identify transcription factors that may mediate tissue-specific effects. sn-spMF, available at https://github.com/heyuan7676/ts_eQTLs , can be applied to learn biologically interpretable patterns of eQTL tissue-specificity and generate testable mechanistic hypotheses.
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Affiliation(s)
- Yuan He
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, 21218, MD, USA
| | - Surya B Chhetri
- HudsonAlpha Institute for Biotechnology, Huntsville, 35806, AL, USA
- Current Address: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, 21218, MD, USA
| | - Marios Arvanitis
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, 21218, MD, USA
- Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, 21287, MD, USA
| | - Kaushik Srinivasan
- Department of Computer Science, Johns Hopkins University, Baltimore, 21218, MD, USA
| | - François Aguet
- The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | | | - Alvaro N Barbeira
- Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
| | - Rodrigo Bonazzola
- Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
| | - Hae Kyung Im
- Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA
| | - Christopher D Brown
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, PA, USA.
| | - Alexis Battle
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, 21218, MD, USA.
- Department of Computer Science, Johns Hopkins University, Baltimore, 21218, MD, USA.
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17
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Malhotra P, Gill RK, Saksena S, Alrefai WA. Disturbances in Cholesterol Homeostasis and Non-alcoholic Fatty Liver Diseases. Front Med (Lausanne) 2020; 7:467. [PMID: 32984364 PMCID: PMC7492531 DOI: 10.3389/fmed.2020.00467] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 07/13/2020] [Indexed: 12/21/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major health problem associated with obesity and other features of the metabolic syndrome including insulin resistance and dyslipidemia. The accumulation of lipids in hepatocytes causes liver damage and triggers inflammation, fibrosis, and cirrhosis. Beside fatty acids and triglycerides, evidence showed an increased accumulation of free cholesterol in the liver with subsequent toxic effects contributing to liver damage. The maintenance of cholesterol homeostasis in the body requires a balance between several pathways responsible for cholesterol synthesis, transport and conversion into bile acids. Intestinal absorption is also one of the major determinants of cholesterol homeostasis. The nature of changes in cholesterol homeostasis associated with NAFLD has been a subject of extensive investigations. In this article, we will attempt to provide a brief overview of the current knowledge about the disturbances in cholesterol metabolism associated with NAFLD and discuss how certain molecular targets of these pathways could be exploited for the treatment of this multifactorial disease.
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Affiliation(s)
- Pooja Malhotra
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Ravinder K Gill
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Seema Saksena
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States.,Jesse Brown VA Medical Center, Chicago, IL, United States
| | - Waddah A Alrefai
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States.,Jesse Brown VA Medical Center, Chicago, IL, United States
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18
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Hayakawa EH, Kato H, Nardone GA, Usukura J. A prospective mechanism and source of cholesterol uptake by Plasmodium falciparum-infected erythrocytes co-cultured with HepG2 cells. Parasitol Int 2020; 80:102179. [PMID: 32853776 DOI: 10.1016/j.parint.2020.102179] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 06/23/2020] [Accepted: 07/20/2020] [Indexed: 12/17/2022]
Abstract
Plasmodium falciparum (P. falciparum) parasites still cause lethal infections worldwide, especially in Africa (https://www.who.int/publications/i/item/world-malaria-report-2019). During P. falciparum blood-stage infections in humans, low-density lipoprotein, high-density lipoprotein and cholesterol levels in the blood become low. Because P. falciparum lacks a de novo cholesterol synthesis pathway, it must import cholesterol from the surrounding environment. However, the origin of the cholesterol and how it is taken up by the parasite across the multiple membranes that surround it is not fully understood. To answer this, we used a cholesterol synthesis inhibiter (simvastatin), a cholesterol transport inhibitor (ezetimibe), and an activating ligand of the peroxisome proliferator-activated receptor α, called ciprofibrate, to investigate the effects of these agents on the intraerythrocytic growth of P. falciparum, both with and without HepG2 cells as the lipoprotein feeders. P. falciparum growth was inhibited in the presence of ezetimibe, but ezetimibe was not very effective at inhibiting P. falciparum growth when used in the co-culture system, unlike simvastatin, which strongly promoted parasite growth in this system. Ezetimibe is known to inhibit cholesterol absorption by blocking the activity of Niemann-Pick C1 like 1 (NPC1L1) protein, and simvastatin is known to enhance NPC1L1 expression in the human body's small intestine. Collectively, our results support the possibility that cholesterol import by P. falciparum involves hepatocytes, and cholesterol uptake into the parasite occurs via NPC1L1 protein or an NPC1L1 homolog during the erythrocytic stages of the P. falciparum lifecycle.
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Affiliation(s)
- Eri H Hayakawa
- Division of Medical Zoology, Department of Infection and Immunity, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
| | - Hirotomo Kato
- Division of Medical Zoology, Department of Infection and Immunity, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan
| | - Glenn A Nardone
- Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-5766, USA
| | - Jiro Usukura
- Institute of Material and Systems for Sustainability, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
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19
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Selective Ah receptor modulators attenuate NPC1L1-mediated cholesterol uptake through repression of SREBP-2 transcriptional activity. J Transl Med 2020; 100:250-264. [PMID: 31417158 PMCID: PMC6989381 DOI: 10.1038/s41374-019-0306-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/26/2019] [Accepted: 07/02/2019] [Indexed: 02/07/2023] Open
Abstract
The ability of the aryl hydrocarbon receptor (AHR) to alter hepatic expression of cholesterol synthesis genes in a DRE-independent manner in mice and humans has been reported. We have examined the influence of functionally distinct classes of AHR ligands on the levels of Niemann-Pick C1-like intracellular cholesterol transporter (NPC1L1) and enzymes involved in the cholesterol synthesis pathway. NPC1L1 is known to mediate the intestinal absorption of dietary cholesterol and is clinically targeted. AHR ligands were capable of attenuating cholesterol uptake through repression of NPC1L1 expression. Through mutagenesis experiments targeting the two DRE sequences present in the promoter region of the NPC1L1 gene, we provide evidence that the repression does not require functional DRE sequences; while knockdown experiments demonstrated that this regulation is dependent on AHR and sterol-regulatory element-binding protein-2 (SREBP-2). Furthermore, upon ligand activation of AHR, the human intestinal Caco-2 cell line revealed coordinate repression of both mRNA and protein levels for a number of the cholesterol biosynthetic enzymes. Transcription of NPC1L1 and genes of the cholesterol synthesis pathway is predominantly regulated by SREBP-2, especially after treatment with a statin. Immunoblot analyses revealed a significant decrease in transcriptionally active SREBP-2 levels upon ligand treatment, whereas the precursor form of SREBP-2 was modestly increased by AHR activation. Mechanistic insights indicate that AHR induces proteolytic degradation of mature SREBP-2 in a calcium-dependent manner, which correlates with the AHR ligand-mediated upregulation of the transient receptor potential cation channel subfamily V member 6 (TRPV6) gene encoding for a membrane calcium channel. These observations emphasize a role for AHR in the systemic homeostatic regulation of cholesterol synthesis and absorption, indicating the potential use of this receptor as a target for the treatment of hyperlipidosis-associated metabolic diseases.
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20
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Stahel P, Xiao C, Nahmias A, Lewis GF. Role of the Gut in Diabetic Dyslipidemia. Front Endocrinol (Lausanne) 2020; 11:116. [PMID: 32231641 PMCID: PMC7083132 DOI: 10.3389/fendo.2020.00116] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 02/21/2020] [Indexed: 12/13/2022] Open
Abstract
Type 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD). In insulin resistant states such as the metabolic syndrome, overproduction and impaired clearance of liver-derived very-low-density lipoproteins and gut-derived chylomicrons (CMs) contribute to hypertriglyceridemia and elevated atherogenic remnant lipoproteins. Although ingested fat is the major stimulus of CM secretion, intestinal lipid handling and ultimately CM secretory rate is determined by numerous additional regulatory inputs including nutrients, hormones and neural signals that fine tune CM secretion during fasted and fed states. Insulin resistance and T2D represent perturbed metabolic states in which intestinal sensitivity to key regulatory hormones such as insulin, leptin and glucagon-like peptide-1 (GLP-1) may be altered, contributing to increased CM secretion. In this review, we describe the evidence from human and animal models demonstrating increased CM secretion in insulin resistance and T2D and discuss the molecular mechanisms underlying these effects. Several novel compounds are in various stages of preclinical and clinical investigation to modulate intestinal CM synthesis and secretion. Their efficacy, safety and therapeutic utility are discussed. Similarly, the effects of currently approved lipid modulating therapies such as statins, ezetimibe, fibrates, and PCSK9 inhibitors on intestinal CM production are discussed. The intricacies of intestinal CM production are an active area of research that may yield novel therapies to prevent atherosclerotic CVD in insulin resistance and T2D.
