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Roth K, Yang Z, Agarwal M, Birbeck J, Westrick J, Lydic T, Gurdziel K, Petriello MC. Exposure of Ldlr-/- Mice to a PFAS Mixture and Outcomes Related to Circulating Lipids, Bile Acid Excretion, and the Intestinal Transporter ASBT. ENVIRONMENTAL HEALTH PERSPECTIVES 2024; 132:87007. [PMID: 39177951 PMCID: PMC11343043 DOI: 10.1289/ehp14339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 07/24/2024] [Accepted: 07/29/2024] [Indexed: 08/24/2024]
Abstract
BACKGROUND Previous epidemiological studies have repeatedly found per- and polyfluoroalkyl substances (PFAS) exposure associated with higher circulating cholesterol, one of the greatest risk factors for development of coronary artery disease. The main route of cholesterol catabolism is through its conversion to bile acids, which circulate between the liver and ileum via enterohepatic circulation. Patients with coronary artery disease have decreased bile acid excretion, indicating that PFAS-induced impacts on enterohepatic circulation may play a critical role in cardiovascular risk. OBJECTIVES Using a mouse model with high levels of low-density and very low-density lipoprotein (LDL and VLDL, respectively) cholesterol and aortic lesion development similar to humans, the present study investigated mechanisms linking exposure to a PFAS mixture with increased cholesterol. METHODS Male and female L d l r - / - mice were fed an atherogenic diet (Clinton/Cybulsky low fat, 0.15% cholesterol) and exposed to a mixture of 5 PFAS representing legacy, replacement, and emerging subtypes (i.e., PFOA, PFOS, PFHxS, PFNA, GenX), each at a concentration of 2 mg / L , for 7 wk. Blood was collected longitudinally for cholesterol measurements, and mass spectrometry was used to measure circulating and fecal bile acids. Transcriptomic analysis of ileal samples was performed via RNA sequencing. RESULTS After 7 wk of PFAS exposure, average circulating PFAS levels were measured at 21.6, 20.1, 31.2, 23.5, and 1.5 μ g / mL in PFAS-exposed females and 12.9, 9.7, 23, 14.3, and 1.7 μ g / mL in PFAS-exposed males for PFOA, PFOS, PFHxS, PFNA, and GenX, respectively. Total circulating cholesterol levels were higher in PFAS-exposed mice after 7 wk (352 mg / dL vs. 415 mg / dL in female mice and 392 mg / dL vs. 488 mg / dL in male mice exposed to vehicle or PFAS, respectively). Total circulating bile acid levels were higher in PFAS-exposed mice (2,978 pg / μ L vs. 8,496 pg / μ L in female mice and 1,960 pg / μ L vs. 4,452 pg / μ L in male mice exposed to vehicle or PFAS, respectively). In addition, total fecal bile acid levels were lower in PFAS-exposed mice (1,797 ng / mg vs. 682 ng / mg in females and 1,622 ng / mg vs. 670 ng / mg in males exposed to vehicle or PFAS, respectively). In the ileum, expression levels of the apical sodium-dependent bile acid transporter (ASBT) were higher in PFAS-exposed mice. DISCUSSION Mice exposed to a PFAS mixture displayed higher circulating cholesterol and bile acids perhaps due to impacts on enterohepatic circulation. This study implicates PFAS-mediated effects at the site of the ileum as a possible critical mediator of increased cardiovascular risk following PFAS exposure. https://doi.org/10.1289/EHP14339.
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Affiliation(s)
- Katherine Roth
- Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan, USA
| | - Zhao Yang
- Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan, USA
| | - Manisha Agarwal
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Johnna Birbeck
- Department of Chemistry, Lumigen Instrumentation Center, Wayne State University, Detroit, Michigan, USA
| | - Judy Westrick
- Department of Chemistry, Lumigen Instrumentation Center, Wayne State University, Detroit, Michigan, USA
| | - Todd Lydic
- Department of Physiology, Michigan State University, East Lansing, Michigan, USA
| | - Katherine Gurdziel
- Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan, USA
- Genome Sciences Core, Wayne State University, Detroit, Michigan, USA
| | - Michael C. Petriello
- Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan, USA
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan, USA
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Vargas-Vargas MA, González-Montoya M, Torres-Isidro O, García-Berumen CI, Ortiz-Avila O, Calderón-Cortés E, Cortés-Rojo C. Assessing the impact of concurrent high-fructose and high-saturated fat diets on pediatric metabolic syndrome: A review. World J Clin Pediatr 2024; 13:91478. [PMID: 38947987 PMCID: PMC11212767 DOI: 10.5409/wjcp.v13.i2.91478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 04/22/2024] [Accepted: 05/06/2024] [Indexed: 06/07/2024] Open
Abstract
High-saturated fat (HF) or high-fructose (HFr) consumption in children predispose them to metabolic syndrome (MetS). In rodent models of MetS, diets containing individually HF or HFr lead to a variable degree of MetS. Nevertheless, simultaneous intake of HF plus HFr have synergistic effects, worsening MetS outcomes. In children, the effects of HF or HFr intake usually have been addressed individually. Therefore, we have reviewed the outcomes of HF or HFr diets in children, and we compare them with the effects reported in rodents. In humans, HFr intake causes increased lipogenesis, hypertriglyceridemia, obesity and insulin resistance. On the other hand, HF diets promote low grade-inflammation, obesity, insulin resistance. Despite the deleterious effects of simultaneous HF plus HFr intake on MetS development in rodents, there is little information about the combined effects of HF plus HFr intake in children. The aim of this review is to warn about this issue, as individually addressing the effects produced by HF or HFr may underestimate the severity of the outcomes of Western diet intake in the pediatric population. We consider that this is an alarming issue that needs to be assessed, as the simultaneous intake of HF plus HFr is common on fast food menus.
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Affiliation(s)
- Manuel Alejandro Vargas-Vargas
- Instituto de Investigaciones Químico – Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia 58030, Michoacán, Mexico
| | - Marcela González-Montoya
- Instituto de Investigaciones Químico – Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia 58030, Michoacán, Mexico
| | - Olin Torres-Isidro
- Instituto de Investigaciones Químico – Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia 58030, Michoacán, Mexico
| | - Claudia Isabel García-Berumen
- Instituto de Investigaciones Químico – Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia 58030, Michoacán, Mexico
| | - Omar Ortiz-Avila
- Facultad de Enfermería, Universidad Michoacana de San Nicolás de Hidalgo, Morelia 58020, Michoacán, Mexico
| | - Elizabeth Calderón-Cortés
- Facultad de Enfermería, Universidad Michoacana de San Nicolás de Hidalgo, Morelia 58020, Michoacán, Mexico
| | - Christian Cortés-Rojo
- Instituto de Investigaciones Químico – Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia 58030, Michoacán, Mexico
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Das P, Ingole N. Lipoproteins and Their Effects on the Cardiovascular System. Cureus 2023; 15:e48865. [PMID: 38106760 PMCID: PMC10724412 DOI: 10.7759/cureus.48865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 11/15/2023] [Indexed: 12/19/2023] Open
Abstract
Coronary heart disease is the foremost leading cause of death across the world. It mainly involves the blood vessels, which supply the heart. Plaque formation due to lipid deposition leads to the narrowing of the vessels, obstructing blood flow. Therefore, lipoproteins such as high-density lipoproteins (HDL), low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), and chylomicrons play a crucial role in cardiovascular diseases. Lipoproteins are carrier molecules made up of proteins and fats. They carry cholesterol through the bloodstream and transport it to the peripheral tissues or the liver. There are several classes of lipoproteins in the blood, namely HDL, LDL, VLDL, and chylomicrons. Depending on the lipoproteins, an excess of them can either harm or benefit the body. Low-density lipoprotein, nicknamed 'the bad cholesterol,' transports fatty molecules from the liver and deposits them in peripheral tissues or central vessels. Thus, excess LDL can cause blockage of the arteries supplying major organs. High-density lipoprotein, nicknamed 'the good cholesterol,' transports the excess fatty molecules to the liver for their metabolism and removal from the body. Hence, high levels of HDL are an indication of a healthy body. Thus, lipoproteins are important molecules, and their proper regulation is essential to maintaining a healthy body. An effective way to maintain a balanced lipoprotein level is to have a properly balanced diet with high protein and low fat. Regular exercise, both indoors and outdoors, is recommended. If cholesterol levels are not maintained by diet and exercise, medication is advised after consulting medical experts. This review aims to inform people about lipoproteins, their importance, and maintaining a healthy lipoprotein level.
