High density lipoprotein physiology: Difference between revisions
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====Anti-coagulant Funtions==== | ====Anti-coagulant Funtions==== | ||
HDL has the ability to inhibit platelet activation and aggregation by directly inhibiting platelet activation,<ref name="Calkin-2009">{{Cite journal | last1 = Calkin | first1 = AC. | last2 = Drew | first2 = BG. | last3 = Ono | first3 = A. | last4 = Duffy | first4 = SJ. | last5 = Gordon | first5 = MV. | last6 = Schoenwaelder | first6 = SM. | last7 = Sviridov | first7 = D. | last8 = Cooper | first8 = ME. | last9 = Kingwell | first9 = BA. | title = Reconstituted high-density lipoprotein attenuates platelet function in individuals with type 2 diabetes mellitus by promoting cholesterol efflux. | journal = Circulation | volume = 120 | issue = 21 | pages = 2095-104 | month = Nov | year = 2009 | doi = 10.1161/CIRCULATIONAHA.109.870709 | PMID = 19901191 }}</ref><ref name="Lerch-1998">{{Cite journal | last1 = Lerch | first1 = PG. | last2 = Spycher | first2 = MO. | last3 = Doran | first3 = JE. | title = Reconstituted high density lipoprotein (rHDL) modulates platelet activity in vitro and ex vivo. | journal = Thromb Haemost | volume = 80 | issue = 2 | pages = 316-20 | month = Aug | year = 1998 |doi = | PMID = 9716159 }}</ref> | HDL has the ability to inhibit platelet activation and aggregation by directly inhibiting platelet activation,<ref name="Calkin-2009">{{Cite journal | last1 = Calkin | first1 = AC. | last2 = Drew | first2 = BG. | last3 = Ono | first3 = A. | last4 = Duffy | first4 = SJ. | last5 = Gordon | first5 = MV. | last6 = Schoenwaelder | first6 = SM. | last7 = Sviridov | first7 = D. | last8 = Cooper | first8 = ME. | last9 = Kingwell | first9 = BA. | title = Reconstituted high-density lipoprotein attenuates platelet function in individuals with type 2 diabetes mellitus by promoting cholesterol efflux. | journal = Circulation | volume = 120 | issue = 21 | pages = 2095-104 | month = Nov | year = 2009 | doi = 10.1161/CIRCULATIONAHA.109.870709 | PMID = 19901191 }}</ref><ref name="Lerch-1998">{{Cite journal | last1 = Lerch | first1 = PG. | last2 = Spycher | first2 = MO. | last3 = Doran | first3 = JE. | title = Reconstituted high density lipoprotein (rHDL) modulates platelet activity in vitro and ex vivo. | journal = Thromb Haemost | volume = 80 | issue = 2 | pages = 316-20 | month = Aug | year = 1998 |doi = | PMID = 9716159 }}</ref> downregulating thromboxane A2 synthesis,<ref name="Brill-2011">{{Cite journal | last1 = Brill | first1 = A. | last2 = Fuchs |first2 = TA. | last3 = Chauhan | first3 = AK. | last4 = Yang | first4 = JJ. | last5 = De Meyer | first5 = SF. | last6 = Köllnberger | first6 = M. | last7 = Wakefield | first7 = TW. | last8 = Lämmle | first8 = B. | last9 = Massberg | first9 = S. | title = von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models. | journal = Blood | volume = 117 | issue = 4 | pages = 1400-7 | month = Jan | year = 2011 | doi = 10.1182/blood-2010-05-287623 | PMID = 20959603 }}</ref> increasing the synthesis of prostacyclin,<ref name="Fleisher-1982">{{Cite journal | last1 = Fleisher | first1 = LN. |last2 = Tall | first2 = AR. | last3 = Witte | first3 = LD. | last4 = Miller | first4 = RW. | last5 = Cannon | first5 = PJ. | title = Stimulation of arterial endothelial cell prostacyclin synthesis by high density lipoproteins. | journal = J Biol Chem | volume = 257 | issue = 12 | pages = 6653-5 | month = Jun | year = 1982 | doi = | PMID = 7045092 }}</ref> and lowering the expression of the tissue factor which is required in the coagulation process.<ref name="Viswambharan-2004">{{Cite journal | last1 = Viswambharan | first1 = H. | last2 = Ming | first2 = XF. | last3 = Zhu | first3 = S. | last4 = Hubsch | first4 = A. | last5 = Lerch | first5 = P. | last6 = Vergères | first6 = G. | last7 = Rusconi | first7 = S. | last8 = Yang | first8 = Z. | title = Reconstituted high-density lipoprotein inhibits thrombin-induced endothelial tissue factor expression through inhibition of RhoA and stimulation of phosphatidylinositol 3-kinase but not Akt/endothelial nitric oxide synthase. | journal = Circ Res | volume = 94 | issue = 7 | pages = 918-25 | month = Apr | year = 2004 | doi = 10.1161/01.RES.0000124302.20396.B7 | PMID = 14988229 }}</ref> | ||
====Anti-oxidant Funtions==== | ====Anti-oxidant Funtions==== | ||