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21
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Lalande C, Drouin-Chartier JP, Tremblay AJ, Couture P, Veilleux A. Plasma biomarkers of small intestine adaptations in obesity-related metabolic alterations. Diabetol Metab Syndr 2020; 12:31. [PMID: 32292494 PMCID: PMC7144049 DOI: 10.1186/s13098-020-00530-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 03/13/2020] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Evidence suggests that pathophysiological conditions such as obesity and type 2 diabetes (T2D) are associated with morphologic and metabolic alterations in the small intestinal mucosa. Exploring these alterations generally requires invasive methods, limiting data acquisition to subjects with enteropathies or undergoing bariatric surgery. We aimed to evaluate small intestine epithelial cell homeostasis in a cohort of men covering a wide range of adiposity and glucose homoeostasis statuses. METHODS Plasma levels of citrulline, a biomarker of enterocyte mass, and I-FABP, a biomarker of enterocyte death, were measured by UHPLC‑MS and ELISA in 154 nondiabetic men and 67 men with a T2D diagnosis. RESULTS Plasma citrulline was significantly reduced in men with insulin resistance and T2D compared to insulin sensitive men. Decreased citrulline levels were, however, not observed in men with uncontrolled metabolic parameters during T2D. Plasma I-FABP was significantly higher in men with T2D, especially in presence of uncontrolled glycemic and lipid profile parameters. Integration of both parameters, which estimate enterocyte turnover, was associated with glucose homeostasis as well as with T2D diagnosis. Differences in biomarkers levels were independent of age and BMI and glucose filtration rates. CONCLUSIONS Our study supports a decreased functional enterocyte mass and an increased enterocyte death rate in presence of metabolic alterations but emphasizes that epithelial cell homeostasis is especially altered in presence of severe insulin resistance and T2D. The marked changes in small intestine cellularity observed in obesity and diabetes are thus suggested to be part of gut dysfunctions, mainly at an advanced stage of the disease.
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Affiliation(s)
- Catherine Lalande
- École de nutrition, Faculté des sciences de l’agriculture et de l’alimentation, Université Laval, 2440, boulevard Hochelaga, Québec, QC G1V 0A6 Canada
- Centre Nutrition, santé et société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, Québec, QC Canada
| | - Jean-Philippe Drouin-Chartier
- École de nutrition, Faculté des sciences de l’agriculture et de l’alimentation, Université Laval, 2440, boulevard Hochelaga, Québec, QC G1V 0A6 Canada
- Centre Nutrition, santé et société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, Québec, QC Canada
| | - André J. Tremblay
- Centre Nutrition, santé et société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, Québec, QC Canada
| | - Patrick Couture
- Centre Nutrition, santé et société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, Québec, QC Canada
- Centre des maladies lipidiques, Centre Hospitalier Universitaire (CHU) de Québec, Québec, QC Canada
| | - Alain Veilleux
- École de nutrition, Faculté des sciences de l’agriculture et de l’alimentation, Université Laval, 2440, boulevard Hochelaga, Québec, QC G1V 0A6 Canada
- Centre Nutrition, santé et société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, Québec, QC Canada
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC Canada
- Canada Excellence Research Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health, Québec, QC Canada
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22
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Ahmed O, Littmann K, Gustafsson U, Pramfalk C, Öörni K, Larsson L, Minniti ME, Sahlin S, Camejo G, Parini P, Eriksson M. Ezetimibe in Combination With Simvastatin Reduces Remnant Cholesterol Without Affecting Biliary Lipid Concentrations in Gallstone Patients. J Am Heart Assoc 2019; 7:e009876. [PMID: 30561264 PMCID: PMC6405603 DOI: 10.1161/jaha.118.009876] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Background In randomized trials (SHARP [Study of Heart and Renal Protection], IMPROVE‐IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]), combination of statin and ezetimibe resulted in additional reduction of cardiovascular events. The reduction was greater in patients with type 2 diabetes mellitus (T2DM), where elevated remnant cholesterol and high cardiovascular disease risk is characteristic. To evaluate possible causes behind these results, 40 patients eligible for cholecystectomy, randomized to simvastatin, ezetimibe, combined treatment (simvastatin+ezetimibe), or placebo treatment during 4 weeks before surgery, were studied. Methods and Results Fasting blood samples were taken before treatment start and at the end (just before surgery). Bile samples and liver biopsies were collected during surgery. Hepatic gene expression levels were assessed with qPCR. Lipoprotein, apolipoprotein levels, and content of cholesterol, cholesteryl ester, and triglycerides were measured after lipoprotein fractionation. Lipoprotein subclasses were analyzed by nuclear magnetic resonance. Apolipoprotein affinity for human arterial proteoglycans (PG) was measured. Biomarkers of cholesterol biosynthesis and intestinal absorption and bile lipid composition were analyzed using mass spectrometry. Combined treatment caused a statistically significant decrease in plasma remnant particles and apolipoprotein B (ApoB)/lipoprotein content of cholesterol, cholesteryl esters, and triglycerides. All treatments reduced ApoB‐lipoprotein PG binding. Simvastatin and combined treatment modified the composition of lipoproteins. Changes in biomarkers of cholesterol synthesis and absorption and bile acid synthesis were as expected. No adverse events were found. Conclusions Combined treatment caused atheroprotective changes on ApoB‐lipoproteins, remnant particles, bile components, and in ApoB‐lipoprotein affinity for arterial PG. These effects might explain the decrease of cardiovascular events seen in the SHARP and IMPROVE‐IT trials. Clinical Trial Registration URL: www.clinicaltrialsregister.eu. Unique identifier: 2006‐004839‐30).
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Affiliation(s)
- Osman Ahmed
- 1 Division of Clinical Chemistry Department of Laboratory Medicine Karolinska Institutet Stockholm Sweden.,2 Department of Biochemistry Faculty of Medicine Khartoum University Khartoum Sudan
| | - Karin Littmann
- 1 Division of Clinical Chemistry Department of Laboratory Medicine Karolinska Institutet Stockholm Sweden.,3 Function Area Clinical Chemistry Karolinska University Laboratory Function Karolinska University Hospital Stockholm Sweden
| | - Ulf Gustafsson
- 5 Department of Surgery Karolinska Institutet at Danderyd Hospital Stockholm Sweden
| | - Camilla Pramfalk
- 1 Division of Clinical Chemistry Department of Laboratory Medicine Karolinska Institutet Stockholm Sweden
| | | | - Lilian Larsson
- 1 Division of Clinical Chemistry Department of Laboratory Medicine Karolinska Institutet Stockholm Sweden
| | - Mirko E Minniti
- 1 Division of Clinical Chemistry Department of Laboratory Medicine Karolinska Institutet Stockholm Sweden
| | - Staffan Sahlin
- 5 Department of Surgery Karolinska Institutet at Danderyd Hospital Stockholm Sweden
| | - German Camejo
- 1 Division of Clinical Chemistry Department of Laboratory Medicine Karolinska Institutet Stockholm Sweden
| | - Paolo Parini
- 1 Division of Clinical Chemistry Department of Laboratory Medicine Karolinska Institutet Stockholm Sweden.,4 Patient Area Endocrinology and Nephrology, Inflammation and Infection Theme Karolinska University Hospital Stockholm Sweden.,7 Metabolism Unit Department of Medicine Karolinska Institutet at Karolinska University Hospital Huddinge Stockholm Sweden
| | - Mats Eriksson
- 4 Patient Area Endocrinology and Nephrology, Inflammation and Infection Theme Karolinska University Hospital Stockholm Sweden.,7 Metabolism Unit Department of Medicine Karolinska Institutet at Karolinska University Hospital Huddinge Stockholm Sweden
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23
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Thang SK, Chen PY, Gao WY, Wu MJ, Pan MH, Yen JH. Xanthohumol Suppresses NPC1L1 Gene Expression through Downregulation of HNF-4α and Inhibits Cholesterol Uptake in Caco-2 Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:11119-11128. [PMID: 31525874 DOI: 10.1021/acs.jafc.9b05221] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Xanthohumol (Xan) is a prenylated chalcone mainly found in hops; it has been demonstrated to function against hypercholesterolemia, hyperlipidemia, and atherosclerosis. In this study, we focused on the hypocholesterolemic effect of Xan on cholesterol uptake and the underlying molecular mechanisms of Xan in human intestinal Caco-2 cells. The microarray data showed that Niemann-Pick C1-like 1 (NPC1L1), an essential transporter for dietary cholesterol absorption, was significantly downregulated in Xan-treated Caco-2 cells. We demonstrated that Xan (10 and 20 μM) suppressed the mRNA and protein expression of NPC1L1 by 0.65 ± 0.12-fold and 0.54 ± 0.15-fold and 0.72 ± 0.04-fold and 0.44 ± 0.12-fold, respectively, compared to that of the vehicle-treated Caco-2 cells. Moreover, Xan (10 and 20 μM) significantly inhibited cholesterol uptake by approximately 12 and 32% in Caco-2 cells. NPC1L1 promoter activity was significantly suppressed by Xan, and a DNA element within the NPC1L1 promoter involved in Xan-mediated NPC1L1 reduction located between the -120 and -20 positions was identified. Moreover, Xan markedly decreased the mRNA and protein levels of hepatocyte nuclear factor 4α (HNF-4α), a critical activator of NPC1L1 transcription, and subsequently attenuated HNF-4α/NPC1L1 promoter complex formation, resulting in the suppression of NPC1L1 gene expression. Finally, we demonstrated that Xan markedly abolished lovastatin-induced NPC1L1 overexpression in Caco-2 cells. These findings reveal that Xan suppresses NPC1L1 expression via downregulation of HNF-4α and exerts inhibitory effects on cholesterol uptake in the intestinal Caco-2 cells. Our findings suggest Xan could serve as a potential cholesterol-lowering agent and supplement for statin therapy.
