Lipid spectrum disorders hamburger_and_fries-6478 Lipids nEsters of fatty acids and alcohols (e.g. glycerol, cholesterol, sfingosin) nSometimes, they also contain other chemical groups – e.g. Phosphate, choline, inositol (phospholipids), monosaccharide (glycolipids) nIn wider sense lipid involve generally small hydrophobic or amphiphilic molecule with hydrocarbon chain (which involves free cholesterol, free fatty acids, icosanoids, retinoids) n n n 4+a+Phospholipid+molecule Molecule of phosphatidylcholine Physiological functions of lipids nEnergy storage – 1 gram of triacylglycerol can produce 39 kJ, double compared to saccharides and proteins nStructural – amphiphilic lipids (especially phospholipids, cholesterol) makes most of cellular membranes and intracellular membrane compartments, myelin in nervous system (esp. sphingolipids, cholesterol) nsignal – lipids and their derivates are responsible for endocrine (steroids), paracrine (icosanoids) and intracellular signalization (phosphatidylinositol phosphates) nOther – role in embryogenesis, vision (retinoids), antioxidants (vitamins A, E) Transport of blood lipids nLipids are not soluble in water nPart is transformed into soluble metabolites (ketone bodies) nFree fatty acids (FFA) are bound to albumin in blood nMost lipids in circulation form compounds of lipoprotein particles Lipoproteins nSpecific particles present in blood plasma nThey consist of lipid and protein compounds http://2.bp.blogspot.com/-PlvyZ59vIys/UD6g_W1GacI/AAAAAAAAyiY/HpNKYfz3XYM/s1600/lipoprotein2.jpg Protein compound Apolipoproteins (Apo) A-M Lipid compound Phospholipids Cholesterol Triacylglyceroles (TAG) Lipoprotein classes nA particle is formed out of amphiphilic coat (apolipoproteins, phospholipids, cholesterol) and hydrophobic core (cholesteryl esters, triacylglycerols) nIn increasing diameter, surface increases with the power of two, volume with the power of three nThat means, the greater the diameter, the bigger is the core compared to the coat nWith the diameter, the ratio of TAG to proteins increases and the density decreases nAcording to increasing density (and decreasing diameter), lipoproteins can be divided into 5 basic classes– chylomicrons, VLDL, IDL, LDL and HDL http://dualibra.com/wp-content/uploads/2012/04/037800%7E1/Part%2015.%20Endocrinology%20and%20Metabo lism/Section%203.%20Disorders%20of%20Intermediary%20Metabolism/350_files/loadBinary.gif Apolipoproteins nAre situated on the surface of lipoproteins nEverything what is done with lipoprotein particles is dependent on Apos (i.e.binding specific receptors, induction/inhibition of enzymes and transport proteins) nThey are distinguished by letters A-M nSome apolipoproteins (A, C and E) can be exchanged between different particles ApoA and ApoC are in fact groups of proteins with similar structure, distinguished by Roman numbers. They, together with ApoE, form a structural family. ApoB occurs in two forms, ApoB-48 and ApoB-100, which are products of the same gene (by mRNA editing, stop-codon can be made, which leads into mRNA translation into shorter ApoB-48). 250px-PBB_Protein_APOA1_image Apolipoprotein A-I Metabolism of lipoproteins nDifferent lipoprotein classes can exchange both apolipoproteins and lipid compound nDepending on the composition of protein compound, lipoprotein ensures a specific lipid transport between tissues. nLipoprotein metabolism can be divided into three main pathways: •Exogennous pathway •Endogenous pathway •Reverse transport http://openwetware.org/images/8/83/Lipid_metabolism_pathways.png Lipid transport between tissues lipoproteiny Lipoproteins – exogenous pathway F1 nChylomicrons (CMs) are big particles formed in the small intenstine nThey contain all main types of apolipoproteins (A, B, C, E), ApoB-48 is a specific apolipoprotein nThrough lipoprotein lipase (LPL) on capilary endothelium, induced by ApoC-II and inhibited by ApoC-III, CMs get rid of TAG, newly formed FFA get out of capillaries into tissues. nMost apolipoproteins are, together with TAG, transfered to HDL nThus, chylomicrone remnants are formed. Through their ApoE, they bind to LDL or LRP receptors in the liver, where they are internalized Lipoproteins – endogenous pathway nVLDL are similar to chylomicrons, but they are smaller and