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Affiliation(s)
- Pratyush Das
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Nishikant Ingole
- Pharmacology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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Moldovan R, Mitrea DR, Florea A, Chiş IC, Suciu Ş, David L, Moldovan BE, Mureşan LE, Lenghel M, Ungur RA, Opriş RV, Decea N, Clichici SV. Effects of Gold Nanoparticles Functionalized with Bioactive Compounds from Cornus mas Fruit on Aorta Ultrastructural and Biochemical Changes in Rats on a Hyperlipid Diet-A Preliminary Study. Antioxidants (Basel) 2022; 11:antiox11071343. [PMID: 35883833 PMCID: PMC9311980 DOI: 10.3390/antiox11071343] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/01/2022] [Accepted: 07/06/2022] [Indexed: 02/04/2023] Open
Abstract
Cornus mas L. extract (CM) presents hypolipidemic, antioxidant and anti-inflammatory activity. Gold nanoparticles (AuNPs) are considered potent delivery systems and may be used to release pharmaceutical compounds at the level of injury. In our study, we used gold nanoparticles functionalized with bioactive compounds from Cornus mas L. (AuNPsCM) in an experimental model of a high-fat diet (HFD), and we assessed their effects on aorta wall but also in the serum, as compared to Cornus mas (CM) administration. Sprague Dawley female rats were fed for 9 months with an HFD. During the last month of the experiment, we randomly allocated the animals into three groups that received, by oral gavage: saline solution, CM solution (0.158 mg/mL polyphenols) or AuNPsCM solution (260 μg Au/kg/day), while a Control group received a standard diet and saline solution. At the end of the experiment, we performed an ultrasonography of the aorta and left ventricle and a histology and transmission electron microscopy of the aorta walls; we investigated the oxidative stress and inflammation in aorta homogenates and in serum and, in addition, the lipid profile. AuNPsCM presented better effects in comparison with the natural extract (CM) on lipid peroxidation (p < 0.01) and TNF-alpha (p < 0.001) in aorta homogenates. In serum, both CM and AuNPsCM decreased the triglycerides (p < 0.001) and C-reactive protein (CM, p < 0.01; AuNPsCM, p < 0.001) and increased the antioxidant protection (p < 0.001), in comparison with the HFD group. In intima, AuNPsCM produced ultrastructural lesions, with the disorganization of intima and subendothelial connective layer, whereas CM administration preserved the intima normal aspect, but with a thinned subendothelial connective layer. AuNPsCM oral administration presented certain antioxidant, anti-inflammatory and hypolipidemic effects in an experimental model of HFD, but with a negative impact on the ultrastructure of aorta walls, highlighted by the intima disorganization.
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Affiliation(s)
- Remus Moldovan
- Department of Physiology, Iuliu Hatieganu University of Medicine and Pharmacy, 1-3 Clinicilor Street, 400006 Cluj-Napoca, Romania; (R.M.); (I.-C.C.); (Ş.S.); (N.D.); (S.V.C.)
| | - Daniela-Rodica Mitrea
- Department of Physiology, Iuliu Hatieganu University of Medicine and Pharmacy, 1-3 Clinicilor Street, 400006 Cluj-Napoca, Romania; (R.M.); (I.-C.C.); (Ş.S.); (N.D.); (S.V.C.)
- Correspondence:
| | - Adrian Florea
- Department of Cell and Molecular Biology, Iuliu Hatieganu University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania; (A.F.); (R.V.O.)
| | - Irina-Camelia Chiş
- Department of Physiology, Iuliu Hatieganu University of Medicine and Pharmacy, 1-3 Clinicilor Street, 400006 Cluj-Napoca, Romania; (R.M.); (I.-C.C.); (Ş.S.); (N.D.); (S.V.C.)
| | - Şoimiţa Suciu
- Department of Physiology, Iuliu Hatieganu University of Medicine and Pharmacy, 1-3 Clinicilor Street, 400006 Cluj-Napoca, Romania; (R.M.); (I.-C.C.); (Ş.S.); (N.D.); (S.V.C.)
| | - Luminiţa David
- Research Center for Advanced Chemical Analysis, Instrumentation and Chemometrics, Faculty of Chemistry and Chemical Engineering, Babes-Bolyai University, 11 Arany Janos Street, 400028 Cluj-Napoca, Romania; (L.D.); (B.E.M.)
| | - Bianca Elena Moldovan
- Research Center for Advanced Chemical Analysis, Instrumentation and Chemometrics, Faculty of Chemistry and Chemical Engineering, Babes-Bolyai University, 11 Arany Janos Street, 400028 Cluj-Napoca, Romania; (L.D.); (B.E.M.)
| | - Laura Elena Mureşan
- Raluca Ripan Institute of Research in Chemistry, Babes-Bolyai University, 30 Fantanele Street, 400294 Cluj-Napoca, Romania;
| | - Manuela Lenghel
- Radiology Department, Iuliu Hatieganu University of Medicine and Pharmacy, 1–3 Clinicilor Street, 400006 Cluj-Napoca, Romania;
| | - Rodica Ana Ungur
- Department of Rehabilitation, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania;
| | - Răzvan Vlad Opriş
- Department of Cell and Molecular Biology, Iuliu Hatieganu University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania; (A.F.); (R.V.O.)
| | - Nicoleta Decea
- Department of Physiology, Iuliu Hatieganu University of Medicine and Pharmacy, 1-3 Clinicilor Street, 400006 Cluj-Napoca, Romania; (R.M.); (I.-C.C.); (Ş.S.); (N.D.); (S.V.C.)
| | - Simona Valeria Clichici
- Department of Physiology, Iuliu Hatieganu University of Medicine and Pharmacy, 1-3 Clinicilor Street, 400006 Cluj-Napoca, Romania; (R.M.); (I.-C.C.); (Ş.S.); (N.D.); (S.V.C.)