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Affiliation(s)
- Sang Kim Thang
- Institute of Medical Sciences , Tzu Chi University , Hualien 970 , Taiwan
| | - Pei-Yi Chen
- Center of Medical Genetics , Hualien Tzu Chi Hospital, Buddhist Tzu Chi Foundation , Hualien 970 , Taiwan
| | - Wan-Yun Gao
- Department of Molecular Biology and Human Genetics , Tzu Chi University , Hualien 970 , Taiwan
| | - Ming-Jiuan Wu
- Department of Biotechnology , Chia-Nan University of Pharmacy and Science , Tainan 717 , Taiwan
| | - Min-Hsiung Pan
- Institute of Food Science and Technology , National Taiwan University , Taipei 10617 , Taiwan
| | - Jui-Hung Yen
- Institute of Medical Sciences , Tzu Chi University , Hualien 970 , Taiwan
- Department of Molecular Biology and Human Genetics , Tzu Chi University , Hualien 970 , Taiwan
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24
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Duangjai A, Ontawong A, Srimaroeng C. Siamese neem flower extract suppresses cholesterol absorption by interfering NPC1L1 and micellar property in vitro and in intestinal Caco-2 cells. Res Pharm Sci 2019; 14:190-200. [PMID: 31160896 PMCID: PMC6540922 DOI: 10.4103/1735-5362.258485] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Siamese neem (Azadirachta indica A. Juss var. siamensis Valeton) (A. indica) leaf extract, a traditional ayurvedic medicine, has been reported to exhibit antipyretic, antibacterial, antidyslipidemic, and antihyperglycemia effects. This study investigated the mechanism of hypocholesterolemic effect of methanolic extract of Siamese neem flowers in in vitro studies and in Caco-2 cells. Pancreatic cholesterol esterase and 3-hydroxy 3-methylglutaryl-CoA (HMG-CoA) reductase activities were assessed. Cholesterol micelle formation was prepared for in vitro cholesterol physicochemical property analyses, micelle size and solubility, and transport of cholesterol into the Caco-2 cells. The expression of niemann-pick C1 like 1 (NPC1L1), and its major regulator, peroxisome proliferator-activated receptor δ (PPARδ), were determined by western blot and real time polymerase chain reaction, respectively. A. indica flower extract inhibited pancreatic cholesterol esterase activity and increased cholesterol micelles size. Uptake of cholesterol into Caco-2 cells was inhibited by A. indica flower extract in a dose-dependent manner. In addition, A. indica extract inhibited HMG-CoA reductase activity, resulting in low level of intracellular cholesterol accumulation, together with increased cytosolic NPC1L1 protein expression and decreased PPARδ gene expression. In conclusion, A. indica flower extract has cholesterol-lowering effects by inhibiting intestinal cholesterol absorption, interfering micellar cholesterol formation, and attenuating cholesterol synthesis. As such, A. indica flower extract has potential for developing into nutraceutical product for prevention of hypocholesterolemia.
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Affiliation(s)
- Acharaporn Duangjai
- Division of Physiology, School of Medical Sciences, University of Phayao, Phayao, Thailand
| | - Atcharaporn Ontawong
- Division of Physiology, School of Medical Sciences, University of Phayao, Phayao, Thailand.,Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Chutima Srimaroeng
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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25
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Takata K, Nicholls SJ. Tackling Residual Atherosclerotic Risk in Statin-Treated Adults: Focus on Emerging Drugs. Am J Cardiovasc Drugs 2019; 19:113-131. [PMID: 30565156 DOI: 10.1007/s40256-018-0312-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Epidemiological studies and meta-analyses have consistently suggested the importance of lowering low-density lipoprotein cholesterol (LDL-C) to reduce cardiovascular (CV) events. However, these studies and mechanistic studies using intracoronary imaging modalities have reported patients who continue to experience CV events or disease progression despite optimal LDL-C levels on statins. These findings, including statin intolerance, have highlighted the importance of exploring additional potential therapeutic targets to reduce CV risk. Genomic insights have presented a number of additional novel targets in lipid metabolism. In particular, proprotein convertase subtilisin/kexin type 9 inhibitors have rapidly developed and recently demonstrated their beneficial impact on CV outcomes. Triglyceride (TG)-rich lipoproteins have been recently reported as a causal factor of atherosclerotic cardiovascular disease (ASCVD). Indeed, several promising TG-targeting therapies are being tested at various clinical stages. In this review, we present the evidence to support targeting atherogenic lipoproteins to target residual ASCVD risk in statin-treated patients.
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Affiliation(s)
- Kohei Takata
- South Australian Health and Medical Research Institute, SAHMRI North Terrace, Adelaide, SA, 5001, Australia
| | - Stephen J Nicholls
- South Australian Health and Medical Research Institute, SAHMRI North Terrace, Adelaide, SA, 5001, Australia.
- University of Adelaide, Adelaide, SA, Australia.
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26
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Macchi C, Banach M, Corsini A, Sirtori CR, Ferri N, Ruscica M. Changes in circulating pro-protein convertase subtilisin/kexin type 9 levels - experimental and clinical approaches with lipid-lowering agents. Eur J Prev Cardiol 2019; 26:930-949. [PMID: 30776916 DOI: 10.1177/2047487319831500] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Regulation of pro-protein convertase subtilisin/kexin type 9 (PCSK9) by drugs has led to the development of a still small number of agents with powerful activity on low-density lipoprotein cholesterol levels, associated with a significant reduction of cardiovascular events in patients in secondary prevention. The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) and Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY OUTCOMES) studies, with the two available PCSK9 antagonists, i.e. evolocumab and alirocumab, both reported a 15% reduction in major adverse cardiovascular events. Regulation of PCSK9 expression is dependent upon a number of factors, partly genetic and partly associated to a complex transcriptional system, mainly controlled by sterol regulatory element binding proteins. PCSK9 is further regulated by concomitant drug treatments, particularly by statins, enhancing PCSK9 secretion but decreasing its stimulatory phosphorylated form (S688). These complex transcriptional mechanisms lead to variable circulating levels making clinical measurements of plasma PCSK9 for cardiovascular risk assessment a debated matter. Determination of total PCSK9 levels may provide a diagnostic tool for explaining an apparent resistance to PCSK9 inhibitors, thus indicating the need for other approaches. Newer agents targeting PCSK9 are in clinical development with a major interest in those with a longer duration of action, e.g. RNA silencing, allowing optimal patient compliance. Interest has been expanded to areas not only limited to low-density lipoprotein cholesterol reduction but also investigating other non-lipid pathways raising cardiovascular risk, in particular inflammation associated to raised high-sensitivity C-reactive protein levels, not significantly affected by the present PCSK9 antagonists.
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Affiliation(s)
- C Macchi
- 1 Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy
| | - M Banach
- 2 Department of Hypertension, Medical University of Lodz, Poland.,3 Polish Mother's Memorial Hospital Research Institute (PMMHRI), Poland.,4 Cardiovascular Research Centre, University of Zielona Gora, Poland
| | - A Corsini
- 1 Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy.,5 Multimedica IRCCS, Italy
| | - C R Sirtori
- 6 Dyslipidemia Center, A.S.S.T. Grande Ospedale Metropolitano Niguarda, Italy
| | - N Ferri
- 7 Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Italy
| | - M Ruscica
- 1 Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy
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Ito SM, Yamanashi Y, Takada T, Suzuki H. Clinical Importance of Drug-Drug Interaction Between Warfarin and Prednisolone and Its Potential Mechanism in Relation to the Niemann-Pick C1-Like 1-Mediated Pathway. Circ J 2019; 83:471-480. [PMID: 30568065 DOI: 10.1253/circj.cj-18-0807] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
BACKGROUND Warfarin is an anticoagulant drug used to prevent thromboembolic disorders, but its pharmacological effect is affected by co-administered drugs. Therefore, careful management of warfarin-related drug-drug interactions (DDIs) is necessary for its safety and effectiveness. Recently, intestinal vitamin K1absorption through the Niemann-Pick C1-like 1 (NPC1L1)-mediated pathway was found to affect the pharmacological effect of warfarin. This study aimed to identify high-frequency warfarin-related DDIs in a clinical setting and elucidate their mechanism(s) in terms of changes in NPC1L1 expression and/or activity. METHODS AND RESULTS Prednisolone was the most frequently suspected drug in retrospective surveys of medical records of patients who experienced warfarin-related DDIs. Prednisolone significantly increased the international normalized ratio of prothrombin time (PT-INR) values in warfarin-treated patients. To demonstrate the involvement of NPC1L1 in warfarin-prednisolone DDI, we conducted an in vitro vitamin K1uptake assay using NPC1L1-overexpressing cells and found that prednisolone inhibited NPC1L1-mediated vitamin K1uptake. Additionally, we found that prednisolone downregulates NPC1L1 in a glucocorticoid receptor α-dependent manner. CONCLUSIONS Co-administration of warfarin and prednisolone frequently enhanced the anticoagulant effect of warfarin in a clinical setting. Prednisolone-mediated suppression of NPC1L1 expression and activity could be the mechanism of DDI between warfarin and prednisolone. To manage warfarin therapy, the potential of concomitant drugs to change its anticoagulant effect through NPC1L1-related mechanisms merits consideration.