contain ApoB-100 instead of ApoB-48 nIn peripheral capillaries, they undergo similar modification as chylomicrons. Their remants are called IDL nThrough LPL and hepatic lipase (on the endothelium of hepatic capillaries), they get rid of the rest of lipids (with the exception of cholesterol) and of ApoE nAs a result, LDL particles are formed. They contain only one apolipoprotein, ApoB-100, and dominating lipid compound is cholesterol and its esters nApoB-100 binds only to LDL receptor, which is frequent both in liver and peripheral tissues. The process leads to the transport of cholesterol into periphery n n nClearance of LDL is relatively slow. In a consequence, they are prone to oxidation and other modifications nLDL-receptor is degraded with the help of chaperon PCSK-9 Lipoproteins – reverse transport nHDL are formed as nascent particles in the liver (and intestine), protein compound - ApoA-I – is dominant nUsing ABCA-I transporter, ApoA-I is capable of reverse transport of cholesterol out of peripheral tissues (by other mechanisms, also ApoA-II a ApoE). nApolipoproteins (except of Apo-B), TAG (in exchange for cholesterol esters – CETP) and phospholipids are transferred from other lipoproteins nLarger, lipid-enriched forms of HDL are formed, using LCAT, cholesterol is esterified. nThanks to binding of ApoA-I to SR-BI receptor in liver (and steroidogenic issues), HDL „unloads“ cholesterol and gets back into .circulation. TAG and phospholipides are degraded by hepatic lipase n n n n http://what-when-how.com/wp-content/uploads/2012/04/tmp8629.jpg nIf modified HDL contains ApoE, it can be internalized by binding its receptors nApoA-I and ApoA-II bind to their receptor in kidney and can be excreted, they can return into circulation by binding protein cubilin n n Atherogenic a antiatherogenic lipoproteins nAntiatherogenic nHDL (especially nascent) nAtherogenic nLDL – in subendothelial space and other tissues (gingiva) they undergo oxidative modification, oxLDL are not recognized by LDL-R, but by macrophage scavenger receptors. Formation of oxLDL is easier, when the diet is rich for oxidated lipids. Subgroup of „small dense LDL“ is especially atherogenic nChylomicron remnants and IDL – they bind scavenger receptors without modifications nOther atherogenic modifications nglycation, glucooxidation, carbamylation (urea), aggregation nLipoprotein (a) Aterogenic lipoprotein penetration nThey must be sufficiently small (i.e. not chylomicrons and nascent VLDL) nEndothelium: transcellular transport (vesicles) and paracellular transport („leaky junctions“) nScavenger receptors SR-B participate in transcellular transport (on the other hand, the binding to LDL-receptor supports lipoprotein internalization – role of previous atherogenic modifications) n Retention in subendothelial space nVesicular transport through the endothelium goes both ways ni.e. lipoproteins are rapidly removed from the subendothelial space nBinding to subendothelial glycosaminoglycans → retention nFurther modification (oxidation / glycation / aggregation…) → binding to macrophage scavenger receptors (“toxic lipoproteins“) n ovidweb[1] Lipoprotein (a) nSmall particle containing ApoB-100 and Apo(a) nIts elevated concentration is usually inherited (different genetic substrate) nIt is one of most frequent causes of infarctions in young age (<20 years) nIts physiological function is unclear, Apo(a) is similar to plasminogene and tPA and binds fibrin. Probably, it is used in a repair of damaged vessel wall. n nrcardio Dyslipidemias nDisorders of lipid metabolism nThey are not necessarily connected with obesity (but often they are) nTypically ↑total cholesterol, ↑LDL-cholesterol, ↓HDL-cholesterol and ↑TAG nSometimes, only some components are present (isolated hypertriacylglycerolemia, isolated hypercholesterolemia) nHyper-TAG is in 90% connected with ↓HDL-C (phospholipid and TAG transfer to HDL leads to rapid degradation). Isolated ↓HDL-C (hypoalfalipoproteinemia) is rare nLDL concentration is sometimes not measured directly, but is estimated using Friewald formula: n LDL-C = total chol. – HDL-C – (TAG/2,2) Clinical manifestation of severe hyperchlesterolemia nXanthelasmas, xanthomas of tendons nArcus corneae nPolyarthritis, tendinitis nAccelerated aterosclerosis ANd9GcT9hCKEthEcYsUEufmU8ACUn5mXZr6CB8EgQdWdxkwtSny_JlTn ANd9GcTZyTaXPjDFB9ol3ovSXGHsbUIU00twFpPwWZFjCYFdYD6a78nWhA Cholesterol and cardiovascular risk (SCORE) Consequences of elevated TAG nCardiovascular risk sharply increases up to approx. 