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1
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Dixon ED, Claudel T, Nardo AD, Riva A, Fuchs CD, Mlitz V, Busslinger G, Scharnagl H, Stojakovic T, Senéca J, Hinteregger H, Grabner GF, Kratky D, Verkade H, Zimmermann R, Haemmerle G, Trauner M. Inhibition of ATGL alleviates MASH via impaired PPARα signalling that favours hydrophilic bile acid composition in mice. J Hepatol 2025; 82:658-675. [PMID: 39357546 DOI: 10.1016/j.jhep.2024.09.037] [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: 07/21/2023] [Revised: 09/19/2024] [Accepted: 09/20/2024] [Indexed: 10/04/2024]
Abstract
BACKGROUND & AIMS Adipose triglyceride lipase (ATGL) is an attractive therapeutic target in insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD). This study investigated the effects of pharmacological ATGL inhibition on the development of metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis in mice. METHODS Streptozotocin-injected male mice were fed a high-fat diet to induce MASH. Mice receiving the ATGL inhibitor atglistatin (ATGLi) were compared to controls using liver histology, lipidomics, metabolomics, 16s rRNA, and RNA sequencing. Human ileal organoids, HepG2 cells, and Caco2 cells treated with the human ATGL inhibitor NG-497, HepG2 ATGL knockdown cells, gel-shift, and luciferase assays were analysed for mechanistic insights. We validated the benefits of ATGLi on steatohepatitis and fibrosis in a low-methionine choline-deficient mouse model. RESULTS ATGLi improved serum liver enzymes, hepatic lipid content, and histological liver injury. Mechanistically, ATGLi attenuated PPARα signalling, favouring hydrophilic bile acid (BA) synthesis with increased Cyp7a1, Cyp27a1, Cyp2c70, and reduced Cyp8b1 expression. Additionally, reduced intestinal Cd36 and Abca1, along with increased Abcg5 expression, were consistent with reduced levels of hepatic triacylglycerol species containing polyunsaturated fatty acids, like linoleic acid, as well as reduced cholesterol levels in the liver and plasma. Similar changes in gene expression associated with PPARα signalling and intestinal lipid transport were observed in ileal organoids treated with NG-497. Furthermore, HepG2 ATGL knockdown cells revealed reduced expression of PPARα target genes and upregulation of genes involved in hydrophilic BA synthesis, consistent with reduced PPARα binding and luciferase activity in the presence of the ATGL inhibitors. CONCLUSIONS Inhibition of ATGL attenuates PPARα signalling, translating into hydrophilic BA composition, interfering with dietary lipid absorption, and improving metabolic disturbances. Validation with NG-497 opens a new therapeutic perspective for MASLD. IMPACT AND IMPLICATIONS Despite the recent approval of drugs novel mechanistic insights and pathophysiology-oriented therapeutic options for MASLD (metabolic dysfunction-associated steatotic liver disease) are still urgently needed. Herein, we show that pharmacological inhibition of ATGL, the key enzyme in lipid hydrolysis, using atglistatin (ATGLi), improves MASH (metabolic dysfunction-associated steatohepatitis), fibrosis, and key features of metabolic dysfunction in mouse models of MASH and liver fibrosis. Mechanistically, we demonstrated that attenuation of PPARα signalling in the liver and gut favours hydrophilic bile acid composition, ultimately interfering with dietary lipid absorption. One of the drawbacks of ATGLi is its lack of efficacy against human ATGL, thus limiting its clinical applicability. Against this backdrop, we could show that ATGL inhibition using the human inhibitor NG-497 in human primary ileum-derived organoids, Caco2 cells, and HepG2 cells translated into therapeutic mechanisms similar to ATGLi. Collectively, these findings reveal a possible new avenue for MASLD treatment.
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Affiliation(s)
- Emmanuel Dauda Dixon
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Alexander Daniel Nardo
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Alessandra Riva
- Chair of Nutrition and Immunology, School of Life Sciences, Technische Universität München, Freising-Weihenstephan, Germany
| | - Claudia Daniela Fuchs
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Veronika Mlitz
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Georg Busslinger
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria
| | - Tatjana Stojakovic
- Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Graz, Austria
| | - Joana Senéca
- Joint Microbiome Facility of the Medical University of Vienna and the University of Vienna, Vienna, Austria; Department of Microbiology and Ecosystem Science, Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria
| | - Helga Hinteregger
- Division of Molecular Biology and Biochemistry, Medical University of Graz, Austria
| | - Gernot F Grabner
- Division of Molecular Biology and Biochemistry, Medical University of Graz, Austria
| | - Dagmar Kratky
- Division of Molecular Biology and Biochemistry, Medical University of Graz, Austria
| | - Henkjan Verkade
- Department of Paediatrics, University Medical Centre Groningen, Groningen, Netherlands
| | - Robert Zimmermann
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Guenter Haemmerle
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.
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Stellaard F, Lütjohann D. Phytosterol-Enriched Dietary Supplements for Lowering Plasma LDL-Cholesterol: Yes or No? Nutrients 2025; 17:654. [PMID: 40004982 PMCID: PMC11858453 DOI: 10.3390/nu17040654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 02/09/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Elevated plasma low-density lipoprotein cholesterol (LDL-C) is associated with an increased risk for atherosclerosis and development of cardiovascular disease. An elevated plasma LDL-C concentration is the result of enhanced C synthesis, C absorption, and/or altered C homeostasis. Plasma LDL-C lowering can be achieved using pharmaceutical means. Statin therapy inhibits endogenous C synthesis and leads to a mean 40% LDL-C reduction. Ezetimibe inhibits C absorption and achieves an average 20% LDL-C reduction with a 10 mg daily intake. Phytosterol therapy is established by dietary supplements enriched in phytosterols and/or phytostanols. A dosage of 2 to 3 g a day reduces C absorption and leads to an average 10% LDL-C reduction. This dosage expresses a 10-fold increased daily intake for phytosterols or a 100-fold increased intake of phytostanols. Phytosterol- and -stanol-enriched dietary supplements are freely available in the supermarket. The majority of consumers may be healthy subjects with a plasma LDL-C in the normal range. Scientific evidence reveals that increased phytosterol intake may be associated with the development of atherosclerosis. The degree of increased risk is dependent on the patient's genetic polymorphisms in NPC1L1 and ABCG5/G8 transport proteins as well as on the established risk reduction due to LDL-C lowering. Subjects with a normal or only slightly elevated LDL-C have only minimal LDL-C lowering and lack the compensation for the potential increased risk for atherosclerosis by phytosterols.
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Affiliation(s)
| | - Dieter Lütjohann
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127 Bonn, Germany;
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Garrido-Sanchez L, Leiva-Badosa E, Llop-Talaveron J, Pintó-Sala X, Lozano-Andreu T, Corbella-Inglés E, Alia-Ramos P, Arias-Barquet L, Ramon-Torrel JM, Badía-Tahull MB. Blood Phytosterol Concentration and Genetic Variant Associations in a Sample Population. Nutrients 2024; 16:1067. [PMID: 38613098 PMCID: PMC11013666 DOI: 10.3390/nu16071067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 03/26/2024] [Accepted: 04/01/2024] [Indexed: 04/14/2024] Open
Abstract
The main objective of this study was to determine plasma levels of PS and to study SNVs rs41360247, rs4245791, rs4148217, and rs11887534 of ABCG8 and the r657152 SNV at the ABO blood group locus in a sample of a population treated at our hospital, and to determine whether these SNVs are related to plasma PS concentrations. The secondary objective was to establish the variables associated with plasma PS concentrations in adults. Participants completed a dietary habit questionnaire and a blood sample was collected to obtain the following variables: campesterol, sitosterol, sitostanol, lanosterol, stigmasterol, biochemical parameters, and the SNVs. In addition, biometric and demographic variables were also recorded. In the generalized linear model, cholesterol and age were positively associated with total PS levels, while BMI was negatively related. For rs4245791, homozygous T allele individuals showed a significantly lower campesterol concentration compared with C homozygotes, and the GG alleles of rs657152 had the lowest levels of campesterol compared with the other alleles of the SNV. Conclusions: The screening of certain SNVs could help prevent the increase in plasma PS and maybe PNALD in some patients. However, further studies on the determinants of plasma phytosterol concentrations are needed.
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Affiliation(s)
- Leticia Garrido-Sanchez
- Pharmacy Department, Hospital Universitari Bellvitge, IDIBELL, Universitat Barcelona, 08907 L’Hospitalet de Llobregat, Spain
| | - Elisabet Leiva-Badosa
- Pharmacy Department, Hospital Universitari Bellvitge, IDIBELL, Universitat Barcelona, 08907 L’Hospitalet de Llobregat, Spain
| | - Josep Llop-Talaveron
- Pharmacy Department, Hospital Universitari Bellvitge, IDIBELL, Universitat Barcelona, 08907 L’Hospitalet de Llobregat, Spain
| | - Xavier Pintó-Sala
- Cardiovascular Risk Unit, Internal Medicine, Hospital Universitari de Bellvitge, IDIBELL, Universitat Barcelona, 08907 L’Hospitalet de Llobregat, Spain; (X.P.-S.)
| | - Toni Lozano-Andreu
- Pharmacy Department, Institut Català d’Oncologia, IDIBELL, Universitat Barcelona, 08907 L’Hospitalet de Llobregat, Spain
| | - Emili Corbella-Inglés
- Cardiovascular Risk Unit, Internal Medicine, Hospital Universitari de Bellvitge, IDIBELL, Universitat Barcelona, 08907 L’Hospitalet de Llobregat, Spain; (X.P.-S.)
| | - Pedro Alia-Ramos
- Clinical Laboratory Department, Hospital Universitari Bellvitge, IDIBELL, Universitat Barcelona, 08907 L’Hospitalet de Llobregat, Spain
| | - Lluis Arias-Barquet
- Ophthalmology Department, Hospital Universitari Bellvitge, IDIBELL, Universitat Barcelona, 08907 L’Hospitalet de Llobregat, Spain
| | - Josep Maria Ramon-Torrel
- Preventive Medicine Department, Hospital Universitari Bellvitge, IDIBELL, Universitat Barcelona, 08907 L’Hospitalet de Llobregat, Spain
| | - Maria B. Badía-Tahull
- Pharmacy Department, Hospital Universitari Bellvitge, IDIBELL, Universitat Barcelona, 08907 L’Hospitalet de Llobregat, Spain
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Akiyama Y, Katsuki S, Matoba T, Nakano Y, Takase S, Nakashiro S, Yamamoto M, Mukai Y, Inoue S, Oi K, Higo T, Takemoto M, Suematsu N, Eshima K, Miyata K, Usui M, Sadamatsu K, Kadokami T, Hironaga K, Ichi I, Todaka K, Kishimoto J, Tsutsui H. Association of Serum Oxysterols with Cholesterol Metabolism Markers and Clinical Factors in Patients with Coronary Artery Disease: A Covariance Structure Analysis. Nutrients 2023; 15:2997. [PMID: 37447327 DOI: 10.3390/nu15132997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Oxysterols have been implicated in the pathogenesis of cardiovascular diseases. Serum levels of oxysterols could be positively correlated with cholesterol absorption and synthesis. However, physiological regulation of various serum oxysterols is largely unknown. The aim of this study was to investigate the relationship between clinical factors and cholesterol metabolism markers, and identify oxysterols associated with cholesterol absorption and synthesis in patients with coronary artery disease. Subjects (n = 207) who underwent coronary stenting between 2011 and 2013 were studied cross-sectionally. We measured lipid profiles including serum oxysterols. As for the serum biomarkers of cholesterol synthesis and absorption, oxysterol levels were positively correlated with campesterol and lathosterol. Covariance structure analysis revealed that dyslipidemia and statin usage had a positive correlation with "cholesterol absorption". Statin usage also had a positive correlation with "cholesterol synthesis". Several oxysterols associated with cholesterol absorption and/or synthesis. In conclusion, we elucidated the potential clinical factors that may affect cholesterol metabolism, and the associations between various oxysterols with cholesterol absorption and/or synthesis in patients with coronary artery disease.