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Control of Cholesterol Metabolism Using a Systems Approach. BIOLOGY 2022; 11:biology11030430. [PMID: 35336806 PMCID: PMC8945167 DOI: 10.3390/biology11030430] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 03/06/2022] [Accepted: 03/08/2022] [Indexed: 11/25/2022]
Abstract
Simple Summary Cholesterol is the main sterol in mammals that is essential for healthy cell functionining. It plays a key role in metabolic regulation and signaling, it is a precursor molecule of bile acids, oxysterols, and all steroid hormones. It also contributes to the structural makeup of the membranes. Its homeostasis is tightly controlled since it can harm the body if it is allowed to reach abnormal blood concentrations. One of the diseases associated with elevated cholesterol levels being the major cause of morbidities and mortalities worldwide, is atherosclerosis. In this study, we have developed a model of the cholesterol metabolism taking into account local inflammation and oxidative stress. The aim was to investigate the impact of the interplay of those processes and cholesterol metabolism disturbances on the atherosclerosis development and progression. We have also analyzed the effect of combining different classes of drugs targeting selected components of cholesterol metabolism. Abstract Cholesterol is an essential component of mammalian cells and is involved in many fundamental physiological processes; hence, its homeostasis in the body is tightly controlled, and any disturbance has serious consequences. Disruption of the cellular metabolism of cholesterol, accompanied by inflammation and oxidative stress, promotes the formation of atherosclerotic plaques and, consequently, is one of the leading causes of death in the Western world. Therefore, new drugs to regulate disturbed cholesterol metabolism are used and developed, which help to control cholesterol homeostasis but still do not entirely cure atherosclerosis. In this study, a Petri net-based model of human cholesterol metabolism affected by a local inflammation and oxidative stress, has been created and analyzed. The use of knockout of selected pathways allowed us to observe and study the effect of various combinations of commonly used drugs on atherosclerosis. The analysis results led to the conclusion that combination therapy, targeting multiple pathways, may be a fundamental concept in the development of more effective strategies for the treatment and prevention of atherosclerosis.
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Lee JH, Lee HS, Cho AR, Lee YJ, Kwon YJ. Non-Alcoholic Fatty Liver Disease Is an Independent Risk Factor for LDL Cholesterol Target Level. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18073442. [PMID: 33810315 PMCID: PMC8037151 DOI: 10.3390/ijerph18073442] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/24/2021] [Accepted: 03/24/2021] [Indexed: 12/11/2022]
Abstract
Although patients with non-alcoholic fatty liver disease (NAFLD) face a higher risk of cardiovascular disease (CVD), it is not known whether people with NAFLD are less likely to achieve optimal management of low-density lipoprotein (LDL) cholesterol than those without NAFLD. We aimed to investigate the longitudinal effect of NAFLD on the management of LDL cholesterol in 5610 adults from the Korean Genome and Epidemiology Study. Participants were classified into NAFLD and normal groups. Non-achievement of the target LDL cholesterol level was set according to one's cardiovascular disease (CVD) risk level. The estimated proportion of individuals who did not achieve their LDL cholesterol targets was higher in the NAFLD group than in the normal group during the follow-up period of 12 years in a generalized estimation equation model. Multivariable Cox regression analysis revealed a hazard ratio and 95% confidence interval for incident non-achievement of one's LDL cholesterol target of 1.196 (1.057-1.353) in the NAFLD group (p = 0.005). We found that NAFLD was significantly related to non-achievement of LDL cholesterol targets in this prospective cohort study. Prevention and proper management of NAFLD have important health implications for the prevention of CVD.
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Affiliation(s)
- Jun-Hyuk Lee
- Department of Family Medicine, Nowon Eulji Medical Center, Eulji University, Seoul 01830, Korea;
- School of Medicine, Eulji University, Daejeon 34824, Korea
| | - Hye Sun Lee
- Biostatistics Collaboration Unit, Department of Research Affairs, Yonsei University College of Medicine, Seoul 06273, Korea;
| | - A-Ra Cho
- Department of Family Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul 06273, Korea; (A.-R.C.); (Y.-J.L.)
| | - Yong-Jae Lee
- Department of Family Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul 06273, Korea; (A.-R.C.); (Y.-J.L.)
| | - Yu-Jin Kwon
- Department of Family Medicine, Yonsei University College of Medicine, Yongin Severance Hospital, Yongin-si 16995, Korea
- Correspondence: ; Tel.: +82-31-5189-8777
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Vors C, Joumard-Cubizolles L, Lecomte M, Combe E, Ouchchane L, Drai J, Raynal K, Joffre F, Meiller L, Le Barz M, Gaborit P, Caille A, Sothier M, Domingues-Faria C, Blot A, Wauquier A, Blond E, Sauvinet V, Gésan-Guiziou G, Bodin JP, Moulin P, Cheillan D, Vidal H, Morio B, Cotte E, Morel-Laporte F, Laville M, Bernalier-Donadille A, Lambert-Porcheron S, Malpuech-Brugère C, Michalski MC. Milk polar lipids reduce lipid cardiovascular risk factors in overweight postmenopausal women: towards a gut sphingomyelin-cholesterol interplay. Gut 2020; 69:487-501. [PMID: 31189655 PMCID: PMC7034342 DOI: 10.1136/gutjnl-2018-318155] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 04/29/2019] [Accepted: 04/30/2019] [Indexed: 12/21/2022]
Abstract
OBJECTIVE To investigate whether milk polar lipids (PL) impact human intestinal lipid absorption, metabolism, microbiota and associated markers of cardiometabolic health. DESIGN A double-blind, randomised controlled 4-week study involving 58 postmenopausal women was used to assess the chronic effects of milk PL consumption (0, 3 or 5 g-PL/day) on lipid metabolism and gut microbiota. The acute effects of milk PL on intestinal absorption and metabolism of cholesterol were assessed in a randomised controlled crossover study using tracers in ileostomy patients. RESULTS Over 4 weeks, milk PL significantly reduced fasting and postprandial plasma concentrations of cholesterol and surrogate lipid markers of cardiovascular disease risk, including total/high-density lipoprotein-cholesterol and apolipoprotein (Apo)B/ApoA1 ratios. The highest PL dose preferentially induced a decreased number of intestine-derived chylomicron particles. Also, milk PL increased faecal loss of coprostanol, a gut-derived metabolite of cholesterol, but major bacterial populations and faecal short-chain fatty acids were not affected by milk PL, regardless of the dose. Acute ingestion of milk PL by ileostomy patients shows that milk PL decreased cholesterol absorption and increased cholesterol-ileal efflux, which can be explained by the observed co-excretion with milk sphingomyelin in the gut. CONCLUSION The present data demonstrate for the first time in humans that milk PL can improve the cardiometabolic health by decreasing several lipid cardiovascular markers, notably through a reduced intestinal cholesterol absorption involving specific interactions in the gut, without disturbing the major bacterial phyla of gut microbiota. TRIAL REGISTRATION NUMBER NCT02099032 and NCT02146339; Results.
