Volné radikály a ateroskleróza
Tuky
jsou složené sloučeniny Chemickým charakterem patříkesterům
Z kyselin obsahují nerozvětvené alifatické kyseliny Alkoholickou slo žkou je glycerol
Glycerol jako trojsytný alkohol může tvořit mono-, di- a triacylglyceroly
(v dřívější terminologii mono-, di- a triglyceridy)
The structure of a phospholipid
PHOSPHATIDYLCHOLINE
I
CHj-NCCHj), CH,
o-p-o-
1
o
o o
c-o c = o
CH, CH, CH, CH2
CH2 CH, « CH2
3
o
Si
o
a o
CH2
CH2 CH2 CH, CH2 CH2 CH2 CH2 CH
CH,
2 CH, CH, CH,
CH2 CH? CH, CH,
CH CH, CH,
CHOLINE
PHOSPHATE
GLYCEROL
{
CH, CH, CH, CH, CH, CH3
(a) Structural formula
FATTY ACIDS
Ä—Hydrophilic head
Hydrophobic tails
(b) Space-filling model
(c) Phospholipid symbol
CH«    . CH« < / ^ CH2
ch, ca
Membrane <constituent
Cholesterol
■> Testosterone
Cortisol
T
Bile salts
Oestradiol
Figure A3. The structure of cholesterol.
extracellular fluid (outside)
glycoprotein-
phospholipid
carbohydrate
binding site
phospholipid bilayer
cytoplasm (inside)
Shrnutí
Potravou jsou přijímány tyto základní látky tukovité povahy:
triacylglyceroly cholesterol a jeho estery fosfolipidy (především lecithin)
Major Digestive Organs
adapted from Thibodeau
v
Štěpení tuků v tenkém střevě
	Enzym	Substrát	Optim. podmínky	Konečný produkt
				diacylglyceroly
	pankreatická	triacylglyceroly		monoacylglyceroly
	lipasa			mastné kyseliny
			soli	glycerol
		fosfolipidy		
DUODENUM		(lecithin=	žlučových	mastné kyseliny
	fosfolipasa	fosfatidylcholin)		(lysolecithin)
			kyselin	
		estery		
		cholesterolu		volný cholesterol
	cholesterol	s mastnými		
	esterasa	kyselinami		
Další oddíly tenkého střeva	střevní lipasa	monoacylglyceroly		glycerol mastné kyseliny
h-c-o-
h-c-o-č/VVVN
I ?
h-c-o-^^W\
+
Hydrofobní části žlučových kyselin se vnoří do tukových kapének, hydrofilní části zůstávají na povrchu, to vede ke štěpení. Čím menší kapénky, tím lepší účinek pankreatické lipázy
Hydrolýza triacylglycerolů pankreatickou lipázou. Látka orlistat (Xenical) inhibuje PL - léčba obezity
Micely - malé agregáty lipidů a žlučových kyselin. Micely přilnou k povrchu epiteliálních buněk a tuky jsou absorbovány prostou difuzí nebo pomocí transportního proteinu. Mastné kyseliny a monoacylglyceroly jsou transportovány do ER, kde jsou resyntetizovány triacylglyceroly. Poté jsou v GA tvořeny chylomikra a exocytózou jsou vypuzeny ven do lymfy. Tou s e následně dostávají do krve.