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Affiliation(s)
- Yusuke Akiyama
- Department of Cardiovascular, Respiratory and Geriatric Medicine, Kyushu University Beppu Hospital, Oita 874-0838, Japan
| | - Shunsuke Katsuki
- Department of Cardiovascular Medicine, Kyushu University Hospital, Fukuoka 812-8582, Japan
| | - Tetsuya Matoba
- Department of Cardiovascular Medicine, Kyushu University Hospital, Fukuoka 812-8582, Japan
| | - Yasuhiro Nakano
- Department of Cardiovascular Medicine, Kyushu University Hospital, Fukuoka 812-8582, Japan
| | - Susumu Takase
- Department of Cardiovascular Medicine, Kyushu University Hospital, Fukuoka 812-8582, Japan
| | - Soichi Nakashiro
- Department of Cardiovascular Medicine, Saiseikai Fukuoka General Hospital, Fukuoka 810-0001, Japan
| | - Mitsutaka Yamamoto
- Department of Cardiovascular Medicine, Harasanshin Hospital, Fukuoka 812-0033, Japan
| | - Yasushi Mukai
- Department of Cardiovascular Medicine, Japanese Red Cross Fukuoka Hospital, Fukuoka 815-0082, Japan
| | - Shujiro Inoue
- Department of Cardiovascular Medicine, National Hospital Organization Kyushu Medical Centre, Fukuoka 810-0065, Japan
| | - Keiji Oi
- Department of Cardiovascular Medicine, Harasanshin Hospital, Fukuoka 812-0033, Japan
| | - Taiki Higo
- Wakaba Heart Clinic, Fukuoka 810-0073, Japan
| | - Masao Takemoto
- Cardiovascular Center, Steel Memorial Yahata Hospital, Fukuoka 805-8508, Japan
| | - Nobuhiro Suematsu
- Department of Cardiovascular Medicine, Harasanshin Hospital, Fukuoka 812-0033, Japan
| | - Kenichi Eshima
- Matsuguchi Internal Medicine and Cardiology Clinic, Fukuoka 814-0133, Japan
| | - Kenji Miyata
- Department of Cardiovascular Medicine, Japan Community Health Care Organization, Kyushu Hospital, Fukuoka 806-8501, Japan
| | - Makoto Usui
- Department of Cardiovascular Medicine, Hamanomachi Hospital, Fukuoka 810-0072, Japan
| | - Kenji Sadamatsu
- Department of Cardiovascular Medicine, Omuta City Hospital, Fukuoka 836-0861, Japan
| | - Toshiaki Kadokami
- Department of Cardiovascular Medicine, Saiseikai Futsukaichi Hospital, Fukuoka 818-8516, Japan
| | - Kiyoshi Hironaga
- Department of Cardiovascular Medicine, Fukuoka City Hospital, Fukuoka 812-0046, Japan
| | - Ikuyo Ichi
- Graduate School of Humanities and Science, Ochanomizu University, Tokyo 112-8610, Japan
| | - Koji Todaka
- Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka 812-8582, Japan
| | - Junji Kishimoto
- Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka 812-8582, Japan
| | - Hiroyuki Tsutsui
- School of Medicine and Graduate School, International University of Health and Welfare, Fukuoka 831-8501, Japan
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Windler E, Beil FU, Berthold HK, Gouni-Berthold I, Kassner U, Klose G, Lorkowski S, März W, Parhofer KG, Plat J, Silbernagel G, Steinhagen-Thiessen E, Weingärtner O, Zyriax BC, Lütjohann D. Phytosterols and Cardiovascular Risk Evaluated against the Background of Phytosterolemia Cases-A German Expert Panel Statement. Nutrients 2023; 15:nu15040828. [PMID: 36839186 PMCID: PMC9963617 DOI: 10.3390/nu15040828] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 02/08/2023] Open
Abstract
Phytosterols (PSs) have been proposed as dietary means to lower plasma LDL-C. However, concerns are raised that PSs may exert atherogenic effects, which would offset this benefit. Phytosterolemia was thought to mimic increased plasma PSs observed after the consumption of PS-enriched foods. This expert statement examines the possibility of specific atherogenicity of PSs based on sterol metabolism, experimental, animal, and human data. Observational studies show no evidence that plasma PS concentrations would be associated with an increased risk of atherosclerosis or cardiovascular (CV) events. Since variants of the ABCG5/8 transporter affect the absorption of cholesterol and non-cholesterol sterols, Mendelian randomization studies examining the effects of ABCG5/8 polymorphisms cannot support or refute the potential atherogenic effects of PSs due to pleiotropy. In homozygous patients with phytosterolemia, total PS concentrations are ~4000% higher than under physiological conditions. The prevalence of atherosclerosis in these individuals is variable and may mainly relate to concomitant elevated LDL-C. Consuming PS-enriched foods increases PS concentrations by ~35%. Hence, PSs, on a molar basis, would need to have 20-40 times higher atherogenicity than cholesterol to offset their cholesterol reduction benefit. Based on their LDL-C lowering and absence of adverse safety signals, PSs offer a dietary approach to cholesterol management. However, their clinical benefits have not been established in long-term CV endpoint studies.
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Affiliation(s)
- Eberhard Windler
- Preventive Medicine, University Heart Center, University Hospital Hamburg-Eppendorf, Hamburg-Eppendorf, Martinistr. 52-Bldg. N26, 20246 Hamburg, Germany
| | - Frank-Ulrich Beil
- Ambulanzzentrum, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Heiner K. Berthold
- Department of Internal Medicine and Geriatrics, Bethel Clinic, 33611 Bielefeld, Germany
| | - Ioanna Gouni-Berthold
- Center for Endocrinology, Diabetes and Preventive Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
| | - Ursula Kassner
- Lipid Clinic at the Interdisciplinary Metabolism Center, Charite-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Gerald Klose
- Praxen Dres. T. Beckenbauer & S. Maierhof, Am Markt 11, 28195 Bremen und Dres. I. van de Loo & K. Spieker, Gerold Janssen Straße 2 A, 28359 Bremen, Germany
| | - Stefan Lorkowski
- Institute of Nutritional Science and Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD), Halle-Jena-Leipzig, Friedrich Schiller University Jena, Dornburger Str. 25, 07743 Jena, Germany
| | - Winfried März
- SYNLAB Akademie für Ärztliche Fortbildung, SYNLAB Holding Deutschland GmbH, P5,7, 68161 Mannheim, Germany
- Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8010 Graz, Austria
- Correspondence:
| | - Klaus G. Parhofer
- Medizinische Klinik IV, Klinikum der Universität München, Grosshadern, Marchioninistr. 15, 81377 München, Germany
| | - Jogchum Plat
- Department of Nutrition and Movement Sciences, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, 6211 LK Maastricht, The Netherlands
| | - Günter Silbernagel
- Division of Vascular Medicine, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria
| | - Elisabeth Steinhagen-Thiessen
- Arbeitsbereich Lipidstoffwechsel der Medizinischen Klinik für Endokrinologie und Stoffwechselmedizin, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Oliver Weingärtner
- Klinik für Innere Medizin I, Universitätskliniken Jena, Friedrich-Schiller-Universität Jena, 07743 Jena, Germany
| | - Birgit-Christiane Zyriax
- Midwifery Science—Health Care Research and Prevention, Research Group, Preventive Medicine and Nutrition, Institute for Health Services Research in Dermatology and Nursing (IVDP), University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Dieter Lütjohann
- Institute of Clinical Chemistry and Clinical Pharmacology, University Clinics Bonn, 53127 Bonn, Germany
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Nunes VS, de Campos EVS, Baracat J, França V, Gomes ÉIL, Coelho RP, Nakandakare ER, Zago VHS, de Faria EC, Quintão ECR. Plasma Campesterol Is Positively Associated with Carotid Plaques in Asymptomatic Subjects. Int J Mol Sci 2022; 23:ijms231911997. [PMID: 36233298 PMCID: PMC9569444 DOI: 10.3390/ijms231911997] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 09/29/2022] [Accepted: 10/05/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Increased cholesterol absorption and reduced synthesis are processes that have been associated with cardiovascular disease risk in a controversial way. However, most of the studies involving markers of cholesterol synthesis and absorption include conditions, such as obesity, diabetes, dyslipidemia, which can be confounding factors. The present study aimed at investigating the relationships of plasma cholesterol synthesis and absorption markers with cardiovascular disease (CVD) risk factors, cIMT (carotid intima-media thickness), and the presence of carotid plaques in asymptomatic subjects. METHODS A cross-sectional study was carried out in 270 asymptomatic individuals and anthropometrical parameters, fasting plasma lipids, glucometabolic profiles, high-sensitivity C-reactive protein (hs-CRP), markers of cholesterol synthesis (desmosterol and lathosterol), absorption (campesterol and sitosterol), cIMT, and the presence of atherosclerotic plaques were analyzed. RESULTS Among the selected subjects aged between 19 and 75 years, 51% were females. Age, body mass index, systolic and diastolic blood pressure, total cholesterol, non-HDL-C, triglycerides, glucose, and lathosterol/sitosterol ratios correlated positively with cIMT (p ≤ 0.05). Atherosclerotic plaques were present in 19% of the subjects. A direct association of carotid plaques with campesterol, OR = 1.71 (95% CI = 1.04-2.82, p ≤ 0.05) and inverse associations with both ratios lathosterol/campesterol, OR = 0.29 (CI = 0.11-0.80, p ≤ 0.05) and lathosterol/sitosterol, OR = 0.45 (CI = 0.22-0.95, p ≤ 0.05) were observed in univariate logistic regression analysis. CONCLUSIONS The findings suggested that campesterol may be associated with atherosclerotic plaques and the lathosterol/campesterol or sitosterol ratios suggested an inverse association. Furthermore, synthesis and absorption of cholesterol are inverse processes, and the absorption marker, campesterol, may reflect changes in body cholesterol homeostasis with atherogenic potential.
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Affiliation(s)
- Valéria Sutti Nunes
- Laboratorio de Lipides (LIM10), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01246-900, SP, Brazil
| | - Edite Vieira Silva de Campos
- Lipid Laboratory and Center for Medicine and Experimental Surgery, Department of Clinical Pathology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas 13083-887, SP, Brazil
| | - Jamal Baracat
- Faculty of Medical Sciences, Department of Radiology, Hospital of Clinics, State University of Campinas (UNICAMP), Campinas 13083-888, SP, Brazil
| | - Victor França
- Lipid Laboratory and Center for Medicine and Experimental Surgery, Department of Clinical Pathology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas 13083-887, SP, Brazil
| | - Érica Ivana Lázaro Gomes
- Lipid Laboratory and Center for Medicine and Experimental Surgery, Department of Clinical Pathology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas 13083-887, SP, Brazil
| | - Raissa Peres Coelho
- Lipid Laboratory and Center for Medicine and Experimental Surgery, Department of Clinical Pathology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas 13083-887, SP, Brazil
| | - Edna Regina Nakandakare
- Laboratorio de Lipides (LIM10), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01246-900, SP, Brazil
| | - Vanessa Helena Souza Zago
- Centro de Ciências da Vida, Pontifical Catholic University of Campinas, Campinas 13034-68, SP, Brazil
| | - Eliana Cotta de Faria
- Lipid Laboratory and Center for Medicine and Experimental Surgery, Department of Clinical Pathology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas 13083-887, SP, Brazil
| | - Eder Carlos Rocha Quintão
- Laboratorio de Lipides (LIM10), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01246-900, SP, Brazil
- Correspondence: ; Tel.: +55-11-3061-7263
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7
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Messedi M, Guidara W, Grayaa S, Khrouf W, Snoussi M, Bahloul Z, Bonnefont-Rousselot D, Lamari F, Ayadi F. Selected plasma oxysterols as a potential multi-marker biosignature panel for Behçet's Disease. J Steroid Biochem Mol Biol 2022; 221:106122. [PMID: 35588947 DOI: 10.1016/j.jsbmb.2022.106122] [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: 02/11/2022] [Revised: 04/29/2022] [Accepted: 05/02/2022] [Indexed: 10/18/2022]
Abstract
Clinical, genetic, and medical evidence has shown the inflammatory vasculitis aspect of Behçet's Disease (BD). Whereas oxysterols are vital factors in inflammation and oxidative stress, it is still unknown whether they are involved in the pathophysiology of BD. The current study aims to explore the profile of oxysterols in plasma of BD patients. Thirty patients diagnosed with BD and forty healthy controls matched for age and gender were included. Results showed that the cholestane-3β,5α,6β-triol, 27-hydroxycholesterol (27-OHC) and cholestanol levels were higher in BD than controls. In addition, plasma levels of 7-ketocholesterol (7-KC) and 25-hydroxycholesterol (25-OHC) were lower in BD patient. However, levels of 24S-hydroxycholesterol (24-OHC) did not significantly differ. For BD patients, the plasma 7-KC level was negatively correlated with the BD activity index (BDAI) while 27-OHC was positively correlated with high-sensitivity C-reactive protein (hs-CRP) in patients with active course of the disease. According to ROC analysis, a remarkable increase in the area under the curve (AUC) with a higher sensitivity (Se) and specificity (Sp) for 7-KC, 25-OHC and 27-OHC combined markers was observed. The present study indicated that the identification of the predictive value of these three-selected biomarkers related to oxidative stress and inflammation in patients should lead to a better identification of the etiological mechanism of BD.