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Affiliation(s)
- Sayo M Ito
- Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo
| | - Yoshihide Yamanashi
- Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo
| | - Tappei Takada
- Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo
| | - Hiroshi Suzuki
- Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo
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Erchen Decoction Ameliorates Lipid Metabolism by the Regulation of the Protein CAV-1 and the Receptors VLDLR, LDLR, ABCA1, and SRB1 in a High-Fat Diet Rat Model. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:5309490. [PMID: 30402126 PMCID: PMC6196931 DOI: 10.1155/2018/5309490] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 09/07/2018] [Accepted: 09/24/2018] [Indexed: 12/18/2022]
Abstract
Lipid metabolism disorder is a common metabolic disorder characterized by abnormal lipid levels in blood. Erchen decoction (ECD) is a traditional Chinese medicine prescription, which is used for the treatment of diseases caused by retention of phlegm dampness. It has been reported to ameliorate the disorder of lipid metabolism. The aim of the present study was to investigate the effects and underlying mechanisms of ECD in lipid metabolism disorder induced by a high-fat diet (HFD) in rats. ECD (4.35g/kg/d) and atorvastatin (10mg/kg/d, positive control) were orally administered to HFD-fed rats for four weeks. The parameters, food, water consumption, body weight, body length, liver, and visceral fat weight and the content of serum lipids and lipid transporters were assessed. The effects of ECD on the mRNA and protein expression levels of lipid transport factors were measured by real-time PCR and western blotting. The present study demonstrated that ECD improved the disorders of serum lipid and lipid transporters in HFD-fed rats, TG (0.70±0.08 mmol/L, p<0.01), LDL-C (1.50±0.19 mmol/L, p<0.01), LDL (1.38±0.21 mmol/L, p<0.05), and oxLDL (1.77±0.39 ng/mL, p<0.05) were downregulated, while HDL-C (0.87±0.13 mmol/L, p<0.01), FFA (0.62±0.13 mmol/L, p<0.05), HDL (38.8±4.0 mg/dL, p<0.05), and CETP (903.6±120.0 ng/mL, p<0.05) were upregulated. But ECD obviously had no effects on the indices food/water/energy intake, body/tissue (liver and fat) weight, and BMI (p>0.05). Concomitantly, ECD reversed the abnormal expressions of those lipid transport factors in the liver and visceral fat.
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Martin JM, Cuesta A, Velasco R, Herrero A, Ramon D, Monteagudo C. Two-year-old girl with tuberous xanthomas. J Clin Pathol 2018; 71:860-862. [DOI: 10.1136/jclinpath-2017-204818] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 04/14/2018] [Accepted: 04/16/2018] [Indexed: 11/03/2022]
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Yamanashi Y, Takada T, Suzuki H. Associations between Lifestyle-Related Diseases and Transporters Involved in Intestinal Absorption and Biliary Excretion of Cholesterol. Biol Pharm Bull 2018; 41:1-10. [PMID: 29311470 DOI: 10.1248/bpb.b17-00690] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Westernization of dietary habits leads to an increase in lipid intake and is thought to be responsible for an increase in patients with dyslipidemia. It is a well-known fact that the impaired cholesterol homeostasis is closely related to the development of various lifestyle-related diseases such as fatty liver, diabetes, and gallstone as well as dyslipidemia leading to atherosclerosis and cardiovascular diseases such as heart attack and stroke. Therefore, appropriate management of cholesterol levels in the body is considered important in prevention and treatments of these lifestyle-related diseases and in addition, molecular mechanisms controlling plasma (and/or hepatic) cholesterol levels have been intensively studied. Due to its hydrophobicity, cholesterol was long believed to pass through cell membranes by passive diffusion. However, recent studies have identified a number of plasma membrane transporters that are responsible for the cellular uptake or efflux of cholesterol and involved in developments of lifestyle-related diseases. In this review, we focus on Niemann-Pick C1 Like 1 (NPC1L1) and a heterodimer of ATP-binding cassette transporter G5 and G8 (ABCG5/G8), both of which are responsible for intestinal cholesterol absorption and biliary cholesterol secretion, and discuss the relationship between these cholesterol transporters and lifestyle-related diseases. In addition, we also discuss the related uncertainties that need to be explored in future studies.
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Affiliation(s)
- Yoshihide Yamanashi
- Department of Pharmacy, the University of Tokyo Hospital, Faculty of Medicine, the University of Tokyo
| | - Tappei Takada
- Department of Pharmacy, the University of Tokyo Hospital, Faculty of Medicine, the University of Tokyo
| | - Hiroshi Suzuki
- Department of Pharmacy, the University of Tokyo Hospital, Faculty of Medicine, the University of Tokyo
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Drouin-Chartier JP, Tremblay AJ, Lemelin V, Lamarche B, Couture P. Differential associations between plasma concentrations of insulin and glucose and intestinal expression of key genes involved in chylomicron metabolism. Am J Physiol Gastrointest Liver Physiol 2018; 315:G177-G184. [PMID: 29698057 DOI: 10.1152/ajpgi.00108.2018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The mechanisms underlying the oversecretion of apolipoprotein (apo)B-48-containing triglyceride-rich lipoproteins (TRL) in insulin-resistance (IR) states in humans remain to be fully understood. The objective of this study was to evaluate the association between the plasma levels of insulin and glucose and the intestinal expression of key genes involved in chylomicron metabolism in a large sample of nondiabetic men displaying various degrees of IR. Duodenal biopsies were obtained by gastroduodenoscopy in 127 men free of intestinal disease. Gene expression was measured using quantitative PCR in duodenal samples. Plasma insulin and glucose concentrations were measured in the fasting state. Postprandial TRL apoB-48 kinetics were measured using a primed-constant infusion of l-[5,5,5-D3]leucine for 12 h in a subgroup of 75 subjects maintained in a constant fed state. Plasma insulin levels were negatively associated with intestinal expression of ACS1 (standard β = -0.20, P = 0.007), DGAT1 (β = -0.18, P = 0.001), DGAT2 (β = -0.20, P = 0.02), and MTP (β = -0.27, P = 0.0005), whereas glucose levels were positively associated with MTP expression (β = 0.15, P = 0.04) independent of age, BMI, waist circumference, dietary intake, and duodenal expression of SREBP1c. Insulin levels, but not glucose concentrations, were positively correlated with postprandial TRL apoB-48 production rate ( r = 0.24, P = 0.04) and pool size ( r = 0.27, P = 0.03). In conclusion, plasma insulin and glucose levels are differentially associated with the expression of key genes involved in chylomicron metabolism. These results suggest that alterations in intestinal lipoprotein metabolism associated with IR may be regulated by plasma levels of both insulin and glucose concurrently and are therefore likely modified by the onset of insulin insufficiency. NEW & NOTEWORTHY We demonstrate that plasma insulin and glucose levels are differentially associated with the expression of key genes involved in chylomicron metabolism in men. For instance, intestinal expression of MTP is negatively associated with plasma insulin concentrations and positively associated with plasma glucose concentrations. Alterations in intestinal lipoprotein metabolism associated with insulin resistance may be regulated by plasma levels of both insulin and glucose concurrently and are therefore likely modified by the onset of insulin insufficiency.
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Affiliation(s)
| | - André J Tremblay
- Institute of Nutrition and Functional Foods, Laval University , Quebec City, Quebec , Canada
| | - Valéry Lemelin
- Department of Gastroenterology, Centre hospitalier universitaire de Québec-Laval University , Quebec City, Quebec , Canada
| | - Benoît Lamarche
- Institute of Nutrition and Functional Foods, Laval University , Quebec City, Quebec , Canada
| | - Patrick Couture
- Institute of Nutrition and Functional Foods, Laval University , Quebec City, Quebec , Canada.,Lipid Research Centre, Centre hospitalier universitaire de Québec-Laval University , Quebec City, Quebec , Canada
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Afonso MS, Machado RM, Lavrador MS, Quintao ECR, Moore KJ, Lottenberg AM. Molecular Pathways Underlying Cholesterol Homeostasis. Nutrients 2018; 10:E760. [PMID: 29899250 PMCID: PMC6024674 DOI: 10.3390/nu10060760] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Revised: 06/10/2018] [Accepted: 06/11/2018] [Indexed: 01/14/2023] Open
Abstract
Cholesterol is an essential molecule that exerts pleiotropic actions. Although its presence is vital to the cell, its excess can be harmful and, therefore, sustaining cholesterol homeostasis is crucial to maintaining proper cellular functioning. It is well documented that high plasma cholesterol concentration increases the risk of atherosclerotic heart disease. In the last decades, several studies have investigated the association of plasma cholesterol concentrations and the risk of cardiovascular diseases as well as the signaling pathways involved in cholesterol homeostasis. Here, we present an overview of several mechanisms involved in intestinal cholesterol absorption, the regulation of cholesterol synthesis and uptake. We also discuss the importance of reverse cholesterol transport and transintestinal cholesterol transport to maintain cholesterol homeostasis and prevent atherosclerosis development. Additionally, we discuss the influence of dietary cholesterol on plasma cholesterol concentration and the new recommendations for cholesterol intake in a context of a healthy dietary pattern.
