Low-Density Lipoprotein Receptor–Dependent and Low-Density Lipoprotein Receptor–Independent Mechanisms of Cyclosporin A–Induced Dyslipidemia

Total Page:16

File Type:pdf, Size:1020Kb

Low-Density Lipoprotein Receptor–Dependent and Low-Density Lipoprotein Receptor–Independent Mechanisms of Cyclosporin A–Induced Dyslipidemia Original Research Low-Density Lipoprotein Receptor–Dependent and Low-Density Lipoprotein Receptor–Independent Mechanisms of Cyclosporin A–Induced Dyslipidemia Maaike Kockx, Elias Glaros, Betty Kan, Theodore W. Ng, Jimmy F.P. Berbée, Virginie Deswaerte, Diana Nawara, Carmel Quinn, Kerry-Anne Rye, Wendy Jessup, Patrick C.N. Rensen, Peter J. Meikle, Leonard Kritharides Objective—Cyclosporin A (CsA) is an immunosuppressant commonly used to prevent organ rejection but is associated with hyperlipidemia and an increased risk of cardiovascular disease. Although studies suggest that CsA-induced hyperlipidemia is mediated by inhibition of low-density lipoprotein receptor (LDLr)–mediated lipoprotein clearance, the data supporting this are inconclusive. We therefore sought to investigate the role of the LDLr in CsA-induced hyperlipidemia by using Ldlr-knockout mice (Ldlr−/−). Approach and Results—Ldlr−/− and wild-type (wt) C57Bl/6 mice were treated with 20 mg/kg per d CsA for 4 weeks. On a chow diet, CsA caused marked dyslipidemia in Ldlr−/− but not in wt mice. Hyperlipidemia was characterized by a prominent increase in plasma very low–density lipoprotein and intermediate-density lipoprotein/LDL with unchanged plasma high-density lipoprotein levels, thus mimicking the dyslipidemic profile observed in humans. Analysis of specific lipid species by liquid chromatography–tandem mass spectrometry suggested a predominant effect of CsA on increased very low–density lipoprotein–IDL/LDL lipoprotein number rather than composition. Mechanistic studies indicated that CsA did not alter hepatic lipoprotein production but did inhibit plasma clearance and hepatic uptake of [14C]cholesteryl oleate and glycerol tri[3H]oleate-double-labeled very low–density lipoprotein–like particles. Further studies showed that CsA inhibited plasma lipoprotein lipase activity and increased levels of apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9. Conclusions—We demonstrate that CsA does not cause hyperlipidemia via direct effects on the LDLr. Rather, LDLr deficiency plays an important permissive role for CsA-induced hyperlipidemia, which is associated with abnormal lipoprotein clearance, decreased lipoprotein lipase activity, and increased levels of apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9. Enhancing LDLr and lipoprotein lipase activity and decreasing apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9 levels may therefore provide attractive treatment targets for patients with hyperlipidemia receiving CsA. (Arterioscler Thromb Vasc Biol. 2016;36:00-00. DOI: 10.1161/ATVBAHA.115.307030.) Key Words: apolipoprotein C-III ◼ hyperlipidemia ◼ immunosuppression ◼ lipolysis ◼ triglycerides yperlipidemia is observed in 40% to 60% of organ trans- hyperlipidemia in patients, such as post-transplantation obe- Hplant recipients and has been linked to the use of immu- sity, multiple drug therapy, and diabetes mellitus, CsA mono- nosuppressant agents such as corticosteroids, sirolimus, and therapy can independently lead to elevated plasma triglyceride cyclosporine A (CsA).1–3 Transplant hyperlipidemia is char- and cholesterol levels in humans which are reversible on ces- acterized by high plasma cholesterol and triglyceride levels.2 sation of immunosuppression therapy.4 Specifically, CsA increases very low–density lipoprotein The immunosuppressive effect of CsA is mediated by inhi- (VLDL) and low-density lipoprotein (LDL) concentrations bition of protein phosphatase 2B (calcineurin) and subsequent and shows variable effects on plasma high-density lipo- activation of the transcription factor nuclear factor of transcrip- protein. Although multiple factors potentially contribute to tion. The mechanism(s) by which CsA leads to hyperlipidemia Received on: December 11, 2015; final version accepted on: April 20, 2016. From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.K.), University of New South Wales, Sydney, Australia; Baker IDI Heart and Diabetes Institute, Melbourne, Australia (T.W.N., P.J.M.); Department of Medicine, Division Endocrinology, and Eindhoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands (J.F.P.B., P.C.N.R.); Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Australia (V.D.); Lipid Research Group, School of Medical Sciences, University of New South Wales Australia, Sydney, Australia (K.-A.R.). The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl/doi:10.1161/ATVBAHA.115.307030/-/DC1. Correspondence to Leonard Kritharides, Department of Cardiology, Concord Repatriation General Hospital, Concord, New South Wales 2139, Australia. E-mail [email protected] © 2016 American Heart Association, Inc. Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.115.307030 Downloaded from http://atvb.ahajournals.org/1 at University of Sydney on May 11, 2016 2 Arterioscler Thromb Vasc Biol July 2016 Nonstandard Abbreviations and Acronyms Materials and Methods Materials and Methods are available in the online-only Data apo apolipoprotein Supplement. CE cholesteryl ester CO cholesteryl oleate Results CsA cyclosporin A CsA Treatment Hprt Hypoxanthine guanine phosphoribosyl transferase Mice were administered 20 mg/kg per d CsA or vehicle (con- IDL intermediate-density lipoprotein trol) via osmotic minipumps. This CsA dose has previously LDL low-density lipoprotein been shown to reduce transplant rejection in mice while not LDLr LDL receptor inducing liver and kidney toxicity.12,13 Whole-blood CsA lev- LPL lipoprotein lipase els were 1087±124 ng/mL and 711±91 ng/mL after 1 week PCSK9 proprotein convertase subtilisin/kexin type 9 and 4 weeks, respectively, consistent with levels reported by SM sphingomyelin others using a similar delivery method.14 Mouse weights were TO trioleate/triolein not affected (23.3±0.3 versus 23.2±0.3 g, for control and CsA, VLDL very low–density lipoprotein respectively). Histological examination of liver and kidney wt wild-type sections revealed no signs of toxicity after CsA treatment (Figure I in the online-only Data Supplement). −/− are most likely not related to nuclear factor of transcription It is known that Ldlr mice have increased hepatic lipid inhibition1,4 as tacrolimus (FK506), another nuclear factor of content compared with C57Bl/6 wild-type (wt) mice and transcription–inhibiting immunosuppressant, does not induce are more vulnerable to develop nonalcoholic steatohepatitis hyperlipidemia.3 Animal and cell studies have indicated that after high-fat feeding, although they do not develop fatty 15 CsA may affect many aspects of lipid metabolism.1 In 1996, livers on a chow diet. This was supported by our histologi- Rayyes5 and Winegard6 suggested that CsA increased plasma cal studies (Figure I in the online-only Data Supplement). LDL and VLDL levels via decreased low-density lipopro- Hepatic cholesterol, cholesteryl ester (CE), and triglyc- −/− tein receptor (LDLr) activity. The precise role of the LDLr eride contents were higher in Ldlr mice compared with in mediating CsA-mediated hypercholesterolemia, however, wt mice, most marked in triglyceride content (115 versus is unclear. Cell culture studies identified that CsA can inhibit 30 nmol/mg; P<0.05; Table 1). In the wt mice, CsA