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Affiliation(s)
- Meriam Messedi
- Research Laboratory "Molecular Basis of Human Diseases", LR19ES13, Sfax Medicine School, University of Sfax, Tunisia.
| | - Wassim Guidara
- Research Laboratory "Molecular Basis of Human Diseases", LR19ES13, Sfax Medicine School, University of Sfax, Tunisia
| | - Sahar Grayaa
- Research Laboratory "Molecular Basis of Human Diseases", LR19ES13, Sfax Medicine School, University of Sfax, Tunisia
| | - Walid Khrouf
- Service de Biochimie Métabolique, AP-HP.Sorbonne Université, Hôpitaux Universitaires Pitié-Salpêtrière-Charles Foix, DMU BioGeM, Paris F-75013, France
| | - Mouna Snoussi
- Internal medicine department, Hedi Chaker Hosptital, Sfax, Tunisia
| | - Zouhir Bahloul
- Internal medicine department, Hedi Chaker Hosptital, Sfax, Tunisia
| | - Dominique Bonnefont-Rousselot
- Service de Biochimie Métabolique, AP-HP.Sorbonne Université, Hôpitaux Universitaires Pitié-Salpêtrière-Charles Foix, DMU BioGeM, Paris F-75013, France; Université de Paris, CNRS, Inserm, UTCBS, Paris F-75006, France
| | - Foudil Lamari
- Service de Biochimie Métabolique, AP-HP.Sorbonne Université, Hôpitaux Universitaires Pitié-Salpêtrière-Charles Foix, DMU BioGeM, Paris F-75013, France
| | - Fatma Ayadi
- Research Laboratory "Molecular Basis of Human Diseases", LR19ES13, Sfax Medicine School, University of Sfax, Tunisia
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8
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OUP accepted manuscript. Eur J Prev Cardiol 2022; 29:1731-1739. [DOI: 10.1093/eurjpc/zwac059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/14/2022] [Accepted: 03/15/2022] [Indexed: 11/12/2022]
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Kopylov AT, Malsagova KA, Stepanov AA, Kaysheva AL. Diversity of Plant Sterols Metabolism: The Impact on Human Health, Sport, and Accumulation of Contaminating Sterols. Nutrients 2021; 13:nu13051623. [PMID: 34066075 PMCID: PMC8150896 DOI: 10.3390/nu13051623] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/05/2021] [Accepted: 05/08/2021] [Indexed: 02/07/2023] Open
Abstract
The way of plant sterols transformation and their benefits for humans is still a question under the massive continuing revision. In fact, there are no receptors for binding with sterols in mammalians. However, possible biotransformation to steroids that can be catalyzed by gastro-intestinal microflora, microbial cells in prebiotics or cytochromes system were repeatedly reported. Some products of sterols metabolization are capable to imitate resident human steroids and compete with them for the binding with corresponding receptors, thus affecting endocrine balance and entire physiology condition. There are also tremendous reports about the natural origination of mammalian steroid hormones in plants and corresponding receptors for their binding. Some investigations and reports warn about anabolic effect of sterols, however, there are many researchers who are reluctant to believe in and have strong opposing arguments. We encounter plant sterols everywhere: in food, in pharmacy, in cosmetics, but still know little about their diverse properties and, hence, their exact impact on our life. Most of our knowledge is limited to their cholesterol-lowering influence and protective effect against cardiovascular disease. However, the world of plant sterols is significantly wider if we consider the thousands of publications released over the past 10 years.
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Ming J, Wei X, Han M, Adi D, Abuzhalihan J, Wang YT, Yang YN, Li XM, Xie X, Fu ZY, Gai MT, Ma YT. Genetic variation of RNF145 gene and blood lipid levels in Xinjiang population, China. Sci Rep 2021; 11:5969. [PMID: 33727652 PMCID: PMC7966793 DOI: 10.1038/s41598-021-85503-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 02/24/2021] [Indexed: 01/24/2023] Open
Abstract
Dyslipidemia is one of the main risk factors for coronary heart disease (CHD). The E3 ubiquitin ligase which is encoded by the ring finger protein 145 (RNF145) gene is very important in the mediation of cholesterol synthesis and effectively treats hypercholesterolemia. Thus, the purpose of the present research is to investigate the connection between the polymorphism of the RNF145 gene and cholesterol levels in the populations in Xinjiang, China. A total of 1396 participants (Male: 628, Female: 768) were included in this study for genetic analysis of RNF145 gene, and we used the modified multiple connection detection response (iMLDR) technology to label two SNPs (rs17056583, rs12188266) of RNF145 genotyping. The relationship between the genotypes and the lipid profiles was analyzed with general linear model analysis after adjusting confounding variables. Through the analysis of the two SNPs in RNF145 gene, we discovered that both rs17056583 and rs12188266 were related to total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) concentrations (All P < 0.001). In addition, the association of rs17056583 and rs12188266 with lipid profiles concentrations is still statistically significant after multivariate adjustment of sex, age, smoking, obesity, drinking, diabetes, hypertension and lipid profiles. Meanwhile, we also found that rs17056583 was associated with high triglycerides concentrations before and after adjustment (All P < 0.001). Our study shows that both rs17056583 and rs12188266 SNPs of RNP145 gene are related to TC and LDL-C concentrations in Xinjiang population.
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Affiliation(s)
- Jing Ming
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People's Republic of China.,Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, 830054, People's Republic of China
| | - Xian Wei
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People's Republic of China.,Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, 830054, People's Republic of China
| | - Min Han
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People's Republic of China.,Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, 830054, People's Republic of China
| | - Dilare Adi
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People's Republic of China.,Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, 830054, People's Republic of China
| | - Jialin Abuzhalihan
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People's Republic of China.,Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, 830054, People's Republic of China
| | - Yong-Tao Wang
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People's Republic of China.,Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, 830054, People's Republic of China
| | - Yi-Ning Yang
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People's Republic of China.,Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, 830054, People's Republic of China
| | - Xiao-Mei Li
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People's Republic of China.,Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, 830054, People's Republic of China
| | - Xiang Xie
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People's Republic of China.,Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, 830054, People's Republic of China
| | - Zhen-Yan Fu
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People's Republic of China.,Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, 830054, People's Republic of China
| | - Min-Tao Gai
- Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, 830054, People's Republic of China
| | - Yi-Tong Ma
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People's Republic of China. .,Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, 830054, People's Republic of China.
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11
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Fujisue K, Yamanaga K, Nagamatsu S, Shimomura H, Yamashita T, Nakao K, Nakamura S, Ishihara M, Matsui K, Sakaino N, Miyazaki T, Yamamoto N, Koide S, Matsumura T, Fujimoto K, Tsunoda R, Morikami Y, Matsuyama K, Oshima S, Sakamoto K, Izumiya Y, Kaikita K, Hokimoto S, Ogawa H, Tsujita K. Effects of Statin Plus Ezetimibe on Coronary Plaques in Acute Coronary Syndrome Patients with Diabetes Mellitus: Sub-Analysis of PRECISE-IVUS Trial. J Atheroscler Thromb 2021; 28:181-193. [PMID: 32435011 PMCID: PMC7957031 DOI: 10.5551/jat.54726] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 03/13/2020] [Indexed: 11/16/2022] Open
Abstract
AIM Coronary plaque regression is weak in acute coronary syndrome (ACS) patients with diabetes mellitus (DM). We evaluated whether dual lipid-lowering therapy (DLLT) with ezetimibe and atorvastatin attenuates coronary plaques in ACS patients with DM. METHODS The prospective, randomized controlled, multicenter PRECISE-IVUS (Plaque Regression with Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound) trial assigned 246 patients undergoing percutaneous coronary intervention to DLLT or atorvastatin monotherapy and evaluated IVUS-derived changes in percent atheroma volume (ΔPAV), at baseline and 9-12-month follow-up, in 126 ACS cases, including 25 DM patients. The atorvastatin dose was up-titrated to achieve low-density lipoprotein cholesterol (LDL-C) ＜70 mg/dL. RESULTS In DM patients, the monotherapy group (n=13) and the DLLT group (n=12) showed a similar prevalence of coronary risks and baseline lipid profiles. During the study, the change in LDL-C level was similar between DM and non-DM patients. Compared with non-DM patients, DM patients showed weaker regression of ΔPAV by DLLT than those who underwent monotherapy (DM: -2.77±3.47% vs. -0.77±2.51%, P=0.11; non-DM: -2.01±3.36% vs. -0.08±2.66%, P=0.008). The change in LDL-C level was not correlated with ΔPAV in non-DM patients, but there was significant correlation between the change in LDL-C level and ΔPAV in DM patients (r=0.52, P=0.008). CONCLUSIONS ACS patients with DM showed weaker coronary plaque regression than their counterparts. A significant correlation between the change in LDL-C level and ΔPAV in DM patients suggested that more intensive lipid-lowering therapy is required in ACS patients with DM.
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Affiliation(s)
- Koichiro Fujisue
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University, Kumamoto, Japan
| | - Kenshi Yamanaga
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University, Kumamoto, Japan
| | - Suguru Nagamatsu
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University, Kumamoto, Japan
| | - Hideki Shimomura
- Department of Cardiovascular Medicine, Fukuoka Tokushukai Medical Center, Kasuga, Japan
| | - Takuro Yamashita
- Division of Cardiology, Social Insurance Omuta Tenryo Hospital, Omuta, Japan
| | - Koichi Nakao
- Division of Cardiology, Saiseikai Kumamoto Hospital Cardiovascular Center, Kumamoto, Japan
| | - Sunao Nakamura
- Interventional Cardiology Unit, New Tokyo Hospital, Matsudo, Japan
| | - Masaharu Ishihara
- Department of Cardiovascular and Renal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Kunihiko Matsui
- Department of Community Medicine, Kumamoto University, Kumamoto, Japan
| | | | | | - Nobuyasu Yamamoto
- Division of Cardiology, Miyazaki Prefectural Nobeoka Hospital, Nobeoka, Japan
| | - Shunichi Koide
- Division of Cardiology, Japan Community Health care Organization Kumamoto General Hospital, Yatsushiro, Japan
| | - Toshiyuki Matsumura
- Division of Cardiology, Japan Labor Health and Welfare Organization Kumamoto Rosai Hospital, Yatsushiro, Japan
| | - Kazuteru Fujimoto
- Department of Cardiology, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan
| | - Ryusuke Tsunoda
- Division of Cardiology, Japanese Red Cross Kumamoto Hospital, Kumamoto, Japan
| | | | - Koushi Matsuyama
- Division of Cardiology, Social Insurance Omuta Tenryo Hospital, Omuta, Japan
| | - Shuichi Oshima
- Division of Cardiology, Kumamoto Central Hospital, Kumamoto, Japan
| | - Kenji Sakamoto
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University, Kumamoto, Japan
| | - Yasuhiro Izumiya
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University, Kumamoto, Japan
- Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Koichi Kaikita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University, Kumamoto, Japan
| | - Seiji Hokimoto
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University, Kumamoto, Japan
| | - Hisao Ogawa
- National Cerebral and Cardiovascular Center, Suita, Japan
| | - Kenichi Tsujita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University, Kumamoto, Japan
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12
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Quintão ECR. Plasma Non-cholesterol Sterols as Markers of Cholesterol Synthesis and Intestinal Absorption: A Critical Review. Curr Pharm Des 2020; 26:5152-5162. [PMID: 32744960 DOI: 10.2174/1381612826666200730220230] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 07/01/2020] [Indexed: 11/22/2022]
Abstract
Plasma concentrations of phytosterols and non-cholesterol sterol precursors of cholesterol synthesis have been used as markers of intestinal cholesterol absorption and synthesis in inherited and secondary dyslipidemias and in population-based investigations to evaluate the risk for cardiovascular disease, respectively. The method aims at replacing initial research procedures such as the use of stable isotopes associated with fecal steroid balance, which are limited by the high cost and tedious procedures. However, we show in this review that numerous results obtained with serum sterol measurements are contradictory. In this regard, the following points are discussed: 1) how phytosterols relate to atherosclerosis considering that defects in biliary output or in the transport of phytosterols from the intestinal mucosa back into the intestinal lumen provide increased content of phytosterols and other sterols in plasma and tissues, thus not allowing to conclude that their presence in arteries and atheromas represents the etiology of atherosclerosis; 2) serum non-cholesterol sterols as markers of cholesterol synthesis and absorption, such as cholestanol, present discrepant results, rendering them often inadequate to identify cases of coronary artery disease as well as alterations in the whole body cholesterol metabolism; 3) such methods of measurement of cholesterol metabolism are confounded by factors like diabetes mellitus, body weight and other pathologies including considerable hereditary hyperlipidemias biological variabilities that influence the efficiency of synthesis and intestinal absorption of cholesterol.