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Affiliation(s)
- Cécile Vors
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Charles Mérieux Medical School, 69600, Oullins, France
- CRNH Rhône-Alpes, Hospices Civils de Lyon, CENS, Centre de Recherche en Nutrition Humaine Rhône-Alpes, 69310, Pierre-Bénite, France
| | - Laurie Joumard-Cubizolles
- Université Clermont Auvergne, INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, 63000, Clermont-Ferrand, France
| | - Manon Lecomte
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Charles Mérieux Medical School, 69600, Oullins, France
| | - Emmanuel Combe
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Charles Mérieux Medical School, 69600, Oullins, France
| | - Lemlih Ouchchane
- Université Clermont Auvergne, CNRS, SIGMA Clermont, Institut Pascal, 63000, Clermont-Ferrand, France
- CHU Clermont-Ferrand, Unité de Biostatistique-Informatique Médicale, 63000, Clermont-Ferrand, France
| | - Jocelyne Drai
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Charles Mérieux Medical School, 69600, Oullins, France
- Unité de Nutrition Endocrinologie Métabolisme, Service de Biochimie, Centre de Biologie et de Pathologie Sud, Hospices Civils de Lyon, 69310, Pierre-Bénite, France
| | - Ketsia Raynal
- ACTALIA Dairy Products and Technologies, 17700, Surgères, France
| | | | - Laure Meiller
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Charles Mérieux Medical School, 69600, Oullins, France
- CRNH Rhône-Alpes, Hospices Civils de Lyon, CENS, Centre de Recherche en Nutrition Humaine Rhône-Alpes, 69310, Pierre-Bénite, France
| | - Mélanie Le Barz
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Charles Mérieux Medical School, 69600, Oullins, France
| | - Patrice Gaborit
- ACTALIA Dairy Products and Technologies, 17700, Surgères, France
| | - Aurélie Caille
- CHU Clermont-Ferrand, CRNH Auvergne, 63000, Clermont-Ferrand, France
| | - Monique Sothier
- CRNH Rhône-Alpes, Hospices Civils de Lyon, CENS, Centre de Recherche en Nutrition Humaine Rhône-Alpes, 69310, Pierre-Bénite, France
| | - Carla Domingues-Faria
- Université Clermont Auvergne, INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, 63000, Clermont-Ferrand, France
| | - Adeline Blot
- CHU Clermont-Ferrand, CRNH Auvergne, 63000, Clermont-Ferrand, France
| | - Aurélie Wauquier
- Université Clermont Auvergne, INRA, UMR 454, MEDIS, 63000, Clermont-Ferrand, France
| | - Emilie Blond
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Charles Mérieux Medical School, 69600, Oullins, France
- Unité de Nutrition Endocrinologie Métabolisme, Service de Biochimie, Centre de Biologie et de Pathologie Sud, Hospices Civils de Lyon, 69310, Pierre-Bénite, France
| | - Valérie Sauvinet
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Charles Mérieux Medical School, 69600, Oullins, France
- CRNH Rhône-Alpes, Hospices Civils de Lyon, CENS, Centre de Recherche en Nutrition Humaine Rhône-Alpes, 69310, Pierre-Bénite, France
| | - Geneviève Gésan-Guiziou
- STLO, Science et Technologie du Lait et de l’Œuf, INRA, AGROCAMPUS OUEST, 35000, Rennes, France
| | | | - Philippe Moulin
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Charles Mérieux Medical School, 69600, Oullins, France
- Fédération d’Endocrinologie, Maladies Métaboliques, Diabète et Nutrition, Hôpital Louis Pradel, Hospices Civils de Lyon, 69500, Bron, France
| | - David Cheillan
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Charles Mérieux Medical School, 69600, Oullins, France
- Unité Maladies Héréditaires du Métabolisme, Service de Biochimie et Biologie Moléculaire Grand Est, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, 69500, Bron, France
| | - Hubert Vidal
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Charles Mérieux Medical School, 69600, Oullins, France
| | - Béatrice Morio
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Charles Mérieux Medical School, 69600, Oullins, France
| | - Eddy Cotte
- Université Claude Bernard Lyon 1, Faculté de médecine Lyon-Sud-Charles Mérieux, EMR 3738, 69600, Oullins, France
- Centre Hospitalier Lyon Sud, Service de Chirurgie Digestive, Hospices Civils de Lyon, 69310, Pierre-Bénite, France
| | | | - Martine Laville
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Charles Mérieux Medical School, 69600, Oullins, France
- CRNH Rhône-Alpes, Hospices Civils de Lyon, CENS, Centre de Recherche en Nutrition Humaine Rhône-Alpes, 69310, Pierre-Bénite, France
| | | | - Stéphanie Lambert-Porcheron
- CRNH Rhône-Alpes, Hospices Civils de Lyon, CENS, Centre de Recherche en Nutrition Humaine Rhône-Alpes, 69310, Pierre-Bénite, France
- Hospices Civils de Lyon, 69000, Lyon, France
| | - Corinne Malpuech-Brugère
- Université Clermont Auvergne, INRA, UNH, Unité de Nutrition Humaine, CRNH Auvergne, 63000, Clermont-Ferrand, France
| | - Marie-Caroline Michalski
- Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Charles Mérieux Medical School, 69600, Oullins, France
- CRNH Rhône-Alpes, Hospices Civils de Lyon, CENS, Centre de Recherche en Nutrition Humaine Rhône-Alpes, 69310, Pierre-Bénite, France
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8
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Szostak J, Wong ET, Titz B, Lee T, Wong SK, Low T, Lee KM, Zhang J, Kumar A, Schlage WK, Guedj E, Phillips B, Leroy P, Buettner A, Xiang Y, Martin F, Sewer A, Kuczaj A, Ivanov NV, Luettich K, Vanscheeuwijck P, Peitsch MC, Hoeng J. A 6-month systems toxicology inhalation study in ApoE -/- mice demonstrates reduced cardiovascular effects of E-vapor aerosols compared with cigarette smoke. Am J Physiol Heart Circ Physiol 2020; 318:H604-H631. [PMID: 31975625 DOI: 10.1152/ajpheart.00613.2019] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Smoking cigarettes is harmful to the cardiovascular system. Considerable attention has been paid to the reduced harm potential of alternative nicotine-containing inhalable products such as e-cigarettes. We investigated the effects of E-vapor aerosols or cigarette smoke (CS) on atherosclerosis progression, cardiovascular function, and molecular changes in the heart and aorta of female apolipoprotein E-deficient (ApoE-/-) mice. The mice were exposed to aerosols from three different E-vapor formulations: 1) carrier (propylene glycol and vegetable glycerol), 2) base (carrier and nicotine), or 3) test (base and flavor) or to CS from 3R4F reference cigarettes for up to 6 mo. Concentrations of CS and base or test aerosols were matched at 35 µg nicotine/L. Exposure to CS, compared with sham-exposed fresh air controls, accelerated atherosclerotic plaque formation, whereas no such effect was seen for any of the three E-vapor aerosols. Molecular changes indicated disease mechanisms related to oxidative stress and inflammation in general, plus changes in calcium regulation, and altered cytoskeletal organization and microtubule dynamics in the left ventricle. While ejection fraction, fractional shortening, cardiac output, and isovolumic contraction time remained unchanged following E-vapor aerosols exposure, the nicotine-containing base and test aerosols caused an increase in isovolumic relaxation time similar to CS. A nicotine-related increase in pulse wave velocity and arterial stiffness was also observed, but it was significantly lower for base and test aerosols than for CS. These results demonstrate that in comparison with CS, E-vapor aerosols induce substantially lower biological responses associated with smoking-related cardiovascular diseases.NEW & NOTEWORTHY Analysis of key urinary oxidative stress markers and proinflammatory cytokines showed an absence of oxidative stress and inflammation in the animals exposed to E-vapor aerosols. Conversely, animals exposed to conventional cigarette smoke had high urinary levels of these markers. When compared with conventional cigarette smoke, E-vapor aerosols induced smaller atherosclerotic plaque surface area and volume. Systolic and diastolic cardiac function, as well as endothelial function, were further significantly less affected by electronic cigarette aerosols than conventional cigarette smoke. Molecular analysis demonstrated that E-vapor aerosols induce significantly smaller transcriptomic dysregulation in the heart and aorta compared with conventional cigarette smoke.