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Affiliation(s)
- Milessa Silva Afonso
- Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
| | - Roberta Marcondes Machado
- Laboratorio de Lipides (LIM 10), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP 05403-000, Brazil.
| | - Maria Silvia Lavrador
- Laboratorio de Lipides (LIM 10), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP 05403-000, Brazil.
| | - Eder Carlos Rocha Quintao
- Laboratorio de Lipides (LIM 10), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP 05403-000, Brazil.
| | - Kathryn J Moore
- Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
- Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
| | - Ana Maria Lottenberg
- Laboratorio de Lipides (LIM 10), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP 05403-000, Brazil.
- Faculdade Israelita de Ciências da Saúde, Albert Einstein, São Paulo, SP 05403-000, Brazil.
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Malhotra P, Aloman C, Ankireddy A, Khadra H, Ooka K, Gill RK, Saksena S, Dudeja PK, Alrefai WA. Overactivation of intestinal sterol response element-binding protein 2 promotes diet-induced nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2017; 313:G376-G385. [PMID: 28774869 PMCID: PMC5792218 DOI: 10.1152/ajpgi.00174.2017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 07/28/2017] [Accepted: 07/28/2017] [Indexed: 01/31/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation in the liver that may progress to hepatic fibrosis and nonalcoholic steatohepatitis (NASH). Mechanisms underlying NAFLD and NASH are not yet fully understood. Dietary cholesterol was recently shown to be a risk factor for the development of NASH, suggesting a role for intestinal handling of cholesterol. One important regulator of cholesterol homeostasis is the sterol response element-binding protein-2 (SREBP-2) transcription factor. We tested the hypothesis that the overactivation of intestinal SREBP-2 increases the susceptibility to diet-induced NASH. A transgenic mouse model with intestine-specific overexpression of active SREBP-2 (ISR2 mice) driven by villin promoter was used. ISR2 mice and their wild-type littermates were fed a regular chow diet or a high-fat, high-cholesterol (HFHC) diet (15% fat, 1% cholesterol) for 15 wk. Results showed that HFHC feeding to ISR2 mice caused hepatic inflammation with increased levels of proinflammatory cytokines. Histological examination demonstrated extensive fibrosis after a HFHC diet associated with a perivascular as well as pericellular collagen deposits in ISR2 mice compared with wild-type littermates. The severe hepatic inflammation and advanced fibrosis in ISR2 mice was not associated with a difference in lipid accumulation in ISR2 mice compared with wild type littermates after HFHC feeding. These data indicate that overactivation of intestinal SREBP2 promotes diet-induced hepatic inflammation with features of human NASH resulting in rapid severe fibrosis and provide a novel link between regulatory processes of intestinal cholesterol and progression of fatty liver.NEW & NOTEWORTHY The current study highlights the role of overactivation of intestinal SREBP-2 transcription factor in the progression of hepatic fibrosis associated with diet-induced NASH. Mice with intestine-specific overexpression of SREBP-2 demonstrated more inflammation and severe fibrosis in the liver in response to 15 wk of being fed a high-cholesterol, high-fat diet as compared with their wild-type littermates. These data demonstrate a novel link between intestinal regulatory processes of cholesterol metabolism and the pathogenesis of fatty liver diseases.
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Affiliation(s)
- Pooja Malhotra
- 2Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and
| | | | - Aparna Ankireddy
- 2Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and
| | - Hani Khadra
- 2Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and
| | - Kohtaro Ooka
- 3Rush University Medical Center, Chicago, Illinois
| | - Ravinder K. Gill
- 2Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and
| | - Seema Saksena
- 1Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois; ,2Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and
| | - Pradeep K. Dudeja
- 1Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois; ,2Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and
| | - Waddah A. Alrefai
- 1Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois; ,2Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; and
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El-Tamalawy MM, Ibrahim OM, Hassan TM, El-Barbari AA. Effect of Combination Therapy of Ezetimibe and Atorvastatin on Remnant Lipoprotein Versus Double Atorvastatin Dose in Egyptian Diabetic Patients. J Clin Pharmacol 2017; 58:34-41. [PMID: 28858387 DOI: 10.1002/jcph.976] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 06/05/2017] [Indexed: 11/10/2022]
Abstract
A high level of remnant lipoprotein cholesterol (RLP-C) is a predominant feature in diabetic patients with atherosclerosis. This study aimed to investigate the effect of ezetimibe added to statin therapy compared to doubling standard statin dose. Sixty-five eligible patients were recruited then prospectively randomized to receive ezetimibe 10 mg/day plus their 40 mg daily atorvastatin dose (group 1) or atorvastatin 80 mg/day (group 2) for 3 months. Efficacy was evaluated using plasma levels of RLP-C, apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL), percentage of brachial artery flow-mediated dilation, and lipid profile. Forty patients completed the study and provided efficacy data. Group 1 showed more reduction in RLP-C (45.7% vs 31.7%, P = .02), apolipoprotein B (28.5% vs 9.5%, P = .01), total cholesterol (34.7% vs 24.6%, P = .003), triglycerides (49% vs 24.4%, P = .000), non-HDL (49.3% vs 33%, P = .002), and low-density lipoprotein cholesterol (49.6% vs 35.2%, P = .02) compared to group 2. Group 1 showed a greater increase in HDL (66% vs 35%, P = .002); and flow-mediated dilation (30% vs 17%, P = .01) compared to group 2. It is concluded that adding ezetimibe 10 mg to atorvastatin 40 mg may be a better choice than doubling atorvastatin dose in improving RLPs, endothelial function, and lipid profile in diabetic cardiovascular patients who could not achieve their therapeutic treatment goals with the standard atorvastatin dose.
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Affiliation(s)
| | | | | | - Ali Ali El-Barbari
- Diagnostic Radiology Department, College of Medicine, Tanta University, Tanta, Egypt
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Nozue T. Lipid Lowering Therapy and Circulating PCSK9 Concentration. J Atheroscler Thromb 2017; 24:895-907. [PMID: 28804094 PMCID: PMC5587514 DOI: 10.5551/jat.rv17012] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 07/20/2017] [Indexed: 12/22/2022] Open
Abstract
Hypercholesterolemia, particularly an increase in low-density lipoprotein cholesterol (LDL-C) levels, contributes substantially to the development of coronary artery disease and the risk for cardiovascular events. As the first-line pharmacotherapy, statins have been shown to reduce both LDL-C levels and cardiovascular events. However, despite intensive statin therapy, a sizable proportion of statin-treated patients are unable to achieve the recommended target LDL-C levels, and not all patients can avoid future cardiovascular events. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis by enhancing the degradation of hepatic low-density lipoprotein receptor (LDLR). Owing to its importance in lipid metabolism, PCSK9 has emerged as a novel pharmacological target for lowering LDL-C levels. In this review, the potential role of circulating PCSK9 as a new biomarker of lipid metabolism is described. Next, previous studies evaluating the effects of lipid-modifying pharmacological agents, particularly statins, on circulating PCSK9 concentrations are summarized. Statins decrease hepatic intracellular cholesterol, resulting in increased LDLRs as well as increased PCSK9 protein. There is a clear dose-response effect of statin treatment on PCSK9 level, as increasing doses of statins also increase the level of circulating PCSK9. Finally, the available therapeutic strategies to inhibit PCSK9 are present. Monoclonal antibodies against PCSK9, in combination with statins, are one of the most promising and novel approaches to achieve further reduction of LDL-C levels and reduce the risk of cardiovascular events.
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Affiliation(s)
- Tsuyoshi Nozue
- Division of Cardiology, Department of Internal Medicine, Yokohama Sakae Kyosai Hospital, Yokohama, Japan
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36
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Yamanashi Y, Takada T, Kurauchi R, Tanaka Y, Komine T, Suzuki H. Transporters for the Intestinal Absorption of Cholesterol, Vitamin E, and Vitamin K. J Atheroscler Thromb 2017; 24:347-359. [PMID: 28100881 PMCID: PMC5392472 DOI: 10.5551/jat.rv16007] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Humans cannot synthesize fat-soluble vitamins such as vitamin E and vitamin K. For this reason, they must be obtained from the diet via intestinal absorption. As the deficiency or excess of these vitamins has been reported to cause several types of diseases and disorders in humans, the intestinal absorption of these nutrients must be properly regulated to ensure good health. However, the mechanism of their intestinal absorption remains poorly understood. Recent studies on cholesterol using genome-edited mice, genome-wide association approaches, gene mutation analyses, and the development of cholesterol absorption inhibitors have revealed that several membrane proteins play crucial roles in the intestinal absorption of cholesterol. Surprisingly, detailed analyses of these cholesterol transporters have revealed that they can also transport vitamin E and vitamin K, providing clues to uncover the molecular mechanisms underlying the intestinal absorption of these fat-soluble vitamins. In this review, we focus on the membrane proteins (Niemann-Pick C1 like 1, scavenger receptor class B type I, cluster of differentiation 36, and ATP-binding cassette transporter A1) that are (potentially) involved in the intestinal absorption of cholesterol, vitamin E, and vitamin K and discuss their physiological and pharmacological importance. We also discuss the related uncertainties that need to be explored in future studies.