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13
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The coronary artery calcium score is linked to plasma cholesterol synthesis and absorption markers: Brazilian Longitudinal Study of Adult Health. Biosci Rep 2020; 40:225472. [PMID: 32579186 PMCID: PMC7332684 DOI: 10.1042/bsr20201094] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 06/03/2020] [Accepted: 06/23/2020] [Indexed: 12/27/2022] Open
Abstract
It is controversial whether atherosclerosis is linked to increased intestinal cholesterol absorption or synthesis in humans. The aim of the present study was to relate atherosclerosis to the measurements of plasma markers of cholesterol synthesis (desmosterol, lathosterol) and absorption (campesterol, sitosterol). In healthy male (n=344), non-obese, non-diabetics, belonging to the city of São Paulo branch of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), we measured in plasma these non-cholesterol sterol markers, together with their anthropometric, dietary parameters, traditional atherosclerotic risk factors, and blood chemistry, coronary arterial calcium score (CAC), and ultrasonographically measured common carotid artery intima-media thickness (CCA-IMT). Cases with CAC>zero had the following parameters higher than cases with CAC = zero: age, waist circumference (WC), plasma total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), and non-high density lipoprotein-cholesterol (non HDL-C). Plasma desmosterol and campesterol, duly corrected for TC, age, body mass index (BMI), waist circumference (WC), hypertension, smoking, and the homeostasis model assessment-insulin resistance (HOMA-IR) correlated with CAC, but not with CCA-IMT. The latter related to increased age, BMI, waist circumference (WC), and systolic blood pressure (SBP). Plasma HDL-C concentrations did not define CAC or CCA-IMT degrees, although in relation to the lower tertile of HDL-C in plasma the higher tertile of HDL-C had lower HOMA-IR and concentration of a cholesterol synthesis marker (desmosterol). Present work indicated that increased cholesterol synthesis and absorption represent primary causes of CAD, but not of the common carotid artery atherosclerosis.
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Roles of Achieved Levels of Low-Density Lipoprotein Cholesterol and High-Sensitivity C-Reactive Protein on Cardiovascular Outcome in Statin Therapy. Cardiovasc Ther 2019; 2019:3824823. [PMID: 31885691 PMCID: PMC6906885 DOI: 10.1155/2019/3824823] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 08/16/2019] [Accepted: 08/29/2019] [Indexed: 12/13/2022] Open
Abstract
In statin therapy, the prognostic role of achieved low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hsCRP) in cardiovascular outcomes has not been fully elucidated. A total of 4,803 percutaneous coronary intervention (PCI)-naïve patients who prescribed moderate intensity of statin therapy were followed up. Total and each component of major adverse cardiovascular events (MACE) according to LDL-C and hsCRP quartiles were compared. The incidence of 5-year total MACEs in the highest quartile group according to the followed-up hsCRP was higher than that in the lowest quartile (hazard ratio (HR) = 2.16, p < 0.001). However, there was no difference between the highest and lowest quartiles of the achieved LDL-C (HR = 0.95, p = 0.743). After adjustment of potential confounders, the incidence of total death, de novo PCI, atrial fibrillation, and heart failure in the highest quartile of followed-up hsCRP, was higher than that in the lowest quartile (all p < 0.05). However, other components except for de novo PCI in the highest quartile by achieved LDL-C was not different to that in the lowest quartile. These results suggest that followed-up hsCRP can be more useful for predicting future cardiovascular outcome than achieved LDL-C in PCI-naïve patients with statin therapy.
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15
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Safaryan AS, Kamyshova TV, Nebieridze DV, Sargsyan VD. The role of plant stanols in the primary prevention of hypercholesterolemia in patients with arterial hypertension. КАРДИОВАСКУЛЯРНАЯ ТЕРАПИЯ И ПРОФИЛАКТИКА 2019. [DOI: 10.15829/1728-8800-2019-3-5-10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Aim.To assess the efficacy and safety of plant stanols in patients with arterial hypertension (AH) and disorders of lipid metabolism, without clinical manifestations of atherosclerosis.Material and methods.The study included 40 patients — men at the age of 50-55 years, with AH (stage 1) and cholesterol above 5,0 mmol/l and LDL cholesterol above 3,0 mmol/l with low and medium risk (SCORE — 1-4%). Patients with coronary artery disease and other clinical manifestations of atherosclerosis, secondary hypertension, liver diseases, diabetes mellitus, secondary dyslipoproteinemia, cardiovascular diseases requiring constant therapy, bronchial asthma were excluded from the study. Patients were randomized into 2 groups of 20 people. In the study group of patients within 3 months received plant stanols (2 tab./day), in the control group — only healthy diet. In addition, patients with high blood pressure received antihypertensive therapy. Assessment of lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) was performed at baseline and after 3 months. At the beginning of the study, after 3 months of the study patients underwent a full medical examination. Safety control of plant stanols was carried out by determination of liver enzymes (aspartic transaminase (AST), alanine transaminase (ALT)), before and after the completion of the study.Results.Patients of two groups were comparable in baseline characteristics (lipid parameters, blood pressure level). After 3 months of research beginning patients from study group have statistically significant decrease of total cholesterol and LDL cholesterol. The average level of total cholesterol before treatment was 5,8±0,32 mmol/l, and after treatment — 5,3±0,32 mmol/l, p<0,001. The average level of LDL cholesterol before treatment was 3,6±0,26 mmol/l, and after treatment — 3,3±0,25 mmol/l, p<0,001. According to other lipid parameters (HDL cholesterol, triglycerides) significant differences are not obtained. As a result, there was a significant reduction in the total risk from 4% to 3,1%. As for the control group, the dynamics of lipid parameters were practically not observed. For example, the average level of total cholesterol before treatment was 5,7±0,39 mmol/l, and after treatment — 5,6±0,42 mmol/l. The average level of LDL cholesterol before treatment was 3,6±0,21 mmol/l, and after treatment — 3,6±0,21 mmol/l. The differences between the study and control groups in the reduction of total and LDL cholesterol were highly significant (p<0,001). The study did not reveal the dynamics of liver enzymes. The level of AST before treatment in the study group was 28,4±6,54, and after treatment — 29,5±5,56. ALT levels were 32,3±7,38 and 33,9±5,65, before and after the study, respectively.Conclusion.The study shows the high efficacy and safety of plant stanols. We found a significant decrease of the two most important parameters of lipid metabolism — total cholesterol and LDL cholesterol.
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Affiliation(s)
- A. S. Safaryan
- National Medical Research Center for Preventive Medicine
| | | | | | - V. D. Sargsyan
- National Medical Research Center for Preventive Medicine
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Lütjohann D, Stellaard F, Mulder MT, Sijbrands EJG, Weingärtner O. The emerging concept of "individualized cholesterol-lowering therapy": A change in paradigm. Pharmacol Ther 2019; 199:111-116. [PMID: 30877023 DOI: 10.1016/j.pharmthera.2019.03.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 03/06/2019] [Indexed: 12/17/2022]
Abstract
High LDL-cholesterol concentrations constitute a risk for atherosclerotic cardiovascular disease. By consensus, cholesterol-lowering therapy is initiated with a statin that reduces endogenous cholesterol synthesis, upregulates hepatic LDL receptor activity, increases LDL clearance and lowers LDL-cholesterol concentrations in the bloodstream. The efficacy of statin treatment is dose dependent and achieves a risk reduction of up to 50%. However, a substantial body of evidence suggests that a quarter of statin-treated patients do not respond adequately as a result of low endogenous cholesterol synthesis. In humans fractional cholesterol absorption varies from 20% to 80%. High cholesterol absorbers, which are characterized by a low-to-normal cholesterol synthesis, exhibit poor responsiveness to statin treatment. On the other hand, the cholesterol absorption inhibitor ezetimibe effectively reduces serum cholesterol levels in these patients. On this background, we suggest to "get personal" and individualize cholesterol-lowering therapies, according to the individual's status of cholesterol synthesis and absorption.
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Affiliation(s)
- Dieter Lütjohann
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany
| | - Frans Stellaard
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany
| | - Monique T Mulder
- Department of Internal Medicine, Section of Pharmacology Vascular and Metabolic Diseases, Cardiovascular Research School COEUR, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Eric J G Sijbrands
- Department of Internal Medicine, Section of Pharmacology Vascular and Metabolic Diseases, Cardiovascular Research School COEUR, Erasmus Medical Center, Rotterdam, The Netherlands
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17
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Plat J, Baumgartner S, Vanmierlo T, Lütjohann D, Calkins KL, Burrin DG, Guthrie G, Thijs C, Te Velde AA, Vreugdenhil ACE, Sverdlov R, Garssen J, Wouters K, Trautwein EA, Wolfs TG, van Gorp C, Mulder MT, Riksen NP, Groen AK, Mensink RP. Plant-based sterols and stanols in health & disease: "Consequences of human development in a plant-based environment?". Prog Lipid Res 2019; 74:87-102. [PMID: 30822462 DOI: 10.1016/j.plipres.2019.02.003] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 02/13/2019] [Accepted: 02/25/2019] [Indexed: 01/27/2023]
Abstract
Dietary plant sterols and stanols as present in our diet and in functional foods are well-known for their inhibitory effects on intestinal cholesterol absorption, which translates into lower low-density lipoprotein cholesterol concentrations. However, emerging evidence suggests that plant sterols and stanols have numerous additional health effects, which are largely unnoticed in the current scientific literature. Therefore, in this review we pose the intriguing question "What would have occurred if plant sterols and stanols had been discovered and embraced by disciplines such as immunology, hepatology, pulmonology or gastroenterology before being positioned as cholesterol-lowering molecules?" What would then have been the main benefits and fields of application of plant sterols and stanols today? We here discuss potential effects ranging from its presence and function intrauterine and in breast milk towards a potential role in the development of non-alcoholic steatohepatitis (NASH), cardiovascular disease (CVD), inflammatory bowel diseases (IBD) and allergic asthma. Interestingly, effects clearly depend on the route of entrance as observed in intestinal-failure associated liver disease (IFALD) during parenteral nutrition regimens. It is only until recently that effects beyond lowering of cholesterol concentrations are being explored systematically. Thus, there is a clear need to understand the full health effects of plant sterols and stanols.
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Affiliation(s)
- J Plat
- Department of Nutrition and Movement Sciences, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands.
| | - S Baumgartner
- Department of Nutrition and Movement Sciences, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - T Vanmierlo
- Department of Immunology and Biochemistry, Biomedical Research Institute (Biomed) Hasselt University, Hasselt, Belgium; Division of Translational Neuroscience, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, the Netherlands
| | - D Lütjohann
- Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
| | - K L Calkins
- David Geffen School of Medicine, University of California Los Angeles, Mattel Children's Hospital at UCLA, Los Angeles, CA; Department of Pediatrics, Division of Neonatology and Developmental Biology, Neonatal Research Center, USA
| | - D G Burrin
- Department of Pediatrics, USDA Children's Nutrition Research Center, Baylor College of Medicine, Houston, USA
| | - G Guthrie
- Department of Pediatrics, USDA Children's Nutrition Research Center, Baylor College of Medicine, Houston, USA
| | - C Thijs
- Department of Epidemiology, Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, the Netherlands
| | - A A Te Velde
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Medical Center, the Netherlands
| | - A C E Vreugdenhil
- Department of Pediatrics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - R Sverdlov
- Department of Molecular Genetics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - J Garssen
- Utrecht University, Division Pharmacology, Utrecht Institute for Pharmaceutical Sciences, the Netherlands
| | - K Wouters
- Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
| | | | - T G Wolfs
- Department of Pediatrics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - C van Gorp
- Department of Pediatrics, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - M T Mulder
- Department of Internal Medicine, Rotterdam University, Rotterdam, the Netherlands
| | - N P Riksen
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
| | - A K Groen
- Amsterdam Diabetes Center and Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
| | - R P Mensink
- Department of Nutrition and Movement Sciences, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
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Non-Cholesterol Sterol Concentrations as Biomarkers for Cholesterol Absorption and Synthesis in Different Metabolic Disorders: A Systematic Review. Nutrients 2019; 11:nu11010124. [PMID: 30634478 PMCID: PMC6356200 DOI: 10.3390/nu11010124] [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] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 12/21/2018] [Accepted: 12/28/2018] [Indexed: 12/27/2022] Open
Abstract
Non-cholesterol sterols are validated biomarkers for intestinal cholesterol absorption and endogenous cholesterol synthesis. However, their use in metabolic disturbances has not been systematically explored. Therefore, we conducted a systematic review to provide an overview of non-cholesterol sterols as markers for cholesterol metabolism in different metabolic disorders. Potentially relevant studies were retrieved by a systematic search of three databases in July 2018 and ninety-four human studies were included. Cholesterol-standardized levels of campesterol, sitosterol and cholestanol were collected to reflect cholesterol absorption and those of lathosterol and desmosterol to reflect cholesterol synthesis. Their use as biomarkers was examined in the following metabolic disorders: overweight/obesity (n = 16), diabetes mellitus (n = 15), metabolic syndrome (n = 5), hyperlipidemia (n = 11), cardiovascular disease (n = 17), and diseases related to intestine (n = 16), liver (n = 22) or kidney (n = 2). In general, markers for cholesterol absorption and synthesis displayed reciprocal patterns, showing that cholesterol metabolism is tightly regulated by the interplay of intestinal absorption and endogenous synthesis. Distinctive patterns for cholesterol absorption or cholesterol synthesis could be identified, suggesting that metabolic disorders can be classified as 'cholesterol absorbers or cholesterol synthesizers'. Future studies should be performed to confirm or refute these findings and to examine whether this information can be used for targeted (dietary) interventions.