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Affiliation(s)
- Justyna Szostak
- Philip Morris International Research and Development, Philip Morris Products, Neuchâtel, Switzerland
| | - Ee Tsin Wong
- Philip Morris International Research and development, Philip Morris International Research Laboratories, Singapore
| | - Bjoern Titz
- Philip Morris International Research and Development, Philip Morris Products, Neuchâtel, Switzerland
| | - Tom Lee
- Philip Morris International Research and development, Philip Morris International Research Laboratories, Singapore
| | - Sin Kei Wong
- Philip Morris International Research and development, Philip Morris International Research Laboratories, Singapore
| | - Tiffany Low
- Philip Morris International Research and development, Philip Morris International Research Laboratories, Singapore
| | | | | | | | | | - Emmanuel Guedj
- Philip Morris International Research and Development, Philip Morris Products, Neuchâtel, Switzerland
| | - Blaine Phillips
- Philip Morris International Research and development, Philip Morris International Research Laboratories, Singapore
| | - Patrice Leroy
- Philip Morris International Research and Development, Philip Morris Products, Neuchâtel, Switzerland
| | | | - Yang Xiang
- Philip Morris International Research and Development, Philip Morris Products, Neuchâtel, Switzerland
| | - Florian Martin
- Philip Morris International Research and Development, Philip Morris Products, Neuchâtel, Switzerland
| | - Alain Sewer
- Philip Morris International Research and Development, Philip Morris Products, Neuchâtel, Switzerland
| | - Arkadiusz Kuczaj
- Philip Morris International Research and Development, Philip Morris Products, Neuchâtel, Switzerland
| | - Nikolai V Ivanov
- Philip Morris International Research and Development, Philip Morris Products, Neuchâtel, Switzerland
| | - Karsta Luettich
- Philip Morris International Research and Development, Philip Morris Products, Neuchâtel, Switzerland
| | - Patrick Vanscheeuwijck
- Philip Morris International Research and Development, Philip Morris Products, Neuchâtel, Switzerland
| | - Manuel C Peitsch
- Philip Morris International Research and Development, Philip Morris Products, Neuchâtel, Switzerland
| | - Julia Hoeng
- Philip Morris International Research and Development, Philip Morris Products, Neuchâtel, Switzerland
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9
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Solly EL, Dimasi CG, Bursill CA, Psaltis PJ, Tan JTM. MicroRNAs as Therapeutic Targets and Clinical Biomarkers in Atherosclerosis. J Clin Med 2019; 8:E2199. [PMID: 31847094 PMCID: PMC6947565 DOI: 10.3390/jcm8122199] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 12/11/2019] [Indexed: 12/21/2022] Open
Abstract
Atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Atherosclerosis develops over several decades and is mediated by a complex interplay of cellular mechanisms that drive a chronic inflammatory milieu and cell-to-cell interactions between endothelial cells, smooth muscle cells and macrophages that promote plaque development and progression. While there has been significant therapeutic advancement, there remains a gap where novel therapeutic approaches can complement current therapies to provide a holistic approach for treating atherosclerosis to orchestrate the regulation of complex signalling networks across multiple cell types and different stages of disease progression. MicroRNAs (miRNAs) are emerging as important post-transcriptional regulators of a suite of molecular signalling pathways and pathophysiological cellular effects. Furthermore, circulating miRNAs have emerged as a new class of disease biomarkers to better inform clinical diagnosis and provide new avenues for personalised therapies. This review focusses on recent insights into the potential role of miRNAs both as therapeutic targets in the regulation of the most influential processes that govern atherosclerosis and as clinical biomarkers that may be reflective of disease severity, highlighting the potential theranostic (therapeutic and diagnostic) properties of miRNAs in the management of cardiovascular disease.
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Affiliation(s)
- Emma L. Solly
- Vascular Research Centre, Heart and Vascular Health Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide SA 5000, Australia; (E.L.S.); (C.G.D.); (C.A.B.); (P.J.P.)
- Adelaide Medical School, University of Adelaide, Adelaide SA 5005, Australia
| | - Catherine G. Dimasi
- Vascular Research Centre, Heart and Vascular Health Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide SA 5000, Australia; (E.L.S.); (C.G.D.); (C.A.B.); (P.J.P.)
| | - Christina A. Bursill
- Vascular Research Centre, Heart and Vascular Health Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide SA 5000, Australia; (E.L.S.); (C.G.D.); (C.A.B.); (P.J.P.)
- Adelaide Medical School, University of Adelaide, Adelaide SA 5005, Australia
| | - Peter J. Psaltis
- Vascular Research Centre, Heart and Vascular Health Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide SA 5000, Australia; (E.L.S.); (C.G.D.); (C.A.B.); (P.J.P.)
- Adelaide Medical School, University of Adelaide, Adelaide SA 5005, Australia
| | - Joanne T. M. Tan
- Vascular Research Centre, Heart and Vascular Health Program, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide SA 5000, Australia; (E.L.S.); (C.G.D.); (C.A.B.); (P.J.P.)
- Adelaide Medical School, University of Adelaide, Adelaide SA 5005, Australia
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10
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Hyun MH, Jang JW, Choi BG, Na JO, Choi CU, Kim JW, Kim EJ, Rha SW, Park CG, Lee E, Seo HS. The low-density lipoprotein cholesterol lowering is an ineffective surrogate marker of statin responsiveness to predict cardiovascular outcomes: The 10-year experience of matched population (a STROBE-compliant article). Medicine (Baltimore) 2019; 98:e18510. [PMID: 31861037 PMCID: PMC6940163 DOI: 10.1097/md.0000000000018510] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Statins therapy decrease both low-density lipoprotein cholesterol (LDL-C) levels and the risk of atherosclerotic cardiovascular disease (ASCVD) with considerable individual variability. Whether the amount of LDL-C lowering is a surrogate maker of statin responsiveness to ASCVD prevention has not been fully investigated. Among 2352 eligible patients with statin prescriptions in a cardiovascular center between January 2005 and February 2014, one-third of patients (33%) on statin therapy failed to achieve effective reductions in LDL-C (LDL-C level reduction of less than 15%). By using, propensity-score matched population (480 pairs, n = 960), the 5-year cumulative incidences of total major adverse cardiac events (MACE) were evaluated. The 5-year total MACE did not differ between normal cholesterol responders and non-responders (15.4% vs 16.1%, respectively; P = .860). In the subgroup analysis, male sex, older age, percutaneous coronary intervention, and heart failure were positive predictors, and dyslipidemia at the beginning of statin therapy was the only negative predictor of MACE in the 5-year follow-up (all P value < .05). However, cholesterol responsiveness after statin therapy did not influence the incidence of MACE (P = .860). The amount of LDL-C lowering did not predict beneficial effect on clinical outcomes of ASCVD after statin therapy. This result supports that given statin therapy, total ASCVD risk reduction should be tailored, which may not dependent to adherence to degree of LDL-C lowering or LDL-C goal based treatment.