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Affiliation(s)
- Yoshihide Yamanashi
- Department of Pharmacy, the University of Tokyo Hospital, Faculty of Medicine, the University of Tokyo
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Abstract
PURPOSE Chronic kidney disease (CKD) is accompanied by a number of secondary metabolic dysregulations, such as lipid abnormalities, presenting with unique characteristics. Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors have been introduced as the new era in the management of dyslipidemia with promising results in groups with refractory lipid abnormalities. Increasing number of studies investigate the possible association of PCSK9 levels with kidney function, especially with nephrotic range proteinuria, as well as its role as a prognostic cardiovascular risk marker in CKD. In this review, we discuss the existing evidence for PCSK9 levels in patient groups with nephrotic syndrome, non-dialysis CKD, end-stage renal disease and kidney transplantation. METHODS Online research was conducted in MEDLINE database to identify articles investigating PCSK9 in all different aspects of CKD. References from relevant studies were screened for supplementary articles. RESULTS Four cross-sectional studies, one secondary analysis, one publication from two independent cohort studies and one multicentre prospective cohort study assessed PCSK9 plasma levels in different subgroups of CKD patients. PCSK9 levels increase in nephrotic syndrome and have a positive correlation with proteinuria. In CKD patients, no correlation was found between PCSK9 levels and estimated GFR. Peritoneal dialysis patients have higher PCSK9 levels compared with hemodialysis and renal transplant patients as well as general population. CONCLUSION Accumulative evidence focuses on the possible association of PCSK9 levels with kidney function. No data are available for the administration of PCSK9 inhibitors in CKD patients. Further research will optimize knowledge on the role of PCSK9 levels and PCSK9 inhibitors in CKD.
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Quinlivan VH, Farber SA. Lipid Uptake, Metabolism, and Transport in the Larval Zebrafish. Front Endocrinol (Lausanne) 2017; 8:319. [PMID: 29209275 PMCID: PMC5701920 DOI: 10.3389/fendo.2017.00319] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 11/01/2017] [Indexed: 01/08/2023] Open
Abstract
The developing zebrafish is a well-established model system for studies of energy metabolism, and is amenable to genetic, physiological, and biochemical approaches. For the first 5 days of life, nutrients are absorbed from its endogenous maternally deposited yolk. At 5 days post-fertilization, the yolk is exhausted and the larva has a functional digestive system including intestine, liver, gallbladder, pancreas, and intestinal microbiota. The transparency of the larval zebrafish, and the genetic and physiological similarity of its digestive system to that of mammals make it a promising system in which to address questions of energy homeostasis relevant to human health. For example, apolipoprotein expression and function is similar in zebrafish and mammals, and transgenic animals may be used to examine both the transport of lipid from yolk to body in the embryo, and the trafficking of dietary lipids in the larva. Additionally, despite the identification of many fatty acid and lipid transport proteins expressed by vertebrates, the cell biological processes that mediate the transport of dietary lipids from the intestinal lumen to the interior of enterocytes remain to be elucidated. Genetic tractability and amenability to live imaging and a range of biochemical methods make the larval zebrafish an ideal model in which to address open questions in the field of lipid transport, energy homeostasis, and nutrient metabolism.
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Affiliation(s)
- Vanessa H. Quinlivan
- Carnegie Institution for Science (CIS), Baltimore, MD, United States
- The Johns Hopkins University, Baltimore, MD, United States
| | - Steven A. Farber
- Carnegie Institution for Science (CIS), Baltimore, MD, United States
- The Johns Hopkins University, Baltimore, MD, United States
- *Correspondence: Steven A. Farber,
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Drouin-Chartier JP, Tremblay AJ, Lemelin V, Lépine MC, Lamarche B, Couture P. Ezetimibe increases intestinal expression of the LDL receptor gene in dyslipidaemic men with insulin resistance. Diabetes Obes Metab 2016; 18:1226-1235. [PMID: 27460541 DOI: 10.1111/dom.12749] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 07/11/2016] [Accepted: 07/21/2016] [Indexed: 01/25/2023]
Abstract
AIM To gain further insight into intestinal cholesterol homeostasis in dyslipidaemic men with insulin resistance (IR) by examining the impact of treatment with ezetimibe on the expression of key genes involved in cholesterol synthesis and LDL receptor (R)-mediated uptake of lipoproteins. METHODS A total of 25 men with dyslipidaemia and IR were recruited to participate in this double-blind, randomized, crossover, placebo-controlled trial. Participants received 10 mg/day ezetimibe or placebo for periods of 12 weeks each. Intestinal gene expression was measured by quantitative PCR in duodenal biopsy samples collected by gastroduodenoscopy at the end of each treatment. RESULTS A total of 20 participants completed the protocol. Treatment with ezetimibe significantly increased intestinal LDLR (+16.2%; P = .01), 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoAR; +14.0%; P = .04) and acetyl-Coenzyme A acetyltransferase 2 (ACAT-2) mRNA expression (+12.5%; P = .03). Changes in sterol regulatory element-binding transcription factor 2 (SREBP-2) expression were significantly correlated with changes in HMG-CoAR (r = 0.55; P < .05), ACAT-2 (r = 0.69; P < .001) and proprotein convertase substilisin/kexin type 9 (PCSK9) expression (r = 0.45; P < .05). CONCLUSIONS These results show that inhibition of intestinal cholesterol absorption by ezetimibe increases expression of the LDLR gene, supporting the concept that increased LDL clearance with ezetimibe treatment occurs not only in the liver but also in the small intestine.
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Affiliation(s)
| | - André J Tremblay
- Department of Medicine, Institute of Nutrition and Functional Foods, Laval University, Quebec City, Canada
| | - Valéry Lemelin
- Department of Gastroenterology, CHU de Québec-Université Laval, Quebec City, Canada
| | - Marie-Claude Lépine
- Department of Medicine, Institute of Nutrition and Functional Foods, Laval University, Quebec City, Canada
| | - Benoît Lamarche
- Department of Medicine, Institute of Nutrition and Functional Foods, Laval University, Quebec City, Canada
| | - Patrick Couture
- Department of Medicine, Institute of Nutrition and Functional Foods, Laval University, Quebec City, Canada
- Department of Medicine, Lipid Research Center, CHU de Québec-Université Laval, Quebec City, Canada
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40
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Smit RA, Postmus I, Trompet S, Barnes MR, Warren H, Arsenault BJ, Chasman DI, Cupples LA, Hitman GA, Krauss RM, Li X, Psaty BM, Stein CM, Rotter JI, Jukema JW. Rooted in risk: genetic predisposition for low-density lipoprotein cholesterol level associates with diminished low-density lipoprotein cholesterol response to statin treatment. Pharmacogenomics 2016; 17:1621-1628. [PMID: 27648687 DOI: 10.2217/pgs-2016-0091] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIMS To utilize previously reported lead SNPs for low-density lipoprotein cholesterol (LDL-c) levels to find additional loci of importance to statin response, and examine whether genetic predisposition to LDL-c levels associates with differential statin response. METHODS We investigated effects on statin response of 59 LDL-c SNPs, by combining summary level statistics from the Global Lipids Genetics and Genomic Investigation of Statin Therapy consortia. RESULTS Lead SNPs for APOE, SORT1 and NPC1L1 were associated with a decreased LDL-c response to statin treatment, as was overall genetic predisposition for increased LDL-c levels as quantified with 59 SNPs, with a 5.4% smaller statin response per standard deviation increase in genetically raised LDL-c levels. CONCLUSION Genetic predisposition for increased LDL-c level may decrease efficacy of statin therapy.