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19
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Silbernagel G, Steiner LK, Hollstein T, Fauler G, Scharnagl H, Stojakovic T, Schumann F, Bölükbasi B, März W, Steinhagen-Thiessen E, Laufs U, Kassner U. The interrelations between PCSK9 metabolism and cholesterol synthesis and absorption. J Lipid Res 2019; 60:161-167. [PMID: 30323110 PMCID: PMC6314261 DOI: 10.1194/jlr.p088583] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 10/06/2018] [Indexed: 01/12/2023] Open
Abstract
Very few studies have investigated the interrelations between proprotein convertase subtilisin/kexin type 9 (PCSK9) metabolism, cholesterol synthesis, and cholesterol absorption. We aimed to address this issue in a large clinical trial of 245 patients with hypercholesterolemia. Serum lipids, PCSK9, lathosterol (cholesterol synthesis marker), campesterol, and sitosterol (cholesterol absorption markers) were measured before and 4-8 weeks after the start of treatment with PCSK9-antibodies (alirocumab or evolocumab). The patients had mean (standard error) LDL-cholesterol and PCSK9 concentrations of 3.87 (0.10) mmol/l and 356 (17) ng/ml, respectively. Eighty-four patients received no lipid-lowering pretreatment, 26 ezetimibe, 38 statins, and 97 ezetimibe + statins. Circulating PCSK9 increased in parallel with the potency of lipid-lowering pretreatment with circulating PCSK9 being highest in the ezetimibe + statin group (P < 0.001). Treatment with PCSK9-antibodies strongly decreased LDL-cholesterol, lathosterol, campesterol, and sitosterol (all P < 0.001) but hardly affected noncholesterol sterol to cholesterol ratios. Lipid-lowering pretreatment was not associated with the effects of PCSK9-antibodies on noncholesterol sterols (all P > 0.05). Summing up, circulating PCSK9 is increased by cholesterol synthesis and absorption inhibitors. Increased PCSK9 expression may partly explain the strong reductions of LDL-cholesterol achieved with PCSK9-antibodies after such pretreatment. On the other hand, treatment with PCSK9-antibodies does not significantly change the balance between cholesterol synthesis and absorption.
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Affiliation(s)
- Günther Silbernagel
- Division of Angiology, Department of Internal Medicine Medical University of Graz, 8036 Graz, Austria
- Lipid Clinic at the Interdisciplinary Metabolism Center, Campus Virchow-Klinikum, Charité Universitatsmedizin Berlin, 13353 Berlin, Germany
| | - Lars K Steiner
- Division of Angiology, Department of Internal Medicine Medical University of Graz, 8036 Graz, Austria
| | - Tim Hollstein
- Lipid Clinic at the Interdisciplinary Metabolism Center, Campus Virchow-Klinikum, Charité Universitatsmedizin Berlin, 13353 Berlin, Germany
| | - Günter Fauler
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria
| | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria
| | - Tatjana Stojakovic
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria
| | - Friederike Schumann
- Lipid Clinic at the Interdisciplinary Metabolism Center, Campus Virchow-Klinikum, Charité Universitatsmedizin Berlin, 13353 Berlin, Germany
| | - Bediha Bölükbasi
- Klinik für Innere Medizin III-Kardiologie, Angiologie, und internistische Intensivmedizin, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany
| | - Winfried März
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria
- Department of Internal Medicine 5 (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Mannheim Medical Faculty, University of Heidelberg, 68167 Mannheim, Germany
- Synlab Academy, Synlab Holding Germany GmbH, 68161 Mannheim, Germany
| | - Elisabeth Steinhagen-Thiessen
- Lipid Clinic at the Interdisciplinary Metabolism Center, Campus Virchow-Klinikum, Charité Universitatsmedizin Berlin, 13353 Berlin, Germany
| | - Ulrich Laufs
- Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, 04103 Leipzig, Germany
| | - Ursula Kassner
- Lipid Clinic at the Interdisciplinary Metabolism Center, Campus Virchow-Klinikum, Charité Universitatsmedizin Berlin, 13353 Berlin, Germany
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20
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Wadsack D, Sattler H, Kleber ME, Eirich K, Scharnagl H, Fauler G, März W, Grammer TB. Recurrent tendosynovitis as a rare manifestation of a lipid disorder. J Clin Lipidol 2018; 13:54-61. [PMID: 30459115 DOI: 10.1016/j.jacl.2018.10.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 10/15/2018] [Accepted: 10/16/2018] [Indexed: 10/28/2022]
Abstract
A 33-year-old female had suffered from spontaneously recurrent bursitis and tendosynovitis/enthesitis of the patellar and Achilles tendons for about 10 years. The episodes of immobilization increased. Ultrasound imaging of the swollen and painful tendons showed chronic inflammation with neoangiogenesis within the tendons and hypoechoic lesions. Clinical and laboratory tests did not provide evidence for a rheumatic disease. Low density lipoprotein cholesterol was elevated. Biopsies of skin lesions did not confirm the suspicion of cutaneous xanthomas. Genetic testing for familial hypercholesterolemia was negative. Campesterol and sitosterol were elevated 7- to 12-fold and 20- to 38-fold over the upper limit of normal on two occasions. There was no relevant mutation in ABCG5. In ABCG8, we identified a missense mutation c.1267G>A in exon 9 changing glutamic acid 423 into lysine within the transmembrane domain, and an insertion of adenine (c.1487insA) leading to a frameshift and a premature stop codon (Ile497Aspfs*105). The patient had no clinical evidence of premature atherosclerosis. Therapeutic approaches with nonsteroidal antirheumatic drugs, prednisone, statins, and ezetimibe accompanied by a diet poor in plant sterols led to a relief of symptoms. This case report shows that tendon xanthoma along with tendosynovitis, especially on extensor areas, is suspicious for hypercholesterolemia as the underlying cause. The absence of atherosclerotic plaques in the abdominal aorta and in the carotid arteries on ultrasound may suggest that phytosterolemia is not necessarily accompanied by premature vascular disease.
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Affiliation(s)
- Daniel Wadsack
- Department of Medicine A, Klinikum Ludwigshafen, Ludwigshafen, Germany
| | - Horst Sattler
- Department of Medicine A, Klinikum Ludwigshafen, Ludwigshafen, Germany
| | - Marcus E Kleber
- Department of Internal Medicine V (Nephrology, Rheumatology, Hypertensiology, Endocrinolgy, Diabetology), Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany
| | | | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Günter Fauler
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Winfried März
- Department of Internal Medicine V (Nephrology, Rheumatology, Hypertensiology, Endocrinolgy, Diabetology), Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria; Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany
| | - Tanja B Grammer
- Department of Internal Medicine V (Nephrology, Rheumatology, Hypertensiology, Endocrinolgy, Diabetology), Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany; Mannheim Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany.
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21
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Jones PJH, Shamloo M, MacKay DS, Rideout TC, Myrie SB, Plat J, Roullet JB, Baer DJ, Calkins KL, Davis HR, Barton Duell P, Ginsberg H, Gylling H, Jenkins D, Lütjohann D, Moghadasian M, Moreau RA, Mymin D, Ostlund RE, Ras RT, Ochoa Reparaz J, Trautwein EA, Turley S, Vanmierlo T, Weingärtner O. Progress and perspectives in plant sterol and plant stanol research. Nutr Rev 2018; 76:725-746. [PMID: 30101294 PMCID: PMC6130982 DOI: 10.1093/nutrit/nuy032] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Current evidence indicates that foods with added plant sterols or stanols can lower serum levels of low-density lipoprotein cholesterol. This review summarizes the recent findings and deliberations of 31 experts in the field who participated in a scientific meeting in Winnipeg, Canada, on the health effects of plant sterols and stanols. Participants discussed issues including, but not limited to, the health benefits of plant sterols and stanols beyond cholesterol lowering, the role of plant sterols and stanols as adjuncts to diet and drugs, and the challenges involved in measuring plant sterols and stanols in biological samples. Variations in interindividual responses to plant sterols and stanols, as well as the personalization of lipid-lowering therapies, were addressed. Finally, the clinical aspects and treatment of sitosterolemia were reviewed. Although plant sterols and stanols continue to offer an efficacious and convenient dietary approach to cholesterol management, long-term clinical trials investigating the endpoints of cardiovascular disease are still lacking.
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Affiliation(s)
- Peter J H Jones
- Richardson Centre for Functional Foods and Nutraceuticals, University of Manitoba, Winnipeg, Manitoba, Canada
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Maryam Shamloo
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
- George and Fay Yee Centre for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Dylan S MacKay
- George and Fay Yee Centre for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Todd C Rideout
- Department of Exercise and Nutrition Sciences, University of Buffalo, Buffalo, New York, USA
| | - Semone B Myrie
- Richardson Centre for Functional Foods and Nutraceuticals, University of Manitoba, Winnipeg, Manitoba, Canada
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Jogchum Plat
- Department of Human Biology, Maastricht University, Maastricht, the Netherlands
| | - Jean-Baptiste Roullet
- Division of Metabolism, Child Development and Rehabilitation Center—Portland, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, USA
| | - David J Baer
- US Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Beltsville, Maryland, USA
| | - Kara L Calkins
- Department of Pediatrics, Division of Neonatology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA; and the UCLA Mattel’s Children’s Hospital, Los Angeles, California, USA
| | | | - P Barton Duell
- Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon, USA
| | - Henry Ginsberg
- Institute of Human Nutrition, Columbia University Irving Medical Center, New York, New York, USA
| | - Helena Gylling
- University of Helsinki and the Helsinki University Central Hospital, Helsinki, Finland
| | - David Jenkins
- Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada; and the Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Dieter Lütjohann
- Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
| | - Mohammad Moghadasian
- Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Robert A Moreau
- Eastern Regional Research Center, US Department of Agriculture, Agricultural Research Service, Wyndmoor, Pennsylvania, USA
| | - David Mymin
- Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Richard E Ostlund
- Division of Endocrinology, Metabolism and Lipid Research, Washington University, St Louis, USA
| | - Rouyanne T Ras
- Unilever Research & Development Vlaardingen, Vlaardingen, the Netherlands
| | | | - Elke A Trautwein
- Unilever Research & Development Vlaardingen, Vlaardingen, the Netherlands
| | | | - Tim Vanmierlo
- Department of Immunology and Biochemistry, Biomedical Research Institute, Hasselt University, Hasselt, Belgium
| | - Oliver Weingärtner
- Klinik für Innere Medizin I, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany; Abteilung für Kardiologie, Klinikum Oldenburg, European Medical School Oldenburg-Groningen, Oldenburg, Germany
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22
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Brandt EJ, Benes LB, Lee L, Dayspring TD, Sorrentino M, Davidson M. The Effect of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition on Sterol Absorption Markers in a Cohort of Real-World Patients. J Cardiovasc Pharmacol Ther 2018; 24:54-61. [DOI: 10.1177/1074248418780733] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is expressed in multiple tissues, including the small intestine. The effect of PCSK9 inhibition on cholesterol absorption is not known. Objectives: Measure serum cholesterol absorption markers before and after initiation of PCSK9 inhibitors. Methods: Single-center retrospective cohort of patients administered evolocumab and alirocumab between July 2015 and January 2017. Paired t tests were used to compare mean serum cholesterol marker concentrations, and ratios to total cholesterol, before and after PCSK9 inhibitor initiation. Analyses were repeated for those taking and not taking statins and taking or not taking ezetimibe at both initiation and follow-up, for each PCSK9 inhibitor, and based on follow-up time (<60, 60-120, and >120 days). Results: There were 62 possible participants, 34 were excluded for lack of data or unknown PCSK9 inhibitor initiation date. Average follow-up was 92.5 days. Mean campesterol (before 3.14 μg/mL, 95% CI: 2.79-4.38 μg/mL; after 2.09 μg/mL, 95% CI: 1.87-2.31 μg/mL; P < .0001), sitosterol (before 2.46 μg/mL, 95% CI: 2.23-2.70 μg/mL; after 1.62 μg/mL, 95% CI: 1.48-1.75 μg/mL; P < .0001), and cholestanol (before 3.25 μg/mL, 95% CI: 3.04-3.47 μg/mL; after 2.08 μg/mL, 95% CI: 1.96-2.21 μg/mL; P < .0001) all significantly decreased at follow-up. There was no significant change in absorption marker to total cholesterol ratios. Findings were not influenced by statin or ezetimibe use or nonuse, which PCSK9 inhibitor was prescribed, or time to follow-up. Conclusion: Proprotein convertase subtilisin/kexin type 9 inhibition was associated with decreased cholesterol absorption markers.