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Affiliation(s)
- Myung Han Hyun
- Department of Internal Medicine, Korea University Medical Center
| | - Jae Won Jang
- Department of Biostatistics, Korea University College of Medicine
| | - Byoung Geol Choi
- Division of Cardiology, Department of Internal Medicine, Korea University Guro Hospital
| | - Jin Oh Na
- Division of Cardiology, Department of Internal Medicine, Korea University Guro Hospital
| | - Cheol Ung Choi
- Division of Cardiology, Department of Internal Medicine, Korea University Guro Hospital
| | - Jin Won Kim
- Division of Cardiology, Department of Internal Medicine, Korea University Guro Hospital
| | - Eung Ju Kim
- Division of Cardiology, Department of Internal Medicine, Korea University Guro Hospital
| | - Seung-Woon Rha
- Division of Cardiology, Department of Internal Medicine, Korea University Guro Hospital
| | - Chang Gyu Park
- Division of Cardiology, Department of Internal Medicine, Korea University Guro Hospital
| | - Eunmi Lee
- Division of Cardiology, Department of Internal Medicine, Wonkwang University Sanbon Hospital, Gyeonggi-do
| | - Hong Seog Seo
- Division of Cardiology, Department of Internal Medicine, Korea University Guro Hospital
- Graduate School of Converging Science and Technology, Korea University–Korea Institute of Science and Technology (KU-KIST)
- Future Convergence Research Division, Korea Institute of Science and Technology, Seoul, Republic of Korea
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11
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Owens DA, Tomkin GH. Commentary on High-density Lipoprotein Versus Low-density Lipoprotein Therapy and Cardiovascular Outcomes in Patients with Acute Coronary Syndromes by Nikolaos Papageorgiou et al. Curr Cardiol Rev 2018; 14:301-302. [PMID: 30324873 PMCID: PMC6300796 DOI: 10.2174/1573403x1404181008143841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- D A Owens
- Beacon Clinic and Trinity College Dublin, Ireland
| | - G H Tomkin
- Beacon Clinic and Trinity College Dublin, Ireland
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12
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Lydic TA, Goo YH. Lipidomics unveils the complexity of the lipidome in metabolic diseases. Clin Transl Med 2018; 7:4. [PMID: 29374337 PMCID: PMC5786598 DOI: 10.1186/s40169-018-0182-9] [Citation(s) in RCA: 106] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 01/08/2018] [Indexed: 12/30/2022] Open
Abstract
Dysregulation of lipid metabolism is responsible for pathologies of human diseases including metabolic diseases. Recent advances in lipidomics analysis allow for the targeted and untargeted identification of lipid species and for their quantification in normal and diseased conditions. Herein, this review provides a brief introduction to lipidomics, highlights its application to characterize the lipidome at the cellular and physiological levels under different biological conditions, and discusses the potential for the use of lipidomics in the discovery of biomarkers.
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Affiliation(s)
- Todd A Lydic
- Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA.
| | - Young-Hwa Goo
- Department of Molecular and Cellular Physiology, Albany Medical College, 47 New Scotland Avenue, Albany, NY, 12208, USA.
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13
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Rezapour M, Payani E, Taran M, Ghatari AR, Khavanin Zadeh M. Roles of triglyceride and phosphate in atherosclerosis of diabetic hemodialysis patients. Med J Islam Repub Iran 2017; 31:80. [PMID: 29445708 PMCID: PMC5804422 DOI: 10.14196/mjiri.3180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Indexed: 11/18/2022] Open
Abstract
Background: A growing number of patients with End-Stage Renal Disease (ESRD) are undergoing long-term hemodialysis (HD). HD needs a vascular access (VA) and complications of VA account for a sizable proportion of its costs. One of the important cardiovascular diseases (CVD) is atherosclerosis, which is a major cause of premature deaths in the world. So, it is essential to find the risk factors to treat them before they cause an obvious CVD. Methods: We analyzed data from 174 ESRD patients who were candidate for Arterio Venous Fistula (AVF) creation from April 2008 to March 2009 in Hasheminejad Kidney Center by convenient sampling. X-ray images were used and C 4.5 algorithm of data mining techniques revealed the roles of two risk factors for atherosclerosis of diabetic ESRD patients. Pearson coefficient was also used to measure the correlation between the parameters. Results: Diabetic patients had significantly more calcified arteries in their forearm X-ray than other patients (p<0.001). Occurrence of atherosclerotic CVD in diabetic HD patients has an adverse relation compared with the controlled levels of their plasma levels of Triglyceride (TG) and Phosphorus. We found an inverse effect of TG and phosphorus plasma levels on the atherosclerotic involvement of radial and ulnar arteries in diabetic HD patients. We observed that the prevalence of radial and ulnar arteries calcification in these patients is lower when they have higher plasma levels of TG and phosphorous. Conclusion: This study investigates the role of high plasma levels of TG and phosphorous in the development of atherosclerosis in diabetic HD patients. Although many studies showed that hypertriglyceridemia plays a promoting role in the development of CVD, our study also found an inverse effect of plasma levels of TG on the atherosclerotic involvement of radial and ulnar arteries in diabetic patients, and therefore our results support this suspicion that hypertriglyceridemia plays a significant role in developing atherosclerosis.
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Affiliation(s)
- Mohammad Rezapour
- Department of Information Technology Management, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | | | - Masoumeh Taran
- Applied Mathematics Institute for Advanced Studies in Basic Sciences (IASBS), Zanjan, Iran
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14
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Jattan J, Rodia C, Li D, Diakhate A, Dong H, Bataille A, Shroyer NF, Kohan AB. Using primary murine intestinal enteroids to study dietary TAG absorption, lipoprotein synthesis, and the role of apoC-III in the intestine. J Lipid Res 2017; 58:853-865. [PMID: 28159868 DOI: 10.1194/jlr.m071340] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 01/18/2017] [Indexed: 02/01/2023] Open
Abstract
Since its initial report in 2009, the intestinal enteroid culture system has been a powerful tool used to study stem cell biology and development in the gastrointestinal tract. However, a major question is whether enteroids retain intestinal function and physiology. There have been significant contributions describing ion transport physiology of human intestinal organoid cultures, as well as physiology of gastric organoids, but critical studies on dietary fat absorption and chylomicron synthesis in primary intestinal enteroids have not been undertaken. Here we report that primary murine enteroid cultures recapitulate in vivo intestinal lipoprotein synthesis and secretion, and reflect key aspects of the physiology of intact intestine in regard to dietary fat absorption. We also show that enteroids can be used to elucidate intestinal mechanisms behind CVD risk factors, including tissue-specific apolipoprotein functions. Using enteroids, we show that intestinal apoC-III overexpression results in the secretion of smaller, less dense chylomicron particles along with reduced triacylglycerol secretion from the intestine. This model significantly expands our ability to test how specific genes or genetic polymorphisms function in dietary fat absorption and the precise intestinal mechanisms that are critical in the etiology of metabolic disease.