treat- ment increased hepatic CE content from 11 to 20 nmol/mg β-VLDL uptake via the LDLr in the human hepatoma HepG2 cell line.6 CsA was also found to reduce LDLr-mediated bind- (P<0.01) without significantly increasing other lipids. In Ldlr−/− mice, CsA caused no significant changes in hepatic ing and uptake of LDL in HepG2 cells, and this was associated lipid content. with a reduction in hepatic LDLr mRNA levels.5 However, in vivo studies did not corroborate these findings. Hepatic LDLr protein levels decreased in mice treated with CsA7 but were CsA Treatment Increases Plasma Lipid −/− unaffected in rats8 even though both models demonstrated Levels in Ldlr Mice but not in wt Mice CsA-induced hyperlipidemia. These studies suggest that CsA- CsA treatment did not affect plasma total cholesterol or tri- mediated hyperlipidemia may be related to effects on targets glyceride levels in wt mice (Figure 1A and 1B). However, −/− other than the LDLr, such as activation of hepatic cholesterol in Ldlr mice fed a chow diet, CsA markedly elevated total synthesis or inhibition of lipoprotein lipolysis. In vivo studies plasma cholesterol (263±12 versus 527±31 mg/dL, control in rats demonstrated that CsA reduced LDL production and versus CsA, respectively; P<0.0001) and triglyceride levels catabolism,9 while in renal transplant recipients reduced catab- olism of chylomicron-like emulsion particles, and a reduced Table 1. Hepatic Tissue Lipid Levels 10,11 fractional catabolic rate of VLDL has been observed. Control CsA Given the current and increasing clinical importance −/− of contemporary therapies such as statins and proprotein Ldlr convertase subtilisin/kexin type 9 (PCSK9) inhibitors in TG 115±30 86±28 promoting LDLr-mediated lipoprotein uptake, we sought Cholesterol 25±2 28±2 to investigate the role of the LDLr in CsA-induced hyper- CE 30±4 46±16 lipidemia by studying Ldlr-knockout mice. We report that CsA induces hyperlipidemia in chow-fed
Recommended publications
  • Polymorphisms in APOA1 and LPL Genes Are Statistically Independently Associated with Fasting TG in Men with CAD
    European Journal of Human Genetics (2005) 13, 445–451 & 2005 Nature Publishing Group All rights reserved 1018-4813/05 $30.00 www.nature.com/ejhg ARTICLE Polymorphisms in APOA1 and LPL genes are statistically independently associated with fasting TG in men with CAD Olga W Souverein*,1, J Wouter Jukema2, S Matthijs Boekholdt3, Aeilko H Zwinderman1 and Michael WT Tanck1 1Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, The Netherlands; 2Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands; 3Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands The objective of this paper was to identify the single nucleotide polymorphisms (SNPs) that show unshared effects on plasma triglyceride (TG) levels and to investigate whether these SNPs show statistically independent effects on plasma TG levels. In total, 59 polymorphisms in 20 genes involved in lipid metabolism were investigated. Polymorphisms were selected for a multivariate ANOVA model if they showed an univariate association with TG (after adjustment for HDL-C and LDL-C) in more than 50% of bootstrap samples that were made from the original data. The multivariate model included 512 men with coronary artery disease from the REGRESS study who were completely genotyped for eight polymorphisms selected in the univariate procedure (ie, APOA1 G(À75)A, ABCA1 C(À477)T, ABCA1 G1051A, APOC3 T3206G, APOE Arg158Cys, LIPC C(À514)T, LPL Asn291Ser and LPL Ser447Stop). The gene variants APOA1 G(À75)A (P ¼ 0.04) and LPL Asn291Ser (P ¼ 0.03) were significantly associated with plasma TG levels in this multivariate analysis. The eight polymorphisms explained 8.9% of the variation in plasma TG levels.