The formation of free oxygen radicals contributes to the pathogenesis and progression of atherosclerotic plaques. Oxidized LDLs gets engulfed by macrophages, which leads to further oxidation and the production of foam cells. Oxidized LDLs acts as chemotactic agents for circulating monocytes, converts macrophages into foam cells, induce cytotoxic effects on the endothelium, inhibits motility of tissue macrophages, and stimulates the migration and proliferation of vascular smooth muscle cells.<ref name="pmid11795267">{{cite journal| author=Kita T, Kume N, Minami M, Hayashida K, Murayama T, Sano H et al.| title=Role of oxidized LDL in atherosclerosis. | journal=Ann N Y Acad Sci | year= 2001 | volume= 947 | issue= | pages= 199-205; discussion 205-6 | pmid=11795267 | doi= |pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11795267 }} </ref> HDL has been shown to inhibit the oxidative modification of oxidized LDLs,<ref name="pmid2344447">{{cite journal| author=Parthasarathy S, Barnett J, Fong LG|title=High-density lipoprotein inhibits the oxidative modification of low-density lipoprotein. | journal=Biochim Biophys Acta | year= 1990 | volume= 1044 |issue= 2 | pages= 275-83 | pmid=2344447 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2344447 }} </ref> as well as preventing their infiltration into the vessel wall.<ref name="Galle-1994">{{Cite journal | last1 = Galle | first1 = J. | last2 = Ochslen | first2 = M. | last3 = Schollmeyer | first3 = P. | last4 = Wanner | first4 = C. | title = Oxidized lipoproteins inhibit endothelium-dependent vasodilation. Effects of pressure and high-density lipoprotein. | journal = Hypertension |volume = 23 | issue = 5 | pages = 556-64 | month = May | year = 1994 | doi = | PMID = 8175161 }}</ref> | The formation of free oxygen radicals contributes to the pathogenesis and progression of atherosclerotic plaques. Oxidized LDLs gets engulfed by macrophages, which leads to further oxidation and the production of foam cells. Oxidized LDLs acts as chemotactic agents for circulating monocytes, converts macrophages into foam cells, induce cytotoxic effects on the endothelium, inhibits motility of tissue macrophages, and stimulates the migration and proliferation of vascular smooth muscle cells.<ref name="pmid11795267">{{cite journal| author=Kita T, Kume N, Minami M, Hayashida K, Murayama T, Sano H et al.| title=Role of oxidized LDL in atherosclerosis. | journal=Ann N Y Acad Sci | year= 2001 | volume= 947 | issue= | pages= 199-205; discussion 205-6 | pmid=11795267 | doi= |pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11795267 }} </ref> HDL has been shown to inhibit the oxidative modification of oxidized LDLs,<ref name="pmid2344447">{{cite journal| author=Parthasarathy S, Barnett J, Fong LG|title=High-density lipoprotein inhibits the oxidative modification of low-density lipoprotein. | journal=Biochim Biophys Acta | year= 1990 | volume= 1044 |issue= 2 | pages= 275-83 | pmid=2344447 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2344447 }} </ref> as well as preventing their infiltration into the vessel wall.<ref name="Galle-1994">{{Cite journal | last1 = Galle | first1 = J. | last2 = Ochslen | first2 = M. | last3 = Schollmeyer | first3 = P. | last4 = Wanner | first4 = C. | title = Oxidized lipoproteins inhibit endothelium-dependent vasodilation. Effects of pressure and high-density lipoprotein. | journal = Hypertension |volume = 23 | issue = 5 | pages = 556-64 | month = May | year = 1994 | doi = | PMID = 8175161 }}</ref> | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayokunle Olubaniyi, M.B,B.S [2]
Overview
The physiology of HDL centers around the reverse cholesterol transport system. Nascent HDLs secreted into the plasma by the liver or intestines pick up free cholesterol from peripheral tissues and the arterial wall mediated mainly by the ATP-binding cassette A1 (ABCA1). The enzyme LCAT (lecithin-cholesteryl acetyltransferase) catalyzes the esterification of the free cholesterol, and also converts the nascent HDLs into mature forms. The esterified cholesterol is transported to the liver where CETP (cholesterylester transfer protein), an enzyme produced in the liver, acts on it transferring the cholesterol to other apo B containing lipoproteins. The cholesterol-deplete HDLs get broken down by triglyceride lipases into apo A-I which either takes up free cholesterol to continue the cycle, or gets eliminated in the kidney. In addition to HDL being atheroprotective against cardiovascular diseases, it also exhibits anti-oxidant, anti-inflammatory, anti-apoptotic, anti-coagulant, vasodilatory, and metabolic properties.