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Affiliation(s)
- Javeed Jattan
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT
| | - Cayla Rodia
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT
| | - Diana Li
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT
| | - Adama Diakhate
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT
| | - Hongli Dong
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT
| | - Amy Bataille
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT
| | - Noah F Shroyer
- Department of Medicine Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX
| | - Alison B Kohan
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT
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15
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Ebrahim S. Metabolomics, nutrition and why epidemiology matters. Int J Epidemiol 2016; 45:1307-1310. [DOI: 10.1093/ije/dyw304] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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16
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Irawati D, Mamo JCL, Dhaliwal SS, Soares MJ, Slivkoff-Clark KM, James AP. Plasma triglyceride and high density lipoprotein cholesterol are poor surrogate markers of pro-atherogenic chylomicron remnant homeostasis in subjects with the metabolic syndrome. Lipids Health Dis 2016; 15:169. [PMID: 27686975 PMCID: PMC5043522 DOI: 10.1186/s12944-016-0330-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 09/09/2016] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Subjects with metabolic syndrome (MetS) exhibit impaired lipoprotein metabolism and have an increased risk of cardiovascular disease. Although the risk is attributed primarily to the risk associated with individual components, it is also likely affected by other associated metabolic defects. Remnants of postprandial lipoproteins show potent atherogenicity in cell and animal models of insulin resistance and in pre-diabetic subjects with postprandial dyslipidemia. However, few studies have considered regulation of chylomicron remnant homeostasis in MetS per se. This study measured the plasma concentration in Caucasian men and women of small dense chylomicrons following fasting and explored associations with metabolic and anthropometric measures. METHODS A total of 215 Australian Caucasian participants (median age 62 years) were investigated. Of them, 40 participants were classified as having MetS. Apolipoprotein (apo) B-48, an exclusive marker of chylomicrons, metabolic markers and anthropometric measures were determined following an overnight fast. RESULTS The fasting apo B-48 concentration was 40 % higher in subjects with MetS than those without MetS. In all subjects, triglyceride (r = 0.445, P < 0.0005), non-HDL cholesterol (r = 0.28, P < 0.0005) and HDL cholesterol concentration (r = -0.272, P < 0.0005) were weakly associated with apo B-48 concentration. In subjects with MetS, the association of apo B-48 with triglyceride and non-HDL cholesterol was enhanced, but neither were robust markers of elevated apo B-48 in MetS (r = 0.618 and r = 0.595 respectively). There was no association between apo B-48 and HDL cholesterol in subjects with MetS. CONCLUSION This study demonstrates a substantial accumulation of pro-atherogenic remnants in subjects with MetS. We have shown that in a Caucasian cohort, the fasting plasma concentration of triglyceride or HDL/non-HDL cholesterol serves as poor surrogate markers of atherogenic chylomicron remnants. These findings suggest that subjects with MetS exhibit a chronic defect in chylomicron metabolism that is likely to contribute to their increased CV risk.
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Affiliation(s)
- Deasy Irawati
- School of Public Health, Faculty of Health Sciences, Curtin University, Bentley, GPO Box U1987, Perth, WA, 6845, Australia.,Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia.,Faculty of Medicine, Mataram University, West Nusa Tenggara, Indonesia
| | - John C L Mamo
- School of Public Health, Faculty of Health Sciences, Curtin University, Bentley, GPO Box U1987, Perth, WA, 6845, Australia.,Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
| | - Satvinder S Dhaliwal
- School of Public Health, Faculty of Health Sciences, Curtin University, Bentley, GPO Box U1987, Perth, WA, 6845, Australia.,Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
| | - Mario J Soares
- School of Public Health, Faculty of Health Sciences, Curtin University, Bentley, GPO Box U1987, Perth, WA, 6845, Australia.,Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
| | - Karin M Slivkoff-Clark
- School of Public Health, Faculty of Health Sciences, Curtin University, Bentley, GPO Box U1987, Perth, WA, 6845, Australia
| | - Anthony P James
- School of Public Health, Faculty of Health Sciences, Curtin University, Bentley, GPO Box U1987, Perth, WA, 6845, Australia. .,Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia.
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17
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Santos AJM, Nogueira C, Ortega-Bellido M, Malhotra V. TANGO1 and Mia2/cTAGE5 (TALI) cooperate to export bulky pre-chylomicrons/VLDLs from the endoplasmic reticulum. J Cell Biol 2016; 213:343-54. [PMID: 27138255 PMCID: PMC4862334 DOI: 10.1083/jcb.201603072] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 04/14/2016] [Indexed: 01/04/2023] Open
Abstract
Santos et al. show that TANGO1 and a TANGO1-like protein, TALI, bind each other and function together as receptors to export bulky ApoB-containing lipid particles from the endoplasmic reticulum. However, TANGO1-mediated export of bulky collagens by the same cells is TALI independent. Procollagens, pre-chylomicrons, and pre–very low-density lipoproteins (pre-VLDLs) are too big to fit into conventional COPII-coated vesicles, so how are these bulky cargoes exported from the endoplasmic reticulum (ER)? We have shown that TANGO1 located at the ER exit site is necessary for procollagen export. We report a role for TANGO1 and TANGO1-like (TALI), a chimeric protein resulting from fusion of MIA2 and cTAGE5 gene products, in the export of pre-chylomicrons and pre-VLDLs from the ER. TANGO1 binds TALI, and both interact with apolipoprotein B (ApoB) and are necessary for the recruitment of ApoB-containing lipid particles to ER exit sites for their subsequent export. Although export of ApoB requires the function of both TANGO1 and TALI, the export of procollagen XII by the same cells requires only TANGO1. These findings reveal a general role for TANGO1 in the export of bulky cargoes from the ER and identify a specific requirement for TALI in assisting TANGO1 to export bulky lipid particles.
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Affiliation(s)
- António J M Santos
- Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain Universitat Pompeu Fabra, 08002 Barcelona, Spain
| | - Cristina Nogueira
- Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain Universitat Pompeu Fabra, 08002 Barcelona, Spain
| | - Maria Ortega-Bellido
- Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain Universitat Pompeu Fabra, 08002 Barcelona, Spain
| | - Vivek Malhotra
- Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain Universitat Pompeu Fabra, 08002 Barcelona, Spain Institució Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain
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18
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Zhang LS, Xu M, Yang Q, Ryan RO, Howles P, Tso P. Apolipoprotein A-V deficiency enhances chylomicron production in lymph fistula mice. Am J Physiol Gastrointest Liver Physiol 2015; 308:G634-42. [PMID: 25617349 PMCID: PMC4385892 DOI: 10.1152/ajpgi.00339.2014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 01/16/2015] [Indexed: 01/31/2023]
Abstract
Apolipoprotein A-V (apoA-V), a liver-synthesized apolipoprotein discovered in 2001, strongly modulates fasting plasma triglycerides (TG). Little is reported on the effect of apoA-V on postprandial plasma TG, an independent predictor for atherosclerosis. Overexpressing apoA-V in mice suppresses postprandial TG, but mechanisms focus on increased lipolysis or clearance of remnant particles. Unknown is whether apoA-V suppresses the absorption of dietary lipids by the gut. This study examines how apoA-V deficiency affects the steady-state absorption and lymphatic transport of dietary lipids in chow-fed mice. Using apoA-V knockout (KO, n = 8) and wild-type (WT, n = 8) lymph fistula mice, we analyzed the uptake and lymphatic transport of lipids during a continuous infusion of an emulsion containing [(3)H]triolein and [(14)C]cholesterol. ApoA-V KO mice showed a twofold increase in (3)H (P < 0.001) and a threefold increase in (14)C (P < 0.001) transport into the lymph compared with WT. The increased lymphatic transport was accompanied by a twofold reduction (P < 0.05) in mucosal (3)H, suggesting that apoA-V KO mice more rapidly secreted [(3)H]TG out of the mucosa into the lymph. ApoA-V KO mice also produced chylomicrons more rapidly than WT (P < 0.05), as measured by the transit time of [(14)C]oleic acid from the intestinal lumen to lymph. Interestingly, apoA-V KO mice produced a steadily increasing number of chylomicron particles over time, as measured by lymphatic apoB output. The data suggest that apoA-V suppresses the production of chylomicrons, playing a previously unknown role in lipid metabolism that may contribute to the postprandial hypertriglyceridemia associated with apoA-V deficiency.