4 mmol/l, but does not substantially change further (contrary to overall mortality) n n n n n n n nIn high levels of TAG the TAG-rich lipoprotein particles increases in size, but not in number nLarge lipoproteins do not pass into vascular intima, but may obstruct the microcirculation – see further Other complications of hyperTAGemia nAcute pancreatitis nDuring pancreatitis development in hyperTAGemia, cytotoxic damage of acinar cells by unesterified FFA takes place nLipemia retinalis, retinal vein thrombosis nXantelasmas Desired values of blood lipids nCzech atherosclerosis society recommendations, 2007 Patients Without complications Risk factors (e.g. DM2, DM1 with mikroalbuminuria) Presence of atherosclerosis Lipid mmol/l mmol/l mmol/l Cholesterol <5,0 <4,5 <4,0 LDL-C <3,0 <2,5 <2,0 HDL-C >1,0 (men), >1,2 (women) TAG <1,7 Highly above the optimal values, but realistically achievable Primary and secondary dyslipidemias nPrimary nMore frequent nUsually multifactorial, polygenic heritability, usually as a component of „metabolic syndrome“ (syndrom X, Reaven syndrom) nRare monogenic forms – usually mutations of apolipoproteins or their receptors nSecondary nThey are a consequence of other disease nE.g. diabetic dyslipidemia, nephrotic syndrome nThey also may be a component of metabolic syndrome (the boundary between primary and secondary dyslipidemia is not sharp) Frederickson classification of primary dyslipidemia nBased on dominating fraction nType I - ↑ chylomicrons nType IIa - ↑ LDL nType IIb - ↑ LDL and VLDL nType III - ↑ chylomicron remnants and IDL nType IV - ↑ VLDL nType V - ↑ VLDL and chylomicrons n nSimple phenotypic classification: cholesterol predominance vs. mixed vs. TAG predominance Familial hyperlipoproteinemia type I nVery rare (1/1000000), endemic in Québec nHypertriacylglycerolemia with high concentration of circulating chylomicrons nDefect of LPL (LPLD) or deficiency of ApoC-II nTAG up to 50mmol/l, manifestation in the childhood, often through acute pancreatitis or retinal thrombosis nIn serious cases, there is a necessity of plasma transfusion nFrequent, prevalence 1:500 nIt is caused by defects of LDL-receptor, more rarely ApoB-100 (different sites of genes) nPhenotype IIa, TAG are not very much elevated (lipoproteins rich by TAG contain also ApoE, so they can use alternative ways of degradation, while LDL clearance is dependent on ApoB-100 and LDL receptor) nMore serious homozygous, less serious heterozygous form Familial hypercholesterolemia (FH) FH - complications nIn heterozygotes MI in 3rd -5th decade, in homozygotes before 20 years of age nTreatment: plasmapheresis (extracorporal precipitation of LDL by heparin), in serious case, it is an indication for liver transplantation Polygenic hypercholesterolemia (IIa) nCombination of „disadvantageous“, cholesterol-raising common polymorfisms in genes for ApoB, ApoE, PCSK9, LCAT, CETP and other proteins together with environmental factors nOut of environmental factors, namely high caloric intake, high amounts of saturated fats and cholesterol in diet, little physical activity nRole of fetal programing and early postnatal development nClinically, there is also higher susceptibility for gallstones formation Combined hyperlipidemia (IIb) nIt is usually caused by ApoB overproduction in the liver, often elevated ApoC-III nApoB/ApoA-I ratio is one of the most important risk factors for heart and brain atherosclerosis nVariable fenotype, usually together with insulin resistance nMonogenic forms are usually caused by variants of the genes for ApoC-II, Apo-C-III or CETP nMore frequent polygenic form is usually part of the metabolic syndrome, heritability cca 20-30% (which is quite low - „acquired combined hyperlipidemia“), enviromental risk factors are basically the same as in polygennic hypercholesterolemia n Familial hyperlipoproteinemia type III (familiar dysbetalipoproteinemia, FDBL) nApoE occurs in 3 functionally different isoforms, E2, E3, E4, which are coded by three common alleles ε2, ε3 a ε4 (in most European