    [Show full text]
  • The Crucial Roles of Apolipoproteins E and C-III in Apob Lipoprotein Metabolism in Normolipidemia and Hypertriglyceridemia
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Harvard University - DASH The crucial roles of apolipoproteins E and C-III in apoB lipoprotein metabolism in normolipidemia and hypertriglyceridemia The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Sacks, Frank M. 2015. “The Crucial Roles of Apolipoproteins E and C-III in apoB Lipoprotein Metabolism in Normolipidemia and Hypertriglyceridemia.” Current Opinion in Lipidology 26 (1) (February): 56–63. doi:10.1097/mol.0000000000000146. Published Version doi:10.1097/MOL.0000000000000146 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:30203554 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Open Access Policy Articles, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#OAP HHS Public Access Author manuscript Author Manuscript Author ManuscriptCurr Opin Author Manuscript Lipidol. Author Author Manuscript manuscript; available in PMC 2016 February 01. Published in final edited form as: Curr Opin Lipidol. 2015 February ; 26(1): 56–63. doi:10.1097/MOL.0000000000000146. The crucial roles of apolipoproteins E and C-III in apoB lipoprotein metabolism in normolipidemia and hypertriglyceridemia Frank M. Sacks Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA Abstract Purpose of review—To describe the roles of apolipoprotein C-III (apoC-III) and apoE in VLDL and LDL metabolism Recent findings—ApoC-III can block clearance from the circulation of apolipoprotein B (apoB) lipoproteins, whereas apoE mediates their clearance.
    [Show full text]
  • Association Between the APOA2 Rs3813627 Single Nucleotide Polymorphism and HDL and APOA1 Levels Through BMI
    biomedicines Article Association between the APOA2 rs3813627 Single Nucleotide Polymorphism and HDL and APOA1 Levels Through BMI Hatim Boughanem 1 , Borja Bandera-Merchán 2, Pablo Hernández-Alonso 2,3,4 , Noelia Moreno-Morales 5, Francisco José Tinahones 2,3, José Lozano 6 , Sonsoles Morcillo 2,3,* and Manuel Macias-Gonzalez 2,3,* 1 Instituto de Investigación Biomédica de Málaga (IBIMA), Facultad de Ciencias, Universidad de Málaga, 29010 Málaga, Spain; [email protected] 2 Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, 29010 Málaga, Spain; [email protected] (B.B.-M.); [email protected] (P.H.-A.); [email protected] (F.J.T.) 3 Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición, CIBERObn, 28029 Madrid, Spain 4 Human Nutrition Unit, Faculty of Medicine and Health Sciences, Sant Joan Hospital, Institut d’Investigació Sanitària Pere Virgili, Rovira i Virgili University, 43201 Reus, Spain 5 Department of Physiotherapy, School of Health Sciences, University of Malaga-Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Málaga, Spain; [email protected] 6 Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Málaga, 29010 Málaga, Spain; [email protected] * Correspondence: [email protected] (S.M.); [email protected] (M.M.-G.); Tel.: +34-951-032-648 (S.M. & M.M.-G.); Fax: +34-27-951-924-651 (S.M. & M.M.-G.) Received: 18 February 2020; Accepted: 25 February 2020; Published: 27 February 2020 Abstract: Background: The interaction between obesity and genetic traits on high density lipoprotein (HDL) levels has been extensively studied.
    [Show full text]
  • A Case of Ezetimibe-Effective Hypercholesterolemia with a Novel Heterozygous Variant in ABCG5
    2020, 67 (11), 1099-1105 Original A case of ezetimibe-effective hypercholesterolemia with a novel heterozygous variant in ABCG5 Yujiro Nakano1), Chikara Komiya1), Hitomi Shimizu2), 3), Hiroyuki Mishima3), Kumiko Shiba1), Kazutaka Tsujimoto1), Kenji Ikeda1), Kenichi Kashimada4), Sumito Dateki2), Koh-ichiro Yoshiura3), Yoshihiro Ogawa5) and Tetsuya Yamada1) 1) Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan 2) Department of Pediatrics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaski 852-8501, Japan 3) Department of Human Genetics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan 4) Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan 5) Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan Abstract. Sitosterolemia is caused by homozygous or compound heterozygous gene mutations in either ATP-binding cassette subfamily G member 5 (ABCG5) or 8 (ABCG8). Since ABCG5 and ABCG8 play pivotal roles in the excretion of neutral sterols into feces and bile, patients with sitosterolemia present elevated levels of serum plant sterols and in some cases also hypercholesterolemia. A 48-year-old woman was referred to our hospital for hypercholesterolemia. She had been misdiagnosed with familial hypercholesterolemia at the age of 20 and her serum low-density lipoprotein cholesterol (LDL-C) levels had remained about 200–300 mg/dL at the former clinic. Although the treatment of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors was ineffective, her serum LDL-C levels were normalized by ezetimibe, a cholesterol transporter inhibitor.