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Affiliation(s)
- Linda S. Zhang
- 1Children's Hospital Oakland Research Institute, Oakland, California
| | - Min Xu
- 1Children's Hospital Oakland Research Institute, Oakland, California
| | - Qing Yang
- 1Children's Hospital Oakland Research Institute, Oakland, California
| | - Robert O. Ryan
- 2Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; and
| | - Philip Howles
- 1Children's Hospital Oakland Research Institute, Oakland, California
| | - Patrick Tso
- 1Children's Hospital Oakland Research Institute, Oakland, California
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19
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The role of hypertriglyceridemia in the development of atherosclerosis and endothelial dysfunction. Nutrients 2014; 6:1236-50. [PMID: 24667131 PMCID: PMC3967190 DOI: 10.3390/nu6031236] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Revised: 03/07/2014] [Accepted: 03/14/2014] [Indexed: 11/30/2022] Open
Abstract
A hereditary postprandial hypertriglyceridemic rabbit (PHT rabbit) is a new dyslipidemic model showing remarkably high plasma triglycerides with only limited elevation of plasma total cholesterol. In PHT rabbits, plasma triglyceride was markedly elevated postprandially compared with healthy Japanese white (JW) rabbits. In physiological experiments, the ring preparation of the thoracic aorta was suspended in an organ bath filled with modified Krebs-Henseleit solution, and the developed tension was recorded. Endothelial function was evaluated by acetylcholine-induced vasorelaxation in each preparation with intact endothelium. The acetylcholine-induced endothelium-dependent relaxation was diminished in PHT compared with JW rabbits, suggesting endothelial dysfunction in PHT rabbits. Histological examination was carried out in adipose tissue, liver and aorta. They were fixed in formaldehyde and embedded in paraffin. The tissues were sliced (4 μm) and stained using hematoxylin-eosin solution. In the adipose tissue, the visceral fat accumulated, and the size of adipose cells was enlarged in PHT rabbits. The liver of the PHT rabbit was fatty and degenerated. In aorta, increased intimal thickness was observed, suggesting the progression of atherosclerosis in the PHT rabbit. This study suggests the important role of postprandial hypertriglyceridemia in atherosclerosis. By using PHT rabbits, the effects of hypertriglyceridemia on health and diseases could be evaluated precisely.
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Hussain MM, Leung TM, Zhou L, Abu-Merhi S. Regulating intestinal function to reduce atherogenic lipoproteins. ACTA ACUST UNITED AC 2013; 8. [PMID: 24409204 DOI: 10.2217/clp.13.40] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Significant knowledge regarding different molecules involved in the transport of dietary fat into the circulation has been garnered. Studies point to the possibility that accumulation of intestine-derived lipoproteins in the plasma could contribute to atherosclerosis. This article provides a brief overview of dietary lipid metabolism and studies in mice supporting the hypothesis that intestinal lipoproteins contribute to atherosclerosis. Deficiencies in lipoprotein lipase and Gpihbp1, and overexpression of heparanse in mice, are associated with increases in atherosclerosis, suggesting that defects in catabolism of larger lipoproteins in the plasma contribute to atherosclerosis. Furthermore, inositol-requiring enzyme 1β-deficient mice that produce more intestinal lipoproteins also develop more atherosclerosis. Thus, increases in plasma intestinal lipoproteins due to either overproduction or reduced catabolism result in augmented atherosclerosis. Intestinal lipoproteins tend to adhere strongly to subendothelial proteoglycans, elicit an inflammatory response by endothelial cells and activate macrophages, contributing to the initiation and progression of the disease. Thus, molecules that reduce intestinal lipid absorption can be useful in lowering atherosclerosis.
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Affiliation(s)
- M Mahmood Hussain
- Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY 11797, USA ; Department of Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY 11797, USA
| | - Tung Ming Leung
- Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY 11797, USA ; Department of Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY 11797, USA
| | - Liye Zhou
- Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY 11797, USA ; Department of Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY 11797, USA
| | - Sarah Abu-Merhi
- Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY 11797, USA ; Department of Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY 11797, USA
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Zhou L, Yang H, Lin X, Okoro EU, Guo Z. Cholecystokinin elevates mouse plasma lipids. PLoS One 2012; 7:e51011. [PMID: 23300532 PMCID: PMC3533889 DOI: 10.1371/journal.pone.0051011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Accepted: 10/29/2012] [Indexed: 11/18/2022] Open
Abstract
Cholecystokinin (CCK) is a peptide hormone that induces bile release into the intestinal lumen which in turn aids in fat digestion and absorption in the intestine. While excretion of bile acids and cholesterol into the feces eliminates cholesterol from the body, this report examined the effect of CCK on increasing plasma cholesterol and triglycerides in mice. Our data demonstrated that intravenous injection of [Thr28, Nle31]-CCK at a dose of 50 ng/kg significantly increased plasma triglyceride and cholesterol levels by 22 and 31%, respectively, in fasting low-density lipoprotein receptor knockout (LDLR−/−) mice. The same dose of [Thr28, Nle31]-CCK induced 6 and 13% increases in plasma triglyceride and cholesterol, respectively, in wild-type mice. However, these particular before and after CCK treatment values did not achieve statistical significance. Oral feeding of olive oil further elevated plasma triglycerides, but did not alter plasma cholesterol levels in CCK-treated mice. The increased plasma cholesterol in CCK-treated mice was distributed in very-low, low and high density lipoproteins (VLDL, LDL and HDL) with less of an increase in HDL. Correspondingly, the plasma apolipoprotein (apo) B48, B100, apoE and apoAI levels were significantly higher in the CCK-treated mice than in untreated control mice. Ligation of the bile duct, blocking CCK receptors with proglumide or inhibition of Niemann-Pick C1 Like 1 transporter with ezetimibe reduced the hypercholesterolemic effect of [Thr28, Nle31]-CCK in LDLR−/− mice. These findings suggest that CCK-increased plasma cholesterol and triglycerides as a result of the reabsorption of biliary lipids from the intestine.
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Affiliation(s)
- Lichun Zhou
- Department of Physiology, Meharry Medical College, Nashville, Tennessee, United States of America
| | - Hong Yang
- Department of Physiology, Meharry Medical College, Nashville, Tennessee, United States of America
| | - Xinghua Lin
- Department of Physiology, Meharry Medical College, Nashville, Tennessee, United States of America
| | - Emmanuel U. Okoro
- Department of Physiology, Meharry Medical College, Nashville, Tennessee, United States of America
| | - Zhongmao Guo
- Department of Physiology, Meharry Medical College, Nashville, Tennessee, United States of America
- * E-mail:
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Iqbal J, Queiroz J, Li Y, Jiang XC, Ron D, Hussain MM. Increased intestinal lipid absorption caused by Ire1β deficiency contributes to hyperlipidemia and atherosclerosis in apolipoprotein E-deficient mice. Circ Res 2012; 110:1575-84. [PMID: 22556338 DOI: 10.1161/circresaha.112.264283] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
RATIONALE High fasting serum lipid levels are significant risk factors for atherosclerosis. However, the contributions of postprandial excursions in serum lipoproteins to atherogenesis are less well-characterized. OBJECTIVE This study aims to delineate whether changes in intestinal lipid absorption associated with loss of inositol-requiring enzyme 1β (Ire1β) would affect the development of hyperlipidemia and atherosclerosis in Apoe(-/-) mice. METHODS AND RESULTS We used Ire1β-deficient mice to assess the contribution of intestinal lipid absorption to atherosclerosis. Here, we show that Ire1b(-/-)/Apoe(-/-) mice contain higher levels of intestinal microsomal triglyceride transfer protein, absorb more lipids, exhibit hyperlipidemia, and have higher levels of atherosclerotic plaques compared with Apoe(-/-) mice when fed chow and western diets. CONCLUSIONS These studies indicate that Ire1β regulates intestinal lipid absorption and that increased intestinal lipoprotein production contributes to atherosclerosis.
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Affiliation(s)
- Jahangir Iqbal
- Department of Cell Biology, Box 5, SUNY Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11203, USA.
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