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Affiliation(s)
- Roelof Aj Smit
- Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.,Section of Gerontology & Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Iris Postmus
- Section of Gerontology & Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Stella Trompet
- Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.,Section of Gerontology & Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Michael R Barnes
- William Harvey Research Institute, Barts & The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK.,NIHR Barts Cardiovascular Biomedical Research Unit, Barts & The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK
| | - Helen Warren
- William Harvey Research Institute, Barts & The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK.,NIHR Barts Cardiovascular Biomedical Research Unit, Barts & The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK
| | - Benoit J Arsenault
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada
| | - Daniel I Chasman
- Division of Preventive Medicine, Brigham & Women's Hospital, Boston, MA 02215, USA.,Harvard Medical School, Harvard University, Boston, MA 02115, USA
| | - L Adrienne Cupples
- Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.,National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA 01702-5827, USA
| | - Graham A Hitman
- Blizard Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Ronald M Krauss
- Department of Atherosclerosis Research, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA
| | - Xiaohui Li
- Institute for Translational Genomics & Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Bruce M Psaty
- Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology & Health Services, University of Washington, Seattle, WA 98101, USA.,Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA
| | - Charles M Stein
- Department of Medicine, Vanderbilt University, Nashville, TN 37232-6602, USA.,Department of Pharmacology, Vanderbilt University, Nashville, TN 37232-6602, USA
| | - Jerome I Rotter
- Institute for Translational Genomics & Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - J Wouter Jukema
- Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.,Interuniversity Cardiology Institute Netherlands, Utrecht, The Netherlands
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41
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Hashikata T, Yamaoka-Tojo M, Kakizaki R, Nemoto T, Fujiyoshi K, Namba S, Kitasato L, Hashimoto T, Ishii S, Kameda R, Shimohama T, Tojo T, Ako J. Ezetimibe enhances and stabilizes anticoagulant effect of warfarin. Heart Vessels 2016; 32:47-54. [PMID: 27052207 DOI: 10.1007/s00380-016-0832-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 03/25/2016] [Indexed: 01/02/2023]
Abstract
Ezetimibe reduces plasma levels of low-density lipoprotein cholesterol by inhibiting Niemann-Pick C1-like protein 1 (NPC1L1). A recent study demonstrated that NPC1L1 plays an important role in absorption of fat-soluble vitamins including vitamin K. We evaluated whether the add-on treatment of ezetimibe affects anticoagulation in patients taking warfarin. Between October 2007 and March 2015, the administration of ezetimibe was started to a total of 101 outpatients who were already on oral anticoagulation with warfarin. We retrospectively analyzed blood lipid levels, prothrombin time international normalized ratio (PT-INR) and time in therapeutic INR range (TTR). Seventy-one patients (70 %) showed increase in PT-INR after ezetimibe treatment (1.96 ± 0.45 to 2.20 ± 0.61, p < 0.001). It was necessary to reduce the warfarin dose in 9 of 101 patients for clinical indication. There was a significant positive correlation between change in PT-INR and statin usage at baseline (p = 0.03). The mean value of changes in PT-INR of patients with taking statin was significantly larger than that of patients without taking statin (0.34 ± 0.54 vs. 0.06 ± 0.36, p = 0.03). There was an increase in the TTR (52 ± 26 to 61 ± 23 %, p < 0.0001) and a decrease in the frequency to change the dose of warfarin after the ezetimibe treatment [45 times of 735 examination days (6 %) to 20 times of 695 examination days (3 %), p = 0.02]. Our data suggest possible drug interaction between warfarin and ezetimibe. Ezetimibe may increase and stabilize the anticoagulant effect of warfarin, especially in patients taking statins.
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Affiliation(s)
- Takehiro Hashikata
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan.
| | - Minako Yamaoka-Tojo
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan.,Department of Rehabilitation, Kitasato University School of Allied Health Sciences, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan
| | - Ryota Kakizaki
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Teruyoshi Nemoto
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Kazuhiro Fujiyoshi
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Sayaka Namba
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Lisa Kitasato
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Takuya Hashimoto
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Shunsuke Ishii
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Ryo Kameda
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Takao Shimohama
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Taiki Tojo
- Department of Rehabilitation, Kitasato University School of Allied Health Sciences, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan
| | - Junya Ako
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Japan
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42
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Sahebkar A, Simental-Mendía LE, Guerrero-Romero F, Golledge J, Watts GF. Effect of statin therapy on plasma proprotein convertase subtilisin kexin 9 (PCSK9) concentrations: a systematic review and meta-analysis of clinical trials. Diabetes Obes Metab 2015; 17:1042-55. [PMID: 26183252 DOI: 10.1111/dom.12536] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 06/24/2015] [Accepted: 07/02/2015] [Indexed: 02/03/2023]
Abstract
AIMS To evaluate the magnitude of the effect of statin therapy on plasma proprotein convertase subtilisin kexin 9 (PCSK9) levels through a systematic review and meta-analysis of clinical trials. METHODS A random-effects model (using DerSimonian-Laird method) and the generic inverse variance method were used for quantitative data synthesis. Heterogeneity was quantitatively assessed using the I(2) index. Sensitivity analyses were conducted using the one-study remove approach. Random-effects meta-regression was performed using an unrestricted maximum likelihood method to evaluate the association between statin-induced elevation of plasma PCSK9 concentrations with duration of treatment and magnitude of LDL cholesterol reduction. RESULTS A total of 15 clinical trials examining the effects of statin therapy on plasma PCSK9 levels were included. Meta-analysis of data from single-arm statin treatment arms [weighted mean difference (WMD) 40.72 ng/ml, 95% confidence interval (CI) 34.79, 46.65; p < 0.001] and randomized placebo-controlled trials (WMD 22.98 ng/ml, 95% CI 17.95, 28.01; p < 0.001) showed a significant increase in plasma PCSK9 concentrations after statin therapy, irrespective of the type of statin administered in either of the analyses (single-arm or randomized placebo-controlled trial). There was no significant elevation of plasma PCSK9 levels with statin/ezetimibe combination therapy compared with statin monotherapy (WMD 23.14 ng/ml, 95% CI -1.97, 48.25; p = 0.071); however, removal of one study in the meta-analysis yielded a significant result in the sensitivity analysis (WMD 31.41 ng/ml, 95% CI 7.86, 54.97; p = 0.009). CONCLUSIONS This meta-analysis suggests that statin therapy causes a significant increase in plasma PCSK9 concentrations.
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Affiliation(s)
- A Sahebkar
- Biotechnology Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Research Centre, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia
| | - L E Simental-Mendía
- Biomedical Research Unit, Mexican Social Security Institute, Durango, Mexico
| | - F Guerrero-Romero
- Biomedical Research Unit, Mexican Social Security Institute, Durango, Mexico
| | - J Golledge
- Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University Townsville, Townsville, Queensland, Australia
- Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Queensland, Australia
| | - G F Watts
- Lipid Disorders Clinic, Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia
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43
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Guan HP, Yang X, Lu K, Wang SP, Castro-Perez JM, Previs S, Wright M, Shah V, Herath K, Xie D, Szeto D, Forrest G, Xiao JC, Palyha O, Sun LP, Andryuk PJ, Engel SS, Xiong Y, Lin S, Kelley DE, Erion MD, Davis HR, Wang L. Glucagon receptor antagonism induces increased cholesterol absorption. J Lipid Res 2015; 56:2183-95. [PMID: 26373568 DOI: 10.1194/jlr.m060897] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Indexed: 12/26/2022] Open
Abstract
Glucagon and insulin have opposing action in governing glucose homeostasis. In type 2 diabetes mellitus (T2DM), plasma glucagon is characteristically elevated, contributing to increased gluconeogenesis and hyperglycemia. Therefore, glucagon receptor (GCGR) antagonism has been proposed as a pharmacologic approach to treat T2DM. In support of this concept, a potent small-molecule GCGR antagonist (GRA), MK-0893, demonstrated dose-dependent efficacy to reduce hyperglycemia, with an HbA1c reduction of 1.5% at the 80 mg dose for 12 weeks in T2DM. However, GRA treatment was associated with dose-dependent elevation of plasma LDL-cholesterol (LDL-c). The current studies investigated the cause for increased LDL-c. We report findings that link MK-0893 with increased glucagon-like peptide 2 and cholesterol absorption. There was not, however, a GRA-related modulation of cholesterol synthesis. These findings were replicated using structurally diverse GRAs. To examine potential pharmacologic mitigation, coadministration of ezetimibe (a potent inhibitor of cholesterol absorption) in mice abrogated the GRA-associated increase of LDL-c. Although the molecular mechanism is unknown, our results provide a novel finding by which glucagon and, hence, GCGR antagonism govern cholesterol metabolism.
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Affiliation(s)
- Hong-Ping Guan
- Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Xiaodong Yang
- Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Ku Lu
- Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Sheng-Ping Wang
- Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Jose M Castro-Perez
- Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Stephen Previs
- Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Michael Wright
- Late Stage In Vitro Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Vinit Shah
- Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Kithsiri Herath
- Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Dan Xie
- Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Daphne Szeto
- Late Stage In Vivo Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Gail Forrest
- Late Stage In Vivo Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Jing Chen Xiao
- Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Oksana Palyha
- Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Li-Ping Sun
- Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Paula J Andryuk
- Clinical Research Department, Merck Research Laboratories, Rahway, NJ 07065
| | - Samuel S Engel
- Clinical Research Department, Merck Research Laboratories, Rahway, NJ 07065
| | - Yusheng Xiong
- Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Songnian Lin
- Discovery Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033
| | - David E Kelley
- Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Mark D Erion
- Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Harry R Davis
- Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033
| | - Liangsu Wang
- Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033
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Tomkin GH, Owens D. Dyslipidaemia of diabetes and the intestine. World J Diabetes 2015; 6:970-977. [PMID: 26185604 PMCID: PMC4499530 DOI: 10.4239/wjd.v6.i7.970] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Revised: 01/06/2015] [Accepted: 03/09/2015] [Indexed: 02/05/2023] Open
Abstract
Atherosclerosis is the major complication of diabetes and has become a major issue in the provision of medical care. In particular the economic burden is growing at an alarming rate in parallel with the increasing world-wide prevalence of diabetes. The major disturbance of lipid metabolism in diabetes relates to the effect of insulin on fat metabolism. Raised triglycerides being the hallmark of uncontrolled diabetes, i.e., in the presence of hyperglycaemia. The explosion of type 2 diabetes has generated increasing interest on the aetiology of atherosclerosis in diabetic patients. The importance of the atherogenic properties of triglyceride rich lipoproteins has only recently been recognised by the majority of diabetologists and cardiologists even though experimental evidence has been strong for many years. In the post-prandial phase 50% of triglyceride rich lipoproteins come from chylomicrons produced in the intestine. Recent evidence has secured the chylomicron as a major player in the atherogenic process. In diabetes chylomicron production is increased through disturbance in cholesterol absorption, in particular Neimann Pick C1-like1 activity is increased as is intestinal synthesis of cholesterol through 3-hydroxy-3-methyl glutaryl co enzyme A reductase. ATP binding cassette proteins G5 and G8 which regulate cholesterol in the intestine is reduced leading to chylomicronaemia. The chylomicron particle itself is atherogenic but the increase in the triglyceride-rich lipoproteins lead to an atherogenic low density lipoprotein and low high density lipoprotein. The various steps in the absorption process and the disturbance in chylomicron synthesis are discussed.