    [Show full text]
  • Postprandial Lipoprotein Metabolism: VLDL Vs Chylomicrons
    UC Davis UC Davis Previously Published Works Title Postprandial lipoprotein metabolism: VLDL vs chylomicrons. Permalink https://escholarship.org/uc/item/9wx8p0x5 Journal Clinica chimica acta; international journal of clinical chemistry, 412(15-16) ISSN 0009-8981 Authors Nakajima, Katsuyuki Nakano, Takamitsu Tokita, Yoshiharu et al. Publication Date 2011-07-01 DOI 10.1016/j.cca.2011.04.018 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Clinica Chimica Acta 412 (2011) 1306–1318 Contents lists available at ScienceDirect Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim Invited critical review Postprandial lipoprotein metabolism: VLDL vs chylomicrons Katsuyuki Nakajima a,b,d,e,i,⁎, Takamitsu Nakano a,b, Yoshiharu Tokita a, Takeaki Nagamine a, Akihiro Inazu c, Junji Kobayashi d, Hiroshi Mabuchi d, Kimber L. Stanhope e, Peter J. Havel e, Mitsuyo Okazaki f,g, Masumi Ai h,i, Akira Tanaka g,i a School of Health Sciences, Faculty of Medicine, Gunma University, Maebashi, Gunma, Japan b Otsuka Pharmaceuticals Co., Ltd, Tokushima, Japan c Department of Laboratory Sciences, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan d Department of Lipidology and Division of Cardiology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan e Department of Molecular Biosciences, School of Veterinary Medicine and Department of Nutrition, University of California, Davis, CA, USA f Skylight Biotech Inc., Akita, Japan g Department of Vascular Medicine and
    [Show full text]
  • Isolation of HDL by Sequential Flotation Ultracentrifugation Followed by Size
    www.nature.com/scientificreports OPEN Isolation of HDL by sequential fotation ultracentrifugation followed by size exclusion chromatography reveals size‑based enrichment of HDL‑associated proteins Jack Jingyuan Zheng1, Joanne K. Agus1, Brian V. Hong1, Xinyu Tang1, Christopher H. Rhodes1, Hannah E. Houts1, Chenghao Zhu1, Jea Woo Kang1, Maurice Wong2, Yixuan Xie2, Carlito B. Lebrilla2, Emily Mallick3, Kenneth W. Witwer3 & Angela M. Zivkovic1* High‑density lipoprotein (HDL) particles have multiple benefcial and cardioprotective roles, yet our understanding of their full structural and functional repertoire is limited due to challenges in separating HDL particles from contaminating plasma proteins and other lipid‑carrying particles that overlap HDL in size and/or density. Here we describe a method for isolating HDL particles using a combination of sequential fotation density ultracentrifugation and fast protein liquid chromatography with a size exclusion column. Purity was visualized by polyacrylamide gel electrophoresis and verifed by proteomics, while size and structural integrity were confrmed by transmission electron microscopy. This HDL isolation method can be used to isolate a high yield of purifed HDL from a low starting plasma volume for functional analyses. This method also enables investigators to select their specifc HDL fraction of interest: from the least inclusive but highest purity HDL fraction eluting in the middle of the HDL peak, to pooling all of the fractions to capture the breadth of HDL particles in the original plasma sample. We show that certain proteins such as lecithin cholesterol acyltransferase (LCAT), phospholipid transfer protein (PLTP), and clusterin (CLUS) are enriched in large HDL particles whereas proteins such as alpha‑2HS‑glycoprotein (A2HSG), alpha‑1 antitrypsin (A1AT), and vitamin D binding protein (VDBP) are enriched or found exclusively in small HDL particles.