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Affiliation(s)
- Eric J. Brandt
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Lane B. Benes
- Division of Cardiology, Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Linda Lee
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | | | - Matthew Sorrentino
- Division of Cardiology, Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Michael Davidson
- Division of Cardiology, Department of Medicine, University of Chicago, Chicago, IL, USA
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23
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Lin X, Racette SB, Ma L, Wallendorf M, Dávila-Román VG, Ostlund RE. Endogenous Cholesterol Excretion Is Negatively Associated With Carotid Intima-Media Thickness in Humans. Arterioscler Thromb Vasc Biol 2017; 37:2364-2369. [PMID: 28982667 DOI: 10.1161/atvbaha.117.310081] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 09/21/2017] [Indexed: 01/11/2023]
Abstract
OBJECTIVE Epidemiological studies strongly suggest that lipid factors independent of low-density lipoprotein cholesterol contribute significantly to cardiovascular disease risk. Because circulating lipoproteins comprise only a small fraction of total body cholesterol, the mobilization and excretion of cholesterol from plasma and tissue pools may be an important determinant of cardiovascular disease risk. Our hypothesis is that fecal excretion of endogenous cholesterol is protective against atherosclerosis. APPROACH AND RESULTS Cholesterol metabolism and carotid intima-media thickness were quantitated in 86 nondiabetic adults. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d7 solubilized in a lipid emulsion and dietary cholesterol by cholesterol-d5 and the nonabsorbable stool marker sitostanol-d4. Plasma and stool samples were collected while subjects consumed a cholesterol- and phytosterol-controlled metabolic kitchen diet and were analyzed by mass spectrometry. Carotid intima-media thickness was negatively correlated with fecal excretion of endogenous cholesterol (r=-0.426; P<0.0001), total cholesterol (r=-0.472; P≤0.0001), and daily percent excretion of cholesterol from the rapidly mixing cholesterol pool (r=-0.343; P=0.0012) and was positively correlated with percent cholesterol absorption (r=+0.279; P=0.0092). In a linear regression model controlling for age, sex, systolic blood pressure, hemoglobin A1c, low-density lipoprotein, high-density lipoprotein cholesterol, and statin drug use, fecal excretion of endogenous cholesterol remained significant (P=0.0008). CONCLUSIONS Excretion of endogenous cholesterol is strongly, independently, and negatively associated with carotid intima-media thickness. The reverse cholesterol transport pathway comprising the intestine and the rapidly mixing plasma, and tissue cholesterol pool could be an unrecognized determinant of cardiovascular disease risk not reflected in circulating lipoproteins. Further work is needed to relate measures of reverse cholesterol transport to atherosclerotic disease. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603758.
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Affiliation(s)
- Xiaobo Lin
- From the Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine (X.L., S.B.R., L.M., R.E.O.), Program in Physical Therapy (S.B.R.), Division of Biostatistics (M.W.), and Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Medicine (V.G.D.-R.), Washington University School of Medicine, St. Louis, MO
| | - Susan B Racette
- From the Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine (X.L., S.B.R., L.M., R.E.O.), Program in Physical Therapy (S.B.R.), Division of Biostatistics (M.W.), and Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Medicine (V.G.D.-R.), Washington University School of Medicine, St. Louis, MO
| | - Lina Ma
- From the Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine (X.L., S.B.R., L.M., R.E.O.), Program in Physical Therapy (S.B.R.), Division of Biostatistics (M.W.), and Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Medicine (V.G.D.-R.), Washington University School of Medicine, St. Louis, MO
| | - Michael Wallendorf
- From the Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine (X.L., S.B.R., L.M., R.E.O.), Program in Physical Therapy (S.B.R.), Division of Biostatistics (M.W.), and Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Medicine (V.G.D.-R.), Washington University School of Medicine, St. Louis, MO
| | - Victor G Dávila-Román
- From the Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine (X.L., S.B.R., L.M., R.E.O.), Program in Physical Therapy (S.B.R.), Division of Biostatistics (M.W.), and Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Medicine (V.G.D.-R.), Washington University School of Medicine, St. Louis, MO
| | - Richard E Ostlund
- From the Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine (X.L., S.B.R., L.M., R.E.O.), Program in Physical Therapy (S.B.R.), Division of Biostatistics (M.W.), and Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Medicine (V.G.D.-R.), Washington University School of Medicine, St. Louis, MO.
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24
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März W, Grammer TB, Delgado G, Kleber ME. Angeborene Störungen im Lipoproteinstoffwechsel. Herz 2017; 42:449-458. [DOI: 10.1007/s00059-017-4578-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
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25
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Weingärtner O, Lütjohann D, Plösch T, Elsässer A. Individualized lipid-lowering therapy to further reduce residual cardiovascular risk. J Steroid Biochem Mol Biol 2017; 169:198-201. [PMID: 27215141 DOI: 10.1016/j.jsbmb.2016.05.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Revised: 05/10/2016] [Accepted: 05/12/2016] [Indexed: 11/24/2022]
Abstract
Hypercholesterolemia is a major risk factor for cardiovascular diseases. Serum cholesterol concentrations are regulated by enteral absorption, biliary secretion, and hepatic synthesis. Statins inhibit the rate-limiting enzyme of cholesterol synthesis, HMG-CoA-reductase, and reduce serum cholesterol concentrations as well as cardiovascular morbidity and mortality. Some studies indicate that patients with high baseline cholesterol absorption may show only a small response to statin treatment in terms of cholesterol lowering. Data from genetic association studies and from the IMPROVE-IT trial show that reducing intestinal cholesterol absorption via NCP1L1 further reduces cardiovascular risk. However, some patients do not attain LDL-cholesterol targets on combination therapy. For these patients PCSK9-antibody treatment and lipid-apheresis are options to be considered. This article reviews the current literature on this issue and suggests 'individualized lipid-lowering therapy' as an approach to optimize and personalize lipid-lowering treatment of patients with hypercholesterolemia to further reduce residual cardiovascular risk.
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Affiliation(s)
- Oliver Weingärtner
- Department of Cardiology, University Hospital Oldenburg, European Medical School Oldenburg-Groningen, Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany.
| | - Dieter Lütjohann
- Institute for Clinical Chemistry and Clinical Pharmacology, University Clinics Bonn, Bonn, Germany
| | - Torsten Plösch
- Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Albrecht Elsässer
- Department of Cardiology, University Hospital Oldenburg, European Medical School Oldenburg-Groningen, Carl von Ossietzky Universität Oldenburg, Oldenburg, Germany
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26
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Widdowson WM, McGowan A, Phelan J, Boran G, Reynolds J, Gibney J. Vascular Disease Is Associated With the Expression of Genes for Intestinal Cholesterol Transport and Metabolism. J Clin Endocrinol Metab 2017; 102:326-335. [PMID: 27841945 DOI: 10.1210/jc.2016-2728] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 11/07/2016] [Indexed: 01/10/2023]
Abstract
CONTEXT Intestinal cholesterol metabolism is important in influencing postprandial lipoprotein concentrations, and might be important in the development of vascular disease. OBJECTIVE This study evaluated associations between expression of intestinal cholesterol metabolism genes, postprandial lipid metabolism, and endothelial function/early vascular disease in human subjects. DESIGN/PATIENTS One hundred patients undergoing routine oesophago-gastro-duodenoscopy were recruited. mRNA levels of Nieman-Pick C1-like 1 protein (NPC1L1), ABC-G5, ABC-G8, ABC-A1, microsomal tissue transport protein (MTTP), and sterol-regulatory element-binding protein (SREBP)-2 were measured in duodenal biopsies using quantitative reverse transcription polymerase chain reaction. Postprandially, serum lipid and glycemic profiles were measured, endothelial function was assessed using fasting, and postprandial flow-mediated dilatation (FMD) and carotid intima-media thickness (IMT). Subjects were divided into those above and below the median value of relative expression of each gene, and results were compared between the groups. RESULTS There were no between-group differences in demographic variables or classical cardiovascular risks. For all genes, the postprandial triglyceride incremental area under the curve was greater (P < 0.05) in the group with greater expression. Postprandial apolipoprotein B48 (ApoB48) levels were greater (P < 0.05) in groups with greater expression of NPC1L1, ABC-G8, and SREBP-2. For all genes, postprandial but not fasting FMD was lower (P < 0.01) in the group with greater expression. Triglyceride and ApoB48 levels correlated significantly with postprandial FMD. Carotid artery IMT was greater (P < 0.05) in groups with greater expression of MTTP, ABC-A1, and SREBP-2. CONCLUSION Intestinal cholesterol metabolism gene expression is significantly associated with postprandial increment in triglycerides, intestinal ApoB48, and reduced postprandial FMD. Some genes were also associated with increased IMT. These findings suggest a role of intestinal cholesterol metabolism in development of early vascular disease.
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Affiliation(s)
| | - Anne McGowan
- Department of Endocrinology and Diabetes Mellitus and
| | - James Phelan
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
| | - Gerard Boran
- Department of Chemical Pathology, Tallaght Hospital, Tallaght, Dublin 24, Ireland; and
| | - John Reynolds
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
| | - James Gibney
- Department of Endocrinology and Diabetes Mellitus and
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27
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Sahebkar A, Serban MC, Gluba-Brzózka A, Mikhailidis DP, Cicero AF, Rysz J, Banach M. Lipid-modifying effects of nutraceuticals: An evidence-based approach. Nutrition 2016; 32:1179-92. [PMID: 27324061 DOI: 10.1016/j.nut.2016.04.007] [Citation(s) in RCA: 142] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2015] [Revised: 04/04/2016] [Accepted: 04/17/2016] [Indexed: 01/14/2023]
Abstract
The present review provides an up-to-date summary of the findings on the lipid-lowering effects of the most important nutraceuticals and functional foods. Based on current knowledge, nutraceuticals might exert significant lipid-lowering, and their use has several advantages: A number of important questions remain to be addressed, including whether longer durations of therapy would result in a better response and the exact safety profile of nutraceuticals, especially at doses higher than those consumed in an average diet. Additionally, data regarding the effects of nutraceutical supplementation on the incidence of cardiovascular outcomes are lacking, and it is not clear whether additional lipid lowering by nutraceuticals can modify the residual cardiovascular risk that remains after statin therapy.
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Affiliation(s)
- Amirhossein Sahebkar
- Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Research Centre, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia
| | - Maria-Corina Serban
- Department of Functional Sciences, Discipline of Pathophysiology, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Anna Gluba-Brzózka
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Lodz, Poland
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Campus, University College London Medical School, University College London, London, United Kingdom
| | - Arrigo F Cicero
- Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Lodz, Poland
| | - Maciej Banach
- Department of Hypertension, Medical University of Lodz, Lodz, Poland.
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Andrade I, Santos L, Ramos F. Cholesterol absorption and synthesis markers in Portuguese hypercholesterolemic adults: A cross-sectional study. Eur J Intern Med 2016; 28:85-90. [PMID: 26577223 DOI: 10.1016/j.ejim.2015.10.022] [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: 01/12/2015] [Revised: 10/22/2015] [Accepted: 10/27/2015] [Indexed: 11/16/2022]
Abstract
OBJECTIVE The dynamics of cholesterol homeostasis and the development of cardiovascular disease (CVD) are complex and multifactorial, to which adds individual variability in the proportion of cholesterol from exogenous versus endogenous sources. The aim of this study was to undertake the first characterization of cholesterol absorption and synthesis profiles in Portuguese hypercholesterolemic adults through the quantification of surrogate markers, and the analysis of the predictive value of age and sex on the cholesterol homeostasis biomarkers. METHODS Serum samples for the measurement of lipid profiles and cholesterol homeostasis markers were obtained for 100 men and 112 women, aged 30-65, with TC ≥ 5.2 mmol/L (~200mg/dL) and/or LDL-C ≥ 2.6 mmol/L (~100mg/dL), none of whom were on any lipid-lowering therapy. RESULTS Overall, sex-specific significant differences were observed in the cholesterol homeostasis markers and lipid profiles; women had lower cholesterol synthesis marker concentrations (P<0.01 for lathosterol) and lipid parameters (except for HDL-C concentrations). Age-related significant differences were also found, including higher concentrations of cholesterol absorption markers in association with increasing age. CONCLUSION In our study, the predictors of higher levels of cholesterol absorption markers were higher age and female gender.