Enterocyte
Following uptake across the apical membrane of the enterocyte, the products of gastrointestinal (GI) lumen lipid digestion — monoglyceride (MG) and fatty acid (FA) — can either diffuse across the enterocyte and enter the portal vein blood or be re-synthesized to triglyceride (TG) by either the 2-m onoglyceride (2-MG) pathway associated with the smooth endoplasmic reticulum (SER) or the a-glycerol-3 phosphate (G3P) pathway associated with the rough endoplasmi c reticulum (RER). TG formed by these p athways typically enters the ER lumen and is assembled into lipoproteins (LPs; re presented by orange circles). LPs are then tra nsported to the Golgi, exocytosed from the enterocyte and taken up into the intestinal lymphatic system. As lipi d containe d within the lipoprotein assembly pathways and the Golgi is destined fo r transport to the systemic circ ulation by the inte stinal lymphatic system , this pool oflipids is referred to as the lymph lipid precursor pool (dashed blue line). A cytosolic pool of lip ids is also located within th e enterocyte. This lipid pool comprises excess TG formed by the G3P p athway and endogenous lipids taken up from the intestinal blood supply in the form of either FA or chylomi cron (CM) remnants. The cytosolic lipids are subject to hydrolysis by cytosolic lipa se and the di gestion products formed can be re-circulated into TG assembly pathways. However, the majority of lipids from this pool exit the enterocyte in the form of TG or free FA and are taken up into portal vein blood. The pool of lipids th at is transported from the enterocyte by the portal vein is therefore referred to as the portal lipid precursor pool (dashed red line). Recent evidence suggests that the trafficking and pooling of lipids within the enterocyte hav e a signifi cant influence on the intracellular disposition of lipophilic drugs.
Porter et al. Nature Reviews Drug Discovery 6, 231-248 (March 2007) I doi:10.1038/nrd2197
ŮlCTAJTť?AT
r
LP - lipoproteinová lipáza. Stepí triglyceridy, mastné kyseliny vstřebány, zbytek bohatý na cholesterol do jater.
= T[££UÉ,
MLjľLE
.■4 j:
l
í Tissue.
í MUSCLE
VLDL - very low density lipoproteins IDL - intermediate density lipoprotein LDL - low density lipoprotein
HDL - high density lipoprotein
* \ ' * ChOLESTlEPCL
L,0L
U>K. MAJOR CHOLESTEROL CARRIER in the l.l«„«Mr«.m. is :. spheric:.! ,.:.rliclc -ill, :, mass of ihrrr million dallons and :, di:,melir of 22 nanometers (millinnlhs «f a millinulcr) lis core consists of some 1.500 cholcstcn I esters, each a cholesterol molecule attached l.v an ester linkage lo a loiiK fatly acid chain. I hi- oih core is shielded Iron, the a.picnus plasma h\ a deler-pent coal composed of K00 molecules of phospholipid. 50(1 molecules of nmM,, ilied ,holes|,r-ol and one lar^e protein molecule, apopu.fein //. I 00. When hlood cholrstei.,1 Is elctaieil. increasing the risk of atherosclerosis, the reason is :il,,»os| a|u:ns -.,„ increase in • ir. olatii,» |.|)|..
LDL
CHOLESTERYL ESTER
APOPROTEIN 8-100
— LDL RECEPTOR
N-LINKED SUGAR CHAIN
• •••
CLATHRIN
SSSg O-LINKED
«g> SUGAR
oog CHAINS
• PLASMA
MEMBRANE
COOH
LDL RECEPTOR, a glycoprotein embedded in the plasma membrane of most body cells, was purified from the adrenal gland by Wolfgang J. Schneider in the authors' laboratory. David \V. Russell and Tokuo Vamamolo cloned complementary DNA derived from its messenger RNA. The DNA's nucleotide sequence was determined and from it the 839-a mi no-acid sequence of the receptor's protein backbone was deduced. Sites of attachment of sugar chains to nitrogen (.V) and oxygen {O) atoms were identified, as was a stretch likely to traverse ihe membrane. The actual shape of the receptor is not yd known; the drawing is a highly schematic representation.