    [Show full text]
  • Apoa2 Correlates to Gestational Age with Decreased Apolipoproteins A2, C1, C3 and E in Gestational Diabetes
    Metabolism BMJ Open Diab Res Care: first published as 10.1136/bmjdrc-2020-001925 on 5 March 2021. Downloaded from Open access Original research apoA2 correlates to gestational age with decreased apolipoproteins A2, C1, C3 and E in gestational diabetes Manjunath Ramanjaneya ,1 Alexandra E Butler ,2 Mohammed Bashir,3 Ilham Bettahi,1 Abu Saleh Md Moin,2 Lina Ahmed,4 Mohamed A Elrayess ,5 Steven C Hunt ,4 Stephen L Atkin,6 Abdul Badi Abou- Samra1 To cite: Ramanjaneya M, ABSTRACT Butler AE, Bashir M, Introduction Pregnant women with gestational diabetes Significance of this study et al. apoA2 correlates to mellitus (GDM) are at risk of adverse outcomes, including gestational age with decreased gestational hypertension, pre- eclampsia, and preterm What is already known about this subject? apolipoproteins A2, C1, C3 delivery. This study was undertaken to determine if ► Pregnant women with gestational diabetes are at and E in gestational diabetes. risk of adverse outcomes, including hypertension, BMJ Open Diab Res Care apolipoprotein (apo) levels differed between pregnant women with and without GDM and if they were associated pre-ec lampsia, and pre-term delivery, and apolipo- 2021;9:e001925. doi:10.1136/ proteins (apos) may be mechanistically involved in bmjdrc-2020-001925 with adverse pregnancy outcome. Research design and methods Pregnant women (46 the pathophysiology of these adverse outcomes. women with GDM and 26 women without diabetes (ND)) in What are the new findings? ► Supplemental material is their second trimester were enrolled in the study. Plasma ► apoA2, apoC1, apoC3 and apoE levels were reduced published online only. To view, apos were measured and correlated to demographic, please visit the journal online in women with gestational diabetes, while apoA2 biochemical, and pregnancy outcome data.
    [Show full text]
  • Dyslipidemia Infosheet 6-10-19
    Genetic Testing for Dyslipidemias Clinical Features: Dyslipidemias are a clinically and genetically heterogenous group of disorders associated with abnormal levels of lipids and lipoproteins, including increased or decreased levels of LDL or HDL cholesterol or increased levels of triglycerides [1]. Dyslipidemias can have a monogenic cause, or may be associated with other conditions such as diabetes and thyroid disease, or lifestyle factors. The most common subset of monogenic dyslipidemia is familial hypercholesterolemia (FH), which has an estimated prevalence of 1 in 200 in the Caucasian population [2]. Our Dyslipidemia Panes includes analysis of all 23 genes listed below. Dyslipidemia Panel Genes ABCA1 APOA1 CETP LDLR LMF1 SAR1B ABCG5 APOA5 GPD1 LDLRAP1 LPL SCARB1 ABCG8 APOB GPIHBP1 LIPA MTTP STAP1 ANGPTL3 APOC2 LCAT LIPC PCSK9 Gene OMIM# Associated disorders Dyslipidemia Inheritance Reference phenotype s ABCA1 60004 Tangier disease; High Low HDL-C Recessive; [3, 4] 6 density lipoprotein (HDL) Dominant deficiency ABCG5 60545 Sitosterolemia Hypercholesterolemia Recessive [5] 9 , hypersitosterolemia ABCG8 60546 Sitosterolemia Hypercholesterolemia Recessive [5] 0 , hypersitosterolemia ANGPTL 60501 Familial Low LDL-C Recessive [6] 3 9 hypobetalipoproteinemia- 2 APOA1 10768 Apolipoprotein A-I Low HDL-C Recessive; [7, 8] 0 deficiency; HDL Dominant deficiency APOA5 60636 Hyperchylomicronemia; Hypertriglyceridemia Dominant/Recessive [9, 10] 8 Hypertriglyceridemia ; Dominant APOB 10773 Familial High LDL-C; Low Co-dominant [1, 11] 0 hypercholesterolemia;
    [Show full text]
  • The Regulation of Apob Metabolism by Insulin
