Ανάλυση της σχέσεως δομήςλειτουργίας της απολιποπρωτεΐνης CIII Κυριάκος Η. Κυπραίος Αναπληρωτής Καθηγητής Τμήμα Ιατρικής Πανεπιστήμιο Πατρών kkypreos@med.upatras.gr www.kyriakoskypreos.com
Dyslipidemia atherosclerosis and CHD Atherosclerosis and its resulting CHD are a growing international health problem. According to WHO an estimated 7.2 million people died from CHD in 2004, representing ~12% of all global deaths, while it is estimated that in the year 2030, 23.6 million people will die from cardiovascular disease. Dyslipidemia constitutes one of the major risk factors for developing atherosclerosis and CHD, though sedentary lifestyle and genetic predisposition have also been implicated in the development of the disease
Lowering of LDL-cholesterol as a strategy for therapy In the last 20 years or so, the biomedical community has focused on lowering LDL cholesterol as a strategy for preventing atherosclerosis and heart disease. Statins can lower LDL cholesterol by up to 70% however, this reduction is translated to only a 35% or so reduction in CHD related mortality in the general population. This is great if you are one of the 35% but not so great if you are one of the other 65%. Statins have given great results, but the benefits from statin administration in terms of reducing CHD related mortality have now reached a plateau.
There is an urgent need for new medicines against dyslipidemia and atherosclerosis We need new medicines that: A) will efficiently decrease CHD related mortality to a 70%, 80%, or even 90% compared to the ~35% reduction with the current medications B) will: a) prevent plaque formation b) stabilize unstable atherosclerotic plaques b) cause regression of established lesions
HDL cholesterol is an attractive new therapeutic target A number of epidemiological studies have suggested that plasma HDL levels correlated inversely with the incidence of coronary heart disease and atherosclerosis However, more recent findings challenge this view and raise a discussion as to whether low HDL levels are causal for the development of heart disease and atherosclerosis Recent data suggest that in addition to HDL quantity, HDL quality also plays important role in the protection from atherosclerosis However, the concept that raising HDL will protect from atherosclerosis has not been validated to this date. Tsompanidi et al., Atherosclerosis, 2010
HDL is atheroprotective According to the classical view, increased HDL levels correlate with atheroprotection: Men 35 mg/dl Women 40 mg/dl
New view: HDL quality is also very important in conferring atheroprotection No atheroprotection Atheroprotection Reduced RCT Reduced PON Reduced affinity for HPETE and HPODE Increased 3 HDL Reduced 1, pre 1, pre 2 and pre 3 HDL Reduced 17 Estradiol Failure to recruit endothelial progenitor cells at the site of vascular injury Enhanced RCT Increased PON Increased affinity for HPETE and HPODE Reduced 3 HDL Increased 1, pre 1, pre 2 and pre 3 HDL Increased 17 Estradiol Enhanced recruitment of endothelial progenitor cells at the site of vascular injury
But before we design new HDL-based pharmaceuticals it is important to understand what HDL is and what it does
Apolipoprotein CIII Small exchangeable apolipoprotein with a molecular mass of ~8ΚDa with hairpin structure Approximately one-half of apociii is found in HDL, and the remaining in VLDL and chylomicrons. Small quantities of apociii are also found in intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) particles.
Apolipoprotein CIII and hypertriglyceridemia In hypertriglyceridemic patients, apociii was found to be a specific inhibitor of lipoprotein lipase (LpL) while purified apociii acted as a competitive inhibitor of apocii in the hydrolysis of triolein. Plasma apociii concentration is directly proportional to body mass index (BMI). As a result apociii is considered as one of the major factors leading to the development of hypertriglyceridemia in obese patients with metabolic syndrome.
Στόχοι Eργου Απολιποπρωτεΐνη CIII (apociii) σχηματισμό σωματιδίων HDL εμφάνιση υπερτριγλυκεριδαιμίας 1 ος στόχος: Προσδιορισμός περιοχών και κατάλοιπων των αμινοξέων της apociii Υπερτριγλυκεριδαιμία (γονιδιακή μεταφορά μέσω αδενοϊών σε ποντίκια) 2 ος στόχος: Αποσαφήνιση αλληλεπιδράσεων των apociii, ABCA1 και LCAT Σχηματισμό σωματιδίων της HDL που περιέχουν apociii Διαμόρφωση της υπερτριγλυκεριδαιμίας και του μεταβολικού συνδρόμου
Results What is the role of apociii in the biogenesis of HDL? How apociii-containing HDL affects the severity of hypertriglyceridemia in vivo?
We generated a recombinant adenovirus expressing the wild type human apociii m.o.i: 0 3 6 12 24 16 kda apociii 6.5 kda Kypreos KE. Biochemistry (2008) 47:10491-502.