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Affiliation(s)
- Isabel Andrade
- Instituto Politécnico de Coimbra, ESTESC-Coimbra Health School, Ciências Complementares, Rua 5 Outubro, S. Martinho do Bispo, Apartado 7006, 3046-854 Coimbra, Portugal; CEF-Center for Pharmaceutical Studies, Health Sciences Campus, Pharmacy Faculty, University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
| | - Lèlita Santos
- Department of Internal Medicine, Coimbra University Hospitals, Medicine Faculty, University of Coimbra, 3000-075 Coimbra, Portugal
| | - Fernando Ramos
- CEF-Center for Pharmaceutical Studies, Health Sciences Campus, Pharmacy Faculty, University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; CNC-Center for Neuroscience and Cell Biology, Pharmacy Faculty, University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal.
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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: 16] [Impact Index Per Article: 1.6] [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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Katsura T, Katakami N, Irie Y, Yamamoto Y, Okusu T, Kubo F, Kanamaru Y, Nakashoutani I, Yoshiuchi K, Sakamoto K, Kaneto H, Shimomura I, Kosugi K. The usefulness of a cholesterol absorption inhibitor in Japanese type 2 diabetes patients with dyslipidemia. Diabetes Technol Ther 2015; 17:427-34. [PMID: 25714444 DOI: 10.1089/dia.2014.0228] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
AIM Cholesterol absorption has been suggested to be an independent risk factor for cerebral and cardiovascular events. We studied the clinical efficacy of ezetimibe in Japanese patients with type 2 diabetes mellitus complicated by dyslipidemia, in whom increased cholesterol absorption had been reported. SUBJECTS AND METHODS Ninety-six patients with type 2 diabetes complicated by dyslipidemia received ezetimibe at 10 mg/day for 12 weeks. The lipid profile, a cholesterol synthesis marker (lathosterol), and cholesterol absorption markers (cholestanol, sitosterol, and campesterol) were measured before and after the therapy to evaluate the clinical efficacy of ezetimibe. RESULTS Serum low-density lipoprotein-cholesterol (LDL-C) levels were positively associated with cholesterol absorption markers but not associated with a cholesterol synthesis marker, suggesting that serum LDL-C levels are more strongly related to cholesterol absorption than synthesis. During the 12-week ezetimibe treatment period, cholesterol absorption markers significantly decreased, and serum lipid profiles, including LDL-C levels, significantly improved. The LDL-C-lowering rate was greater in those patients who had been receiving statin therapy and were newly started on ezetimibe additionally than in the ezetimibe monotherapy group (-31.4% vs. -18.4%; P<0.001). CONCLUSIONS It is suggested that ezetimibe improves the lipid profile in Japanese type 2 diabetes patients with dyslipidemia through the substantial reduction of cholesterol absorption.
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Potential risks associated with increased plasma plant-sterol levels. DIABETES & METABOLISM 2014; 41:76-81. [PMID: 25497968 DOI: 10.1016/j.diabet.2014.11.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 11/05/2014] [Accepted: 11/07/2014] [Indexed: 12/30/2022]
Abstract
The consumption of plant sterols is associated with a decrease in LDL cholesterol. However, it is also associated with an increase in plasma plant-sterol (sitosterol, campesterol) levels that may be detrimental. Indeed, the genetic disease sitosterolaemia, which is characterized by elevated plasma levels of plant sterol, is associated with premature atherosclerosis. Yet, although plasma plant-sterol levels are recognized markers of cholesterol absorption, the relationship between such levels and atherosclerosis is not clear. Several studies have analysed the association between plasma plant-sterol levels and cardiovascular disease (CVD), but have found conflicting results. Although the largest prospective trials and genome-wide association studies suggest that high plasma levels of plant sterols are associated with increased CV risk, other studies have reported no such association and even an inverse relationship. Thus, the available data cannot confirm an increased CV risk with plant sterols, but cannot rule it out either. Only a prospective interventional trial to analyse the effects of plant-sterol-enriched food on the occurrence of CV events can exclude a potential CV risk linked with their consumption.
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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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Mackay DS, Jones PJH, Myrie SB, Plat J, Lütjohann D. Methodological considerations for the harmonization of non-cholesterol sterol bio-analysis. J Chromatogr B Analyt Technol Biomed Life Sci 2014; 957:116-22. [PMID: 24674990 DOI: 10.1016/j.jchromb.2014.02.052] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 01/15/2014] [Accepted: 02/10/2014] [Indexed: 12/26/2022]
Abstract
Non-cholesterol sterols (NCS) are used as surrogate markers of cholesterol metabolism which can be measured from a single blood sample. Cholesterol precursors are used as markers of endogenous cholesterol synthesis and plant sterols are used as markers of cholesterol absorption. However, most aspects of NCS analysis show wide variability among researchers within the area of biomedical research. This variability in methodology is a significant contributor to variation between reported NCS values and hampers the confidence in comparing NCS values across different research groups, as well as the ability to conduct meta-analyses. This paper summarizes the considerations and conclusions of a workshop where academic and industrial experts met to discuss NCS measurement. Highlighted is why each step in the analysis of NCS merits critical consideration, with the hopes of moving toward more standardized and comparable NCS analysis methodologies. Alkaline hydrolysis and liquid-liquid extraction of NCS followed by parallel detection on GC-FID and GC-MS is proposed as an ideal methodology for the bio-analysis of NCS. Furthermore the importance of cross-comparison or round robin testing between various groups who measure NCS is critical to the standardization of NCS measurement.
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Affiliation(s)
- Dylan S Mackay
- Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Peter J H Jones
- Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, Canada; Department of Food Sciences, University of Manitoba, Winnipeg, MB, Canada.
| | - Semone B Myrie
- Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Jogchum Plat
- Department of Human Biology, Maastricht University, Maastricht, The Netherlands
| | - Dieter Lütjohann
- Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
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Gylling H, Plat J, Turley S, Ginsberg HN, Ellegård L, Jessup W, Jones PJ, Lütjohann D, Maerz W, Masana L, Silbernagel G, Staels B, Borén J, Catapano AL, De Backer G, Deanfield J, Descamps OS, Kovanen PT, Riccardi G, Tokgözoglu L, Chapman MJ. Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease. Atherosclerosis 2014; 232:346-60. [DOI: 10.1016/j.atherosclerosis.2013.11.043] [Citation(s) in RCA: 352] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Accepted: 11/11/2013] [Indexed: 01/02/2023]
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Silbernagel G, Chapman MJ, Genser B, Kleber ME, Fauler G, Scharnagl H, Grammer TB, Mäkelä KM, Kähönen M, Carmena R, Rietzschel ER, Bruckert E, Deanfield JE, Raitakari OT, Lehtimäki T, März W. Reply. J Am Coll Cardiol 2014; 63:696-697. [DOI: 10.1016/j.jacc.2013.09.081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Accepted: 09/25/2013] [Indexed: 10/25/2022]
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Silbernagel G, Baumgartner I, Wanner C, März W. Toward individualized cholesterol-lowering treatment in end-stage renal disease. J Ren Nutr 2014; 24:65-71. [PMID: 24418266 DOI: 10.1053/j.jrn.2013.11.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 11/08/2013] [Accepted: 11/12/2013] [Indexed: 01/12/2023] Open
Abstract
There is broad evidence that lowering low-density lipoprotein (LDL) cholesterol will reduce cardiovascular risk. However, in patients on maintenance hemodialysis treatment, lowering LDL cholesterol is not as effective in preventing cardiovascular complications as in the general population. Cholesterol is either endogenously synthesized or absorbed from the intestine. It has been suggested that the benefit of using statins to prevent atherosclerotic complications is less pronounced in people with high absorption of cholesterol. Recent data indicate that patients on hemodialysis have high absorption of cholesterol. Therefore, these patients may benefit from dietary counseling to reduce cholesterol intake, from functional foods containing plant sterols and stanols, and from drugs that interfere with intestinal absorption of sterols (i.e., ezetimibe, bile acid resins, and sevelamer). This review discusses cholesterol homeostasis and the perspective of personalized treatment of hypercholesterolemia in hemodialysis.
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Affiliation(s)
- Guenther Silbernagel
- Department of Angiology, Swiss Cardiovascular Center, Inselspital, University of Bern, Bern, Switzerland; Division of Endocrinology, Diabetology, Nephrology, Vascular Disease, and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany.
| | - Iris Baumgartner
- Department of Angiology, Swiss Cardiovascular Center, Inselspital, University of Bern, Bern, Switzerland
| | - Christoph Wanner
- Division of Nephrology, Department of Medicine, University of Würzburg, Würzburg, Germany
| | - Winfried März
- Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, and Rheumatology), Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany; Synlab Academy, Synlab Services GmbH, Mannheim, Germany; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
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Nasu K, Terashima M, Habara M, Ko E, Ito T, Yokota D, Ishizuka S, Kurita T, Kimura M, Kinoshita Y, Asakura Y, Tsuchikane E, Katoh O, Suzuki T. Impact of Cholesterol Metabolism on Coronary Plaque Vulnerability of Target Vessels. JACC Cardiovasc Interv 2013; 6:746-55. [DOI: 10.1016/j.jcin.2013.02.018] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2012] [Revised: 01/10/2013] [Accepted: 02/02/2013] [Indexed: 12/31/2022]
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Silbernagel G, Chapman MJ, Genser B, Kleber ME, Fauler G, Scharnagl H, Grammer TB, Boehm BO, Mäkelä KM, Kähönen M, Carmena R, Rietzschel ER, Bruckert E, Deanfield JE, Miettinen TA, Raitakari OT, Lehtimäki T, März W. High Intestinal Cholesterol Absorption Is Associated With Cardiovascular Disease and Risk Alleles in ABCG8 and ABO. J Am Coll Cardiol 2013; 62:291-9. [DOI: 10.1016/j.jacc.2013.01.100] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Accepted: 01/03/2013] [Indexed: 12/01/2022]
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Matthan NR, Zhu L, Pencina M, D'Agostino RB, Schaefer EJ, Lichtenstein AH. Sex-specific differences in the predictive value of cholesterol homeostasis markers and 10-year cardiovascular disease event rate in Framingham Offspring Study participants. J Am Heart Assoc 2013; 2:e005066. [PMID: 23525441 PMCID: PMC3603247 DOI: 10.1161/jaha.112.005066] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2012] [Accepted: 12/24/2012] [Indexed: 01/05/2023]
Abstract
BACKGROUND Available data are inconsistent regarding factors influencing plasma cholesterol homeostasis marker concentrations and their value in predicting subsequent cardiovascular disease (CVD) events. METHODS AND RESULTS To address this issue, the relationship between markers of cholesterol absorption (campesterol, sitosterol, cholestanol) and synthesis (squalene, desmosterol, lathosterol) and 10-year CVD incidence was assessed in Framingham Offspring Study participants (cycle 6) who were without CVD at baseline and not taking lipid-lowering medications (N=2616). The primary end point was "hard" coronary heart disease (HCHD; coronary death and myocardial infarction), and the secondary end point was full CVD (HCHD plus stroke, coronary insufficiency, angina pectoris, peripheral artery disease, and congestive heart failure). In cross-sectional analysis, significant differences by sex, age, body mass index, blood pressure, and smoking status were observed. In both women and men, lower cholesterol absorption was associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol concentrations, whereas lower cholesterol synthesis was associated with higher low-density lipoprotein (LDL) cholesterol concentrations (P for trend <0.05). In women only, lower cholesterol synthesis and absorption were associated with higher non-HDL cholesterol concentrations. Using Cox proportional hazards model adjusting for standard CVD risk factors, squalene concentrations were associated with lower HCHD in women (hazard ratio=0.70 [0.5 to 0.9]). In contrast, squalene (hazard ratio=1.40 [1.1 to 1.8]) concentrations were associated with higher HCHD in men (P<0.0001 for interaction). The cholesterol absorption markers were not predictive of HCHD or full CVD in either women or men. CONCLUSIONS These data suggest significant sex differences in the 10-year prognostic value of cholesterol synthesis markers and HCHD, specifically coronary death and incidence of myocardial infarction. CLINICAL TRIAL REGISTRATION URL:http://ClinicalTrials.gov. Unique identifier: NCT00074464.
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Affiliation(s)
- Nirupa R Matthan
- Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA.