    TEM-879; No. of Pages 7 Review The regulation of ApoB metabolism by insulin 1 2 1 Mary E. Haas , Alan D. Attie , and Sudha B. Biddinger 1 Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA 2 Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA The leading cause of death in diabetic patients is cardio- are not capable of catabolizing cholesterol. They must vascular disease. Apolipoprotein B (ApoB)-containing therefore return excess cholesterol to the liver, which lipoprotein particles, which are secreted and cleared can secrete cholesterol into the bile, either directly or after by the liver, are essential for the development of athero- conversion to bile acids [5]. sclerosis. Insulin plays a key role in the regulation of Lipoproteins can be divided into classes that vary in ApoB. Insulin decreases ApoB secretion by promoting their apolipoproteins, lipid composition and, therefore, ApoB degradation in the hepatocyte. In parallel, insulin function. Apolipoprotein B is a structural protein that is promotes clearance of circulating ApoB particles by the an integral component of chylomicrons, as well as very low- liver via the low-density lipoprotein receptor (LDLR), density lipoprotein (VLDL), intermediate-density lipopro- LDLR-related protein 1 (LRP1), and heparan sulfate pro- tein (IDL), and low-density lipoprotein (LDL) particles. teoglycans (HSPGs). Consequently, the insulin-resistant Chylomicrons are secreted by the intestine and enable state of type 2 diabetes (T2D) is associated with in- the transport of dietary triglycerides to other tissues after creased secretion and decreased clearance of ApoB. feeding. They contain a truncated form of ApoB, referred to Here, we review the mechanisms by which insulin con- as ApoB48 because it is 48% of the full-length protein [6].
    [Show full text]
  • Glycation of Apolipoprotein C1 Impairs Its CETP Inhibitory
    1148 Diabetes Care Volume 37, April 2014 Benjamin Bouillet,1,2 Thomas Gautier,2 Glycation of Apolipoprotein C1 Denis Blache,2 Jean-Paul Pais de Barros,2 Laurence Duvillard,2 Jean-Michel Petit,1,2 Impairs Its CETP Inhibitory Laurent Lagrost,2 and Bruno Verges` 1,2 Property: Pathophysiological Relevance in Patients With Type 1 and Type 2 Diabetes OBJECTIVE Apolipoprotein (apo)C1 is a potent physiological inhibitor of cholesteryl ester transfer protein (CETP). ApoC1 operates through its ability to modify the elec- trostatic charge at the lipoprotein surface. We aimed to determine whether the inhibitory ability of apoC1 is still effective in vivo in patients with diabetes and whether in vitro glycation of apoC1 influences its electrostatic charge and its CETP inhibitory effect. RESEARCH DESIGN AND METHODS ApoC1 concentrations and CETP activity were measured in 70 type 1 diabetic (T1D) patients, 113 patients with type 2 diabetes, and 83 control subjects. The conse- quences of in vitro glycation by methylglyoxal on the electrostatic properties of apoC1 and on its inhibitory effect on CETP activity were studied. An isoelectric analysis of apoC1 was performed in patients with T1D and in normolipidemic- normoglycemic subjects. RESULTS An independent negative correlation was found between CETP activity and apoC1 1Service Endocrinologie, Diabetologie´ et in control subjects but not in patients with diabetes. HbA1c was independently Maladies Metaboliques,´ University Hospital of CARDIOVASCULAR AND METABOLIC RISK associated with CETP activity in T1D patients. In vitro glycation of apoC1 modified Dijon, Dijon, France its electrostatic charge and abrogated its ability to inhibit CETP activity in a 2INSERM, UMR 866, University of Bourgogne, concentration-dependent manner.