The main protein component of HDL is apolipoprotein A I Lipid free apoc III ABCA1 N C LCAT Peripheral tissues or liver Minimally lipidated apoc III Discoidal apoa I HDL Spherical apoa I HDL
ApoCIII HDL and ABCA1 are key modulators in the development of apociii induced hypertriglyceridemia +ABCA1 De novo biogenesis of apociii HDL Accumulation of apociii in HDL Normal levels of apociii on TG rich VLDL TG rich VLDL Lipolysis by LpL VLDL remnant Normal VLDL remnant clearance N C Lipid poor apociii in plasma ABCA1 No apociii HDL formation Accumulation of apociii on VLDL TG rich VLDL Excess apociii on TG rich VLDL Inhibition of lipolysis by LpL X Impaired VLDL remnant clearance Hypertriglyceridemia
HDL act as a buffer that prevents accumulation of excess plasma apolipoproteins (such as apociii and possibly other apolipoproteins) on VLDL. In the absence of ABCA1, this HDL buffering capacity is eliminated, resulting in the abnormal apolipoprotein composition of VLDL and the hypertriglyceridemia that have been previously documented in patients with Tangier s disease. ABCA1, HDL, and Hypertriglyceridemia in Tangier s disease In humans, mutations in ABCA1 that impair its functions cause Tangier s disease, an autosomal codominant disorder that is characterized by an extremely marked reduction in plasma HDL cholesterol and mild to moderate hypertriglyceridemia Deficiency in ABCA1 results in abnormal apolipoprotein composition of VLDL, and reduced reactivity of VLDL-triglycerides with plasma LpL.
Παραδοτέα Τελική Έκθεση Διδακτορικό Δίπλωμα: «Τα συστατικά στοιχεία του συστήματος λιπιδίων και λιποπρωτεϊνών ως κεντρικοί ρυθμιστές στην εμφάνιση της παχυσαρκίας και της μη αλκοολικής λιπώδους νόσου του ήπατος» Αριθμός Παρουσιάσεων σε συνέδρια (με εργασία και κρίση): 2 Αριθμός Δημοσιεύσεων σε περιοδικά με κριτές: 7
Δημοσιεύσεις σε περιοδικά με κριτές Irene-Eva Triantaphyllidou, Eleni Karavia, Eleni Kalyvioti, Ioannis Lilis, Kyriakos E. Kypreos, and Dionysios J. Papachristou (2012) Lecithin:cholesterol acyltransferase deficiency predisposes to the development of osteoarthritis in mice following longterm exposure to Western-type diet. Osteoarthritis and Cartilage., doi:pii: S1063-4584(12)01016-3. 10.1016/j.joca.2012.11.003. (IF=3.888, citations=0) Eleni A. Karavia, Dionysios J. Papachristou, Kassiani Liopeta, Irene-Eva Triantafyllidou, Odyssefs Dimitrakopoulos, and Kyriakos E. Kypreos (2012) Apolipoprotein A-I modulates Processes Associated with Diet-Induced Nonalcoholic Fatty Liver Disease in Mice Mol. Med., 18:901-12. doi: 10.2119/molmed.2012.00113. (IF=5.020, citations=1) Eleni Karavia, Dionysios J. Papachristou, Ioanna Kotsikogianni, Irene-Eva Triantafyllidou, and Kyriakos E. Kypreos (2012) Lecithin:cholesterol acyltransferase modulates the severity of diet-induced nonalcoholic fatty liver disease in mice. J. Nutr. Biochem. DOI: 10.1016/j.jnutbio.2012.02.007. (IF=4.288, citations=1) Anthula E. Kavo, Loukianos Rallidis, George C. Sakellaropoulos, Stefan Lehr, Sonja Hartwig, Juergen Eckel, Polixeni Mpozatzi, Panagiota Tsikrika, and Kyriakos E. Kypreos (2012) Qualitative characteristics of HDL particles in young asymptomatic patients of an acute myocardial infarction. Atherosclerosis, 220:257-64. (IF=4.522, citations=1)
Δημοσιεύσεις σε περιοδικά με κριτές Eleni Karavia, Dionysios J. Papachristou, Ioanna Kotsikogianni and Kyriakos E. Kypreos (2011) Deficiency in Apolipoprotein E has a Protective effect on Diet- Induced Nonalcoholic Fatty Liver Disease in Mice. FEBS J, 278:3119-29. (IF= 3.042, citations=4) Peristera A. Petropoulou, Donald L. Gantz, Yanan Wang, Patrick C.N. Rensen, and Kyriakos E. Kypreos (2011). The aminoterminal 1-185 domain of human apolipoprotein E suffices for the de novo biogenesis of apoe-containing HDL. Atherosclerosis, 219:116-23. (IF=4.522, citations=0) Kyriakos E. Kypreos (2008) ABCA1 promotes the de novo biogenesis of apolipoprotein CIII-containing HDL particles in vivo and modulates the severity of Apolipoprotein CIII-induced hypertriglyceridemia. Biochemistry, 47: 10491-502. (IF=3.226, citations=19)
Επιπλέον όφελος Αποτελέσματα της προτάσεως αυτής αποτέλεσαν τη βάση για την χρηματοδότηση: 1. μιας προτάσεως «Αριστεία Ι», ΓΓΕΤ 2. δύο προτάσεων «Ενίσχυση Μεταδιδακτόρων ερευνητών», ΓΓΕΤ
Acknowledgement Πρόγραμμα υποτροφίων «Καραθεοδωρή» Πανεπιστημίου Πατρών