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45
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Kataoka Y, St John J, Wolski K, Uno K, Puri R, Tuzcu EM, Nissen SE, Nicholls SJ. Atheroma progression in hyporesponders to statin therapy. Arterioscler Thromb Vasc Biol 2015; 35:990-5. [PMID: 25722430 DOI: 10.1161/atvbaha.114.304477] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Lowering low-density lipoprotein cholesterol (LDL-C) with statins has been demonstrated to slow plaque progression. This antiatherosclerotic effect in patients with minimal LDL-C lowering has not been investigated. APPROACH AND RESULTS Six hundred forty-seven patients with angiographic coronary artery disease who were commenced on statin therapy underwent serial imaging with intravascular ultrasound. Responders were defined as a percentage reduction in LDL-C of <15%. Disease progression was compared in responders (n=517) and hyporesponders (n=130) to statin therapy. Twenty percentage of patients demonstrated minimal changes in LDL-C, despite commencement of statin therapy. Statin hyporesponders were younger (55 versus 57 years; P=0.01), more likely to be male (79% versus 66%; P=0.005), and obese (body mass index, 31.5 ± 6.1 versus 30.3 ± 5.9 kg/m(2); P=0.04) and less likely to have a history of dyslipidemia (50% versus 66%; P<0.001). Baseline levels of systolic blood pressure (127 ± 15 versus 132 ± 17 mm Hg; P=0.01) and LDL-C (2.5 ± 0.6 versus 3.4 ± 0.8 mmol/L; P<0.001) were lower in statin hyporesponders. Baseline percent atheroma volume was similar between statin hyporesponders and responders (36.9 ± 9.8% versus 38.3 ± 9.2%; P=0.13). On serial evaluation, greater progression of percent atheroma volume (1.19 ± 0.48% versus 0.09 ± 0.43%; P=0.003) was observed in statin hyporesponders. After adjusting for baseline clinical characteristics and measures of plaque burden, statin hyporesponders still exhibited greater atheroma progression (+0.83 ± 0.58% versus -0.21 ± 0.52%; P=0.006). CONCLUSIONS A substantial proportion of patients with coronary artery disease fail to achieve effective reductions in LDL-C, despite prescription of statin therapy. Greater progression of atherosclerosis is observed in these patients. Our current study underscores monitoring LDL-C level after the commencement of statin to ensure adequate response to statin therapy.
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Affiliation(s)
- Yu Kataoka
- From the South Australian Health and Medical Research Institute, Heart Health Theme, University of Adelaide, Adelaide, Australia (Y.K., S.J.N.); and C5 Research (J.S.J., K.W., K.U., R.P., S.E.N.) and Department of Cardiovascular Medicine, Heart and Vascular Institute (R.P., E.M.T., S.E.N.), Cleveland Clinic, OH
| | - Julie St John
- From the South Australian Health and Medical Research Institute, Heart Health Theme, University of Adelaide, Adelaide, Australia (Y.K., S.J.N.); and C5 Research (J.S.J., K.W., K.U., R.P., S.E.N.) and Department of Cardiovascular Medicine, Heart and Vascular Institute (R.P., E.M.T., S.E.N.), Cleveland Clinic, OH
| | - Kathy Wolski
- From the South Australian Health and Medical Research Institute, Heart Health Theme, University of Adelaide, Adelaide, Australia (Y.K., S.J.N.); and C5 Research (J.S.J., K.W., K.U., R.P., S.E.N.) and Department of Cardiovascular Medicine, Heart and Vascular Institute (R.P., E.M.T., S.E.N.), Cleveland Clinic, OH
| | - Kiyoko Uno
- From the South Australian Health and Medical Research Institute, Heart Health Theme, University of Adelaide, Adelaide, Australia (Y.K., S.J.N.); and C5 Research (J.S.J., K.W., K.U., R.P., S.E.N.) and Department of Cardiovascular Medicine, Heart and Vascular Institute (R.P., E.M.T., S.E.N.), Cleveland Clinic, OH
| | - Rishi Puri
- From the South Australian Health and Medical Research Institute, Heart Health Theme, University of Adelaide, Adelaide, Australia (Y.K., S.J.N.); and C5 Research (J.S.J., K.W., K.U., R.P., S.E.N.) and Department of Cardiovascular Medicine, Heart and Vascular Institute (R.P., E.M.T., S.E.N.), Cleveland Clinic, OH
| | - E Murat Tuzcu
- From the South Australian Health and Medical Research Institute, Heart Health Theme, University of Adelaide, Adelaide, Australia (Y.K., S.J.N.); and C5 Research (J.S.J., K.W., K.U., R.P., S.E.N.) and Department of Cardiovascular Medicine, Heart and Vascular Institute (R.P., E.M.T., S.E.N.), Cleveland Clinic, OH
| | - Steven E Nissen
- From the South Australian Health and Medical Research Institute, Heart Health Theme, University of Adelaide, Adelaide, Australia (Y.K., S.J.N.); and C5 Research (J.S.J., K.W., K.U., R.P., S.E.N.) and Department of Cardiovascular Medicine, Heart and Vascular Institute (R.P., E.M.T., S.E.N.), Cleveland Clinic, OH
| | - Stephen J Nicholls
- From the South Australian Health and Medical Research Institute, Heart Health Theme, University of Adelaide, Adelaide, Australia (Y.K., S.J.N.); and C5 Research (J.S.J., K.W., K.U., R.P., S.E.N.) and Department of Cardiovascular Medicine, Heart and Vascular Institute (R.P., E.M.T., S.E.N.), Cleveland Clinic, OH.
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Kawase A, Araki Y, Ueda Y, Nakazaki S, Iwaki M. Impact of a high-cholesterol diet on expression levels of Niemann–Pick C1-like 1 and intestinal transporters in rats and mice. Eur J Drug Metab Pharmacokinet 2015; 41:457-63. [DOI: 10.1007/s13318-015-0269-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Accepted: 02/13/2015] [Indexed: 10/24/2022]
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47
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Federici M. Effect of ezetimibe on cholesterol absorption and lipoprotein composition in diabetes and metabolic syndrome. ATHEROSCLEROSIS SUPP 2015; 17:17-22. [DOI: 10.1016/s1567-5688(15)50005-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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48
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Hu M, Tomlinson B. Ezetimibe treatment should be considered for patients with sitosterolemia. Pediatr Nephrol 2014; 29:1469-70. [PMID: 24839218 DOI: 10.1007/s00467-014-2843-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Revised: 03/28/2014] [Accepted: 04/29/2014] [Indexed: 10/25/2022]
Affiliation(s)
- Miao Hu
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong-Prince of Wales Hospital, Sha Tin, Hong Kong, SAR, China
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49
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Abstract
PURPOSE OF REVIEW The serum noncholesterol sterols are widely used today in clinical lipid research as surrogate markers of cholesterol absorption and synthesis. Their applicability and some aspects related to their analysis, use, and interpretations are discussed. RECENT FINDINGS The serum markers of cholesterol metabolism have been carefully validated in several populations and during different interventions. If the homeostasis between cholesterol absorption and synthesis is lost, the markers cannot be used as surrogates. The markers have been applied in large population and cohort studies to find out how cholesterol metabolism is related to coronary artery disease. Most of the large studies suggested that increased levels of the markers of cholesterol absorption may conceivably be a risk factor for coronary artery disease. SUMMARY Results even from large population studies vary from population to population. The large number of factors, which interfere with cholesterol metabolism, such as age, sex, BMI, diet, health status, medication, and genetic background, and differences in the analysis methods of the serum markers should be taken into consideration when interpreting the data.
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Affiliation(s)
- Helena Gylling
- Division of Internal Medicine, Department of Medicine, University of Helsinki, Helsinki, Finland
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50
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Mangat R, Proctor SD. Emerging pathways in the regulation of whole body cholesterol flux: therapeutic opportunities to target atherosclerosis? J Lipid Res 2014; 55:796-7. [PMID: 24670991 DOI: 10.1194/jlr.e049502] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Affiliation(s)
- Rabban Mangat
- Metabolic and Cardiovascular Diseases Laboratory, Molecular and Cell Biology of Lipids Group, Alberta Diabetes and Mazankowski Heart Institutes, University of Alberta, Edmonton, Alberta, Canada
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