populations, their frequency is ~5-10%, 70-80%, 10-20%) nIzoform E2 binds badly to LDL-receptor, however ApoE2-containing lipoproteins can be degraded by alternative pathways nIn cca 5% of ε2/ε2 homozygotes, the degradation is impaired as a result of their independent genetic defect and/or metabolic disease (e.g. DM2) ApoE_Fig2 ApoE and FDBL nThis leads into the disease known as familial dysbetalipoproteinemia (FDBL, FH III) nFDBL can be caused also by rare mutations of ApoE, in these cases, it is inherited in dominant fashion with high penetrancy nBoth TAG (more) and cholesterol (less) is present, clinically xanthomas and precocious atherosclerosis nMost ε2/ε2 homozygotes are normo- to hypolipidemic, in its heterozygous form, the allele is protective against the onset of atherosclerosis and its development nAllele ε4 mildly increases the risk (and it markedly increases the risk of late-onset neurodegenerative diseases; because of its preferential binding to large lipoproteins it is insufficient for transferring lipids into neurons during their repair. The transport of lipids in the nervous system uses small, HDL-like particles). n nCommon, phenotype IV nGenetically heterogeneous disease nPolygennic, causes include LPL deficiency, overproduction of VLDL, deficiency of ApoA-V (inhibits chylomicron and VLDL production) nIt often occurs together with diabetes and obesity, but it has probably different genetic background – however the manifestation of hyperTAGemia is much more serious in a coincidence with diabetes nThe onset is usually provoked by alcoholic or nutritional excess nClinically often manifestated by serious forms of pancreatitis Polygennic hypertriacylglycerolemia Familial hyperlipoproteinemia type V nBasically intermediate type between 1 and 4 nAs well as in all hyperTAGemias, there is a susceptibility to acute pancreatitis (esp. in TAG>10 mmol/l). Sometimes, chronic pancreatitis can occur Secondary dyslipidemia n↑ cholesterol ncholestasis nmixed nKidney disease nHypothyreosis nObesity (TAG predominance) n↑ TAG ndiabetes mellitus nAlcohol abuse Diabetic hypertriacylglycerolemia nLack of insulin and insulin resistance leads into enhanced lipolysis in adipocytes and FFA formation nIn the liver, FFA can be used for TAG synthesis. TAG become part of VLDL. nMoreover, insulin directly stimulates the production of LPL (and maybe also hepatic lipase). Activity of these enzymes is then lower in DM and that helps ↑VLDL (secondarily also ↓HDL) nNon-esterified FFA also induce cytolysis of pancreatic β-cells Kidney diseases and dyslipidemia nNephrotic syndrome nLoss of LPL activators (↓ ratio ApoC-II / ApoC-III) → ↑TAG n↓ HDL-cholesterol / total cholesterol nLCAT loss → impaired transport of cholesterol into HDL n↑ PCSK-9 hepatic expression → ↓LDL-R → decreased clearance of LDL (mediated possibly by increased TNF-α from damaged podocytes) nCHRI n↑Apo-CIII nreplacement of ApoA-I in HDL for serum amyloid A n↑PCSK-9 → ↑ small dense LDL nCHRI often follows diabetes – see above Strategies of the treatment nLifestyle adjustment, physical aktivity (HDL) nLowering of caloric intake, low-lipid (in ↑cholesterol) and low-saccharide (in ↑TAG) diet – more efficient in secondary dyslipidemia nPharmacotherapy (clinical efficiency in a range of years!) nstatins (they inhibit cholesterol synthesis) nfibrates, niacin (they lower VLDL synthesis) nresins, ezetimib (they lower intestinal absorption of lipids) nPCSK- inhibitors (they prevent internalization of hepatic LDL-R) nIn serious case aphaeresis, transfusion of blood plasma, exceptionally liver transplantation Most expensive cure of history nAlipogene tiparvorec (Glybera) nAdenoviral vector with a gene for LPL nIndication: familial hyperlipoproteinemia type I (LPLD) nEMA approval in r. 2012 after approx. 10 years of testing – historically first gene therapy nControversial expressions of EMA commitees (weak evidence about clinical efficiency with low power of a test in a rare disease) n60 i.m. injections per a therapy – total price 1 mil. USD nFirst doses came to market in 2015 nSeveral tens of patients during a period of testing, 1 following the approval (2015 – 2017) n2017 the request for prolongation of EMA registration was withdrawn by a company n Thank you for your attention food-pyramid1