    [Show full text]
  • D25V Apolipoprotein C-III Variant Causes Dominant Hereditary Systemic Amyloidosis and Confers Cardiovascular Protective Lipoprotein Profile
    ARTICLE Received 1 Jun 2015 | Accepted 2 Dec 2015 | Published 21 Jan 2016 DOI: 10.1038/ncomms10353 OPEN D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile Sophie Valleix1,2,3,4,w, Guglielmo Verona5,6, Noe´mie Jourde-Chiche7, Brigitte Ne´delec2,3,4, P. Patrizia Mangione5,6, Frank Bridoux8, Alain Mange´9,10,11,12, Ahmet Dogan13,14, Jean-Michel Goujon15, Marie Lhomme16, Carolane Dauteuille17, Miche`le Chabert4,17,18, Riccardo Porcari5, Christopher A. Waudby19, Annalisa Relini20, Philippa J. Talmud21, Oleg Kovrov22, Gunilla Olivecrona22, Monica Stoppini6, John Christodoulou19, Philip N. Hawkins5, Gilles Grateau23, Marc Delpech1, Anatol Kontush17, Julian D. Gillmore5, Athina D. Kalopissis4 & Vittorio Bellotti5,6 Apolipoprotein C-III deficiency provides cardiovascular protection, but apolipoprotein C-III is not known to be associated with human amyloidosis. Here we report a form of amyloidosis char- acterized by renal insufficiency caused by a new apolipoprotein C-III variant, D25V. Despite their uremic state, the D25V-carriers exhibit low triglyceride (TG) and apolipoprotein C-III levels, and low very-low-density lipoprotein (VLDL)/high high-density lipoprotein (HDL) profile. Amyloid fibrils comprise the D25V-variant only, showing that wild-type apolipoprotein C-III does not contribute to amyloid deposition in vivo. The mutation profoundly impacts helical structure stability of D25V-variant, which is remarkably fibrillogenic under physiological conditions in vitro producing typical amyloid fibrils in its lipid-free form. D25V apolipoprotein C-III is a new human amyloido- genic protein and the first conferring cardioprotection even in the unfavourable context of renal failure, extending the evidence for an important cardiovascular protective role of apolipoprotein C-III deficiency.
    [Show full text]
  • Hepatic ABCA1 and VLDL Triglyceride Production Mingxia Liu Department of Pathology/Section on Lipid Sciences, Wake Forest School of Medicine, Winston- Salem, NC
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by DigitalCommons@University of Nebraska University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Nutrition and Health Sciences -- Faculty Nutrition and Health Sciences, Department of Publications 2012 Hepatic ABCA1 and VLDL triglyceride production Mingxia Liu Department of Pathology/Section on Lipid Sciences, Wake Forest School of Medicine, Winston- Salem, NC Soonkyu Chung Department of Food Science and Human Nutrition, University of Florida, Gainesville, FL, [email protected] Gregory S. Shelness Department of Pathology/Section on Lipid Sciences, Wake Forest School of Medicine, Winston- Salem, NC John S. Parks Department of Pathology/Section on Lipid Sciences, Wake Forest School of Medicine, Winston- Salem, NC Follow this and additional works at: http://digitalcommons.unl.edu/nutritionfacpub Liu, Mingxia; Chung, Soonkyu; Shelness, Gregory S.; and Parks, John S., "Hepatic ABCA1 and VLDL triglyceride production" (2012). Nutrition and Health Sciences -- Faculty Publications. 39. http://digitalcommons.unl.edu/nutritionfacpub/39 This Article is brought to you for free and open access by the Nutrition and Health Sciences, Department of at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Nutrition and Health Sciences -- Faculty Publications by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. NIH Public Access Author Manuscript Biochim Biophys Acta. Author manuscript; available in PMC 2013 May 1. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Biochim Biophys Acta. 2012 May ; 1821(5): 770±777. doi:10.1016/j.bbalip.2011.09.020. Hepatic ABCA1 and VLDL triglyceride production Mingxia Liu1, Soonkyu Chung3, Gregory S.
    [Show full text]