CHOLESTERYL ESTER APOPROTEIN S-100
RECEPTOR
RNA AA/V\/^\,
/ INHIBITS
HMGCoA REDUCTASE
INHIBľTS
Of
OVERSUPPLY OF CHOLESTEROL
CELL MEMBRANE. STEROID HORMONES AND BILE ACIDS
ENDOPLASMIC RETICULUM
RECEPTOR Q1Doe^ie PROTEIN RIBOSOME
;2
L
ACTIVATES
AMINO ACIDS
7'V   \ CHOLESTERYL ESTERS
CIRCULATING LDL (/«/» right) is taken into a cell by receptor* mediated endocytosis. LDL is bound by a receptor in a coated pit, which iiivaginatcs and pinches off to form a coated vesicle. Fusion of so eral vesicles gives rise to an endosonie, in whose acidic environment the LDL dissociates from the receptor, which is recycled to the cell surface. The LDL is delivered to a lysosonie, where enzymes break down the apoprotein /MOO into amino acids and cleave the ester hood to \ield uncstcrified cholesterol for membrane synthesis
and other cellular needs. The cellular level of cholesterol is self-re»u-latiug. An ovcrsupply of cholesterol has three metabolic effects. It inhibits the enzyme HMG CoA reductase, which controls the rate of cholesterol synthesis (/); it activates the enzyme .IClf. which esteri. Ties cholesterol for storage (2), and it inhibits the manufacture of new LDL receptors by suppressing transcription of the receptor gene into messenger. RNA (.»), which would ordinarily be translated on ribo-somes of the endoplasmic reticulum to make the receptor protein.
LDL receptor na jaterních a jiných buňkách = zpětnovazebná regulace
Scavenger receptor na = fagocytóza bez regulace = vznik pěnových buněk = základ aterosklerózy
(Brown a Goldstein - Nobelova cena)
Atherosklerose <" atherogenese
trombogenese
= zúžení až uzávěr cév.
Nemá jedinou příčinu (> 200), více spolupůsobících faktorů:
„Abnormální" lipidy, hypertense, nikotin, DM,
hypercholesterolemie, genetické dispozice, faktory srážení krve, homocystein, ...
Cévní endotel
Klíčové postavení v ochraně cévní stěny před atherosklerotickými změnami
- Kontrola permeability
- Kontrola optimálního průtoku
- Zajištění nesmáčivosti povrchu (zabránění adheze a agregace trombocytů)
- Aktivace koagulace
- Kontrola fibrinolýzy, angiogeneze
Působení endotelu
Modifikace LDL
• Přímá oxidace apoproteinu B a PL
• Vazba aldehydu na aminoskupinu Lys = glykace usnadňuje oxidaci LDL
Další obrázky
Tür K E W Ei K Ci LA K D [ OU R K A L af M E D [ Cľ [ K" K
		
	REVI EW ARTICLE	
MECHANISMS OF DISEASE
Inflamma tio n, Athero s clero s is and Coronary Artery Disease
Goran K. Hansson, M.D., Ph.D.
Figure 2. Activating; Effect of LDL Infiltration on Inflammation in the Artery.
In patients with hypercholesterolemia, excess LDL infiltrates the artery and is retained in the intinia, particularly at sites of hemodynamic strain. Oxidative and enzymatic modifications lead to the release of inflammatory lipids chat induce endothelial cells to express leukocyte adhesion molecules. The modified LDL particles are taken up by scavenger receptors of macrophages, which evolve into foam cells.
LDL
!or acelyl-LDL
Rozpadové zbytky
Trombocyty
Hladká svalová buňka
Makrofágy
Trombus Makrofágy Trombocyty       I I
Rozpadové zbytky
Změněná hladká svalová buňka
Table 2 -Initial Classification Based on Total Cholesterol and HDL Levels*
Cholesterol Level Initial Classification
Total Cholesterol
< 200 mg/dl  (5.2 mmol/L) Desirable blood cholesterol
200-239 mg/dl  (5.2-6.2mmol/L) Borderline high blood
cholesterol
240 mg/dl  (6.2 mmol/L)  or greater High blood cholesterol
HDL Cholesterol
< 35 mg/dl   (0.9 mmol/L) Low HDL cholesterol
*HDL indicates high-density lipoprotein
Terapie vysoké hladiny cholesterolu
Food guide pyramid
Fats, Oils, Sweets (Use sparingly)
Milk, Yogurt,
Cheese (2-3 servings)
Vegetable^ (3-5 servings)
Key oFat (naturally occuring and added) Sugars (added)
These symbols show fat and added sugars In foods.