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Abstract
PURPOSE OF REVIEW Plant sterols as ingredients to functional foods are recommended for lowering LDL cholesterol. However, there is an ongoing discussion whether the use of plant sterols is safe. RECENT FINDINGS Genetic analyses showed that common variants of the ATP binding cassette transporter G8 (ABCG8) and ABO genes are associated with elevated circulating plant sterols and higher risk for cardiovascular disease. However, these data do not prove a causal role for plant sterols in atherosclerosis because the risk alleles in ABCG8 and ABO are also related to elevated total and LDL cholesterol levels. The ABO locus exhibits still further pleiotropy. Moreover, analyses in the general population indicated that moderately elevated circulating plant sterols are not correlated with present or future vascular disease. In agreement, novel studies using food frequency questionnaires, studies in experimental animals, and dietary intervention studies support that ingestion of plant sterols may be beneficial to cardiovascular health. SUMMARY Taken together, current evidence supports the recommendations for the use of plant sterols as LDL cholesterol-lowering agents. Nevertheless, a prospective, randomized, controlled, double-blinded, intervention trial conclusively showing that plant sterol supplementation will prevent hard cardiovascular endpoints is not available to date.
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Affiliation(s)
- Günther Silbernagel
- Division of Endocrinology, Diabetology, Nephrology, Vascular Disease, and Clinical Chemistry, Department of Internal Medicine, Eberhard-Karls-University Tübingen, Tübingen, Germany.
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Horenstein RB, Mitchell BD, Post WS, Lütjohann D, von Bergmann K, Ryan KA, Terrin M, Shuldiner AR, Steinle NI. The ABCG8 G574R variant, serum plant sterol levels, and cardiovascular disease risk in the Old Order Amish. Arterioscler Thromb Vasc Biol 2012; 33:413-9. [PMID: 23241408 DOI: 10.1161/atvbaha.112.245480] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE To determine whether long-term exposure to moderate elevations in plasma plant sterol levels increases risk for atherosclerosis. METHODS AND RESULTS In Old Order Amish participants aged 18 to 85 years, with (n=110) and without (n=181) 1 copy of the ABCG8 G574R variant, we compared mean plasma levels of plant sterols and cholesterol precursors and carotid intima-media wall thickness. Carriers of a single 574R allele had increased plant sterol levels (eg, 35%-37% higher plasma levels of sitosterol, campesterol, and stigmasterol) and increased plant sterol/cholesterol ratios (P<0.001 for all). 574R carriers had significantly decreased levels of lathosterol and lanosterol, precursors in a pathway for endogenous cholesterol synthesis, suggesting that plant sterols may alter regulation of genes involved in cholesterol synthesis. The G574R variant was not associated with high-density lipoprotein cholesterol or low-density lipoprotein cholesterol levels. Compared with noncarriers, 574R carriers had decreased carotid intima-media wall thickness (0.62 versus 0.66 mm; age- and sex-adjusted P=0.03). Adjustment for body weight, blood pressure, and standard lipid measures (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides) did not alter this association. CONCLUSIONS Although the G574R variant is associated with moderately elevated plant sterol levels, carriers of the 574R allele had modestly lower levels of carotid wall thickness compared with noncarriers.
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Affiliation(s)
- Richard B Horenstein
- Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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Progress and prospective of plant sterol and plant stanol research: Report of the Maastricht meeting. Atherosclerosis 2012; 225:521-33. [DOI: 10.1016/j.atherosclerosis.2012.09.018] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Accepted: 09/16/2012] [Indexed: 12/29/2022]
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Kasmas SH, Izar MC, França CN, Ramos SC, Moreira FT, Helfenstein T, Moreno RA, Borges NC, Figueiredo-Neto AM, Fonseca FA. Differences in synthesis and absorption of cholesterol of two effective lipid-lowering therapies. Braz J Med Biol Res 2012; 45:1095-101. [PMID: 22801416 PMCID: PMC3854149 DOI: 10.1590/s0100-879x2012007500118] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2012] [Accepted: 05/10/2012] [Indexed: 12/13/2022] Open
Abstract
Effective statin therapy is associated with a marked reduction of cardiovascular events. However, the explanation for full benefits obtained for LDL cholesterol targets by combined lipid-lowering therapy is controversial. Our study compared the effects of two equally effective lipid-lowering strategies on markers of cholesterol synthesis and absorption. A prospective, open label, randomized, parallel design study, with blinded endpoints, included 116 subjects. We compared the effects of a 12-week treatment with 40 mg rosuvastatin or the combination of 40 mg simvastatin/10 mg ezetimibe on markers of cholesterol absorption (campesterol and β-sitosterol), synthesis (desmosterol), and their ratios to cholesterol. Both therapies similarly decreased total and LDL cholesterol, triglycerides and apolipoprotein B, and increased apolipoprotein A1 (P < 0.05 vs baseline for all). Simvastatin/ezetimibe increased plasma desmosterol (P = 0.012 vs baseline), and decreased campesterol and β-sitosterol (P < 0.0001 vs baseline for both), with higher desmosterol (P = 0.007) and lower campesterol and β-sitosterol compared to rosuvastatin, (P < 0.0001, for both). In addition, rosuvastatin increased the ratios of these markers to cholesterol (P < 0.002 vs baseline for all), whereas simvastatin/ezetimibe significantly decreased the campesterol/cholesterol ratio (P = 0.008 vs baseline) and tripled the desmosterol/cholesterol ratio (P < 0.0001 vs baseline). The campesterol/cholesterol and β-sitosterol/cholesterol ratios were lower, whereas the desmosterol/cholesterol ratio was higher in patients receiving simvastatin/ezetimibe (P < 0.0001 vs rosuvastatin, for all). Pronounced differences in markers of cholesterol absorption and synthesis were observed between two equally effective lipid-lowering strategies.
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Affiliation(s)
- S H Kasmas
- Divisão de Cardiologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil
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Abstract
PURPOSE OF REVIEW Noncholesterol sterols (NCSs) in plasma encompass endogenous cholesterol precursors and exogenous phytosterols and cholesterol metabolites, which are used as surrogate measures of cholesterol synthesis and cholesterol absorption, respectively. The ratios of cholesterol synthesis to cholesterol absorption surrogates are also utilized to assess the overall balance of cholesterol metabolism, with higher values representing more synthesis and lower values more absorption. The objective of this review is to focus on recent findings using plasma NCSs and their potential in customizing dietary and pharmacological hypolipidemic therapies. RECENT FINDINGS NCSs are often used to assess the impact of pharmacological and dietary interventions on cholesterol metabolism. Various forms of dyslipidemia have been characterized using NCSs, and NCSs may be a valuable tool in selecting appropriate treatment therapies. NCSs levels are affected by genetic, dietary and physiological factors and have been related to cardiovascular disease risk. SUMMARY The expanded use of plasma NCSs is currently limited by the lack of standardized methodology. However, noncholesterol sterols are still a valuable research tool for the overall assessment of cholesterol metabolism and may have clinical potential in the personalization of diet and medicine.
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Affiliation(s)
- Dylan S MacKay
- Richardson Centre for Functional Foods and Nutraceuticals Department of Human Nutritional Sciences Department of Food Science, University of Manitoba, Winnipeg, Manitoba, Canada
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Lupattelli G, Siepi D, De Vuono S, Roscini AR, Crisanti F, Covelli D, Pirro M, Mannarino E. Cholesterol metabolism differs after statin therapy according to the type of hyperlipemia. Life Sci 2012; 90:846-50. [PMID: 22554491 DOI: 10.1016/j.lfs.2012.03.038] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Revised: 03/16/2012] [Accepted: 03/24/2012] [Indexed: 10/28/2022]
Abstract
AIM Non-cholesterol sterols reflect cholesterol metabolism. Statins reduce cholesterol synthesis usually with a rise in cholesterol absorption. Common hyperlipemias have shown different patterns of cholesterol metabolism. We evaluated whether cholesterol absorption and synthesis may differ after statin therapy in primary hyperlipemias. MAIN METHODS We determined lipid profile, apoprotein B and serum sterols (lathosterol, sitosterol, campesterol by gas chromatography/mass spectrometry) before and after statins in 80 untreated hyperlipemic patients, 40 with polygenic hypercholesterolemia (PH) and 40 with familial combined hyperlipemia (FCH). KEY FINDINGS At baseline in FCH lathosterol was significantly higher while campesterol and sitosterol were significantly lower than in PH. After statins, the reduction in LDL-C did not significantly differ between the two groups; in PH there was a significant decrease of lathosterol from 96.1 to 52.6 102 μmol/mmol cholesterol (p=0.0001) with no significant modifications in campesterol and sitosterol; on the opposite, in FCH lathosterol decreased from 117 to 43 102 μmol/mmol cholesterol (p=0.0001) and campesterol and sitosterol significantly increased from 38 to 48 102 μmol/mmol cholesterol (p=0.0001), and from 75 to 86 102 μmol/mmol cholesterol, (p=0.022), respectively. After statin therapy only in FCH Δ-LDL-C showed a significant inverse correlation with Δ-sitosterol and with Δ-campesterol. SIGNIFICANCE Primary hyperlipemias show different patterns of response to statins: in PH LDL reduction appears completely "synthesis inhibition" dependent, while in FCH LDL decrease appears to be synthesis dependent, partially limited by absorption increase. Studying cholesterol metabolism before and after hypolipemic therapy might be useful in identifying the best tailored treatment.
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Affiliation(s)
- Graziana Lupattelli
- Internal Medicine, Angiology and Atherosclerosis, Department of Clinical and Experimental Medicine, University of Perugia, Italy.
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Genser B, Silbernagel G, De Backer G, Bruckert E, Carmena R, Chapman MJ, Deanfield J, Descamps OS, Rietzschel ER, Dias KC, März W. Plant sterols and cardiovascular disease: a systematic review and meta-analysis. Eur Heart J 2012; 33:444-51. [PMID: 22334625 PMCID: PMC3279314 DOI: 10.1093/eurheartj/ehr441] [Citation(s) in RCA: 138] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The impact of increased serum concentrations of plant sterols on cardiovascular risk is unclear. We conducted a systematic review and meta-analysis aimed to investigate whether there is an association between serum concentrations of two common plant sterols (sitosterol, campesterol) and cardiovascular disease (CVD). We systematically searched the databases MEDLINE, EMBASE, and COCHRANE for studies published between January 1950 and April 2010 that reported either risk ratios (RR) of CVD in relation to serum sterol concentrations (either absolute or expressed as ratios relative to total cholesterol) or serum sterol concentrations in CVD cases and controls separately. We conducted two meta-analyses, one based on RR of CVD contrasting the upper vs. the lower third of the sterol distribution, and another based on standardized mean differences between CVD cases and controls. Summary estimates were derived by fixed and random effects meta-analysis techniques. We identified 17 studies using different designs (four case–control, five nested case–control, three cohort, five cross-sectional) involving 11 182 participants. Eight studies reported RR of CVD and 15 studies reported serum concentrations in CVD cases and controls. Funnel plots showed evidence for publication bias indicating small unpublished studies with non-significant findings. Neither of our meta-analyses suggested any relationship between serum concentrations of sitosterol and campesterol (both absolute concentrations and ratios to cholesterol) and risk of CVD. Our systematic review and meta-analysis did not reveal any evidence of an association between serum concentrations of plant sterols and risk of CVD.
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Affiliation(s)
- Bernd Genser
- Mannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
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Lottenberg AM, Bombo RP, Ilha A, Nunes VS, Nakandakare ER, Quintão EC. Do clinical and experimental investigations support an antiatherogenic role for dietary phytosterols/stanols? IUBMB Life 2012; 64:296-306. [DOI: 10.1002/iub.1006] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2011] [Accepted: 12/31/2011] [Indexed: 11/12/2022]
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Competitive solubilization of cholesterol and β-sitosterol with changing biliary lipid compositions in model intestinal solution. Chem Phys Lipids 2012; 165:7-14. [DOI: 10.1016/j.chemphyslip.2011.10.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2011] [Revised: 10/05/2011] [Accepted: 10/11/2011] [Indexed: 11/17/2022]
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Khuchieva MA, Perova NV, Akhmedzhanov NM. Plant sterols and stanols as dietary factors reducing hypercholesterolemia by inhibiting intestinal cholesterol absorption. КАРДИОВАСКУЛЯРНАЯ ТЕРАПИЯ И ПРОФИЛАКТИКА 2011. [DOI: 10.15829/1728-8800-2011-6-124-132] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
The review is focussed on the mechanisms of action, lipid-lowering activity, structural characteristics, and safety of plant sterins and stanols. Phytosterins and phytostanols inhibit intestinal cholesterol (CH) absorption, therefore decreasing plasma CH levels. The emphasis is put on prospective epidemiological studies of representative samples, which demonstrated that plasma concentrations of phytosterins and phytostanols in patients with coronary heart disease (CHD) are substantially lower than in CHD-free participants. A two-fold increase in serum sytosterin concentration was associated with a reduction in relative risk of CHD by 22 %. Plant sterin and sterol esters could be regarded as effective and safe dietary ingredients decreasing blood levels of CH — one of the major cardiovascular disease risk factors.
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