Meat, Poultry, Fish, Dry Beans, Eggs, Nuts (2-3 servings)
Fruit
(2-4 servings)
Bread, Cereal
(6-11 servings)
dietary recommendations
Eat plenty of fresh fruit and vegetables, at least five different portions per day.
Minimize intake of fats and.red meats, but do not become paranoid about it. Don't worry about polyunsaturates versus saturates.
Check your cholesterol level. If 200 mg/100 ml or below don't worry. If at or above 250 mg/100 ml seek medical advice.
Consume no more than 300 units (200 mg) of vitamin E (d-a-tocopherol, not dl-a-tocopherol) per day from a reliable source such as the 'own brand' of a reputable chain drug store. Take with food as you need fat to absorb it.
If you wish, consume up to 250 mg of vitamin C per day. Again, select a reputable supplier (e.g. the 'own brand' of a reputable chain drug-store). If you smoke, stop. If you can't, eat plenty of fruits and vegetables and consider supplementing with more vitamin C (Table 2, p. 67).
Do not take any form of iron supplements unless there is a clearly identified medical need monitored by laboratory tests.
We see no case at present for consuming /^-carotene supplements.
Positive Risk Factors
Age
Male 45 or older Estrogen Status
Female 55 or older (or premature menopause) without estrogen replacement therapy Family history of premature CHD
definite myocardial infarction or sudden death before 55 y of age in father or other first-degree
relative Current cigarette smoking Hypertension
blood pressure 140/90 or greater** or taking antihypertensive medication Low HDL cholesterol
35 mg/dl [0.9 mmol/L] or less**
Negative Risk Factors***
High HDL cholesterol (60 mg/dl [1.6 mrnoI/L] or greater)
Peripheral Arterial Disease
Carotid artery
(Brain)
Aorta
(To the body)
Superior mesenteric artery & Celiac artery (Intestines)
Renal artery (Kidneys)
"Common lilac artery (Legs)
Narrowed Artery
Ischemia-decreased oxygen-rich blood to an area, which can cause pain and dysfunction.
Arteries become narrowed and blood flow decreases in arteriosclerosis
*Adajvi.
Lipoprotein metabolism has a key role in atherogenesis. It involves the transport of lipids, particularly cholesterol and triglycerides, in the blood. The intestine absorbs dietary fat and packages it into chylomicrons (large triglyceride-rich lipoproteins), which are transported to peripheral tissues through the blood. In muscle and adipose tissues, the enzyme lipoprotein lipase breaks down chylomicrons, and fatty acids enter these tissues. The chyl omicron remnants are subsequently taken up by the liver. The l iver lo ads lipids onto apoB and secretes very-low-density lipoproteins (VLDLs), whic h undergo lipolysis b y lipoprotein lipase to form low-density lipoproteins (LDLs). LDLs are then taken up by the liver through binding to the LDL receptor (LDLR), as well as through other pathways. By contrast, high-density lipoproteins (HDLs) are generated by the intestine and the liver through the secretion of lipid-free apoA-I. ApoA-I then recruits cholesterol from these organs through th e actions of the transporter ABCA1, formi ng nascent HDLs, and this protects apoA-I from being rapidly degraded in the kidneys. In the peripheral tissues, nascent HDLs promote the efflux of cholesterol from tissues, including from macrophages, through the actions of ABCA1. Mature HDLs also promote thi s efflux but through the actions of ABCG1. (In macrophages, the nuclear receptor LXR upregulates the production of both ABCA1 and ABCG1.) The free (unesterified) cholesterol in nascent HDLs is esterified to cholesteryl ester by the enzyme lecithin cholesterol acyltransferase (LCAT), creating mature HDLs. The cholesterol in HDLs is returned to the liver both directly, through uptake by the receptor SR-BI, and indirectly, by transfer to LDLs and VLDLs through the cholesteryl ester transfer protein (CETP). The lipid content of HDLs is altered by the enzymes hepatic lipase and endothelial lipase and by the transfer proteins CETP and phos pholipid transfer protein (PLTP),
affecting hdl catabolism. www.nature.com/.../images/nature06796-f3.2.jpg
Encyclopaedia Britannica