Physiology
HDL Metabolism
The metabolism of HDL can also be described as the Reverse Cholesterol Transport System. HDL serves a mode of transportation for the excess cholesterol from peripheral tissues to the liver.
Synthesis and Uptake of Cholesterol
- HDL consists majorly of apo A-I and/or apo A-II. Both the liver and the small intestine synthesize apo A-I while only the liver synthesizes apo A-II. HDL is normally synthesized consisting mainly of phospholipids and apolipoproteins.
- Free apo A-I is released into the plasma as nascent HDLs. This readily takes up excess free cholesterol (FC) from peripheral tissues such as fibroblasts and macrophages and arterial wall mediated by either ATP-binding cassette A1 (ABCA1), G1/G4, scavenger receptor class B type 1 (SR-B1), Cyp27A1, caveloin, and passive diffusion, leading to the formation of discoid HDL (a.k.a. pre-βHDL).
- Apo A-I activates lecithin:cholesteryl acetyltransferase (LCAT) which catalyses the esterification of the free cholesterol bound to the discoid HDL. The Apolipoprotein A1 acts as a signal protein in mobilizing cholesterol esters from within the cells.
aaaaavvvvvvccccccattttttttttttttttttttttttaaaaaaaaaaLCAT
aaaaavvvvvvaaaaaaaaaaaLecithin + Cholesterol ———-> Lysolecithin + Cholesterol ester
Maturation and Transfer of Cholesterol
- The esterified cholesterol moves into the hydrophobic core of the HDL, changing the HDL particle from discoid to spherical (mature HDL). This process also prevents the re-uptake of cholesterol by cells. LCAT is responsible for the maturation of HDL particles.
- The esterified cholesterol can be delivered back to the liver through a number of routes:
- By the action of cholesterylester transfer protein (CETP) - CETP, secreted in the liver, transfers cholesterol from HDL to the apo B–containing lipoproteins e.g., very low-density lipoprotein (VLDL) or intermediate-density lipoprotein (IDL) to be taken up by the liver. Mutations of this transport protein gene causes familial HDL deficiencies and Tangier disease
- HDL particles may be taken up directly by the liver
- Free cholesterol may be taken up directly by the liver
- HDL cholesterol esters may be selectively taken up via the scavenger receptor SR-B1, which is expressed in the liver.
Catabolism
- Triglyceride lipases degrade these cholesterol-deplete HDL particles into small, dense HDL particles which after dissociation, release apo A-I (nascent HDL). The apo A-1 either rapidly re-uptakes free cholesterol again by ABCA1 to form discoid HDLs or it is endocytosed in the kidney tubule or cleared via glomerular filtration.
Functions
Atheroprotection
It has been established that HDL-cholesterol has an inverse correlation with future atherosclerotic cardiovascular complications. HDL and apo A-I exhibit many atheroprotective functions which primarily aims at removing cholesterol from peripheral tissues and the arterial wall through various efflux mechanisms, mainly the reverse cholesterol transport system. It is also important in the attenuation of plaque progression and promotion of plaque stabilization. These functions are exhibited through its anti-oxidative, anti-platelet, anti-apoptotic, and anti-inflammatory properties. With all these properties in context, HDL will potentially protect against reperfusion ischemic injuries and secondary plaque ruptures frequently observed in post-acute coronary syndrome patients.
Anti-coagulant Funtions
HDL has the ability to inhibit platelet activation and aggregation by directly inhibiting platelet activation,[1][2] downregulating thromboxane A2 synthesis,[3] increasing the synthesis of prostacyclin,[4] and lowering the expression of the tissue factor which is required in the coagulation process.[5]
Anti-oxidant Funtions
The formation of free oxygen radicals contributes to the pathogenesis and progression of atherosclerotic plaques. Oxidized LDLs gets engulfed by macrophages, which leads to further oxidation and the production of foam cells. Oxidized LDLs acts as chemotactic agents for circulating monocytes, converts macrophages into foam cells, induce cytotoxic effects on the endothelium, inhibits motility of tissue macrophages, and stimulates the migration and proliferation of vascular smooth muscle cells.[6] HDL has been shown to inhibit the oxidative modification of oxidized LDLs,[7] as well as preventing their infiltration into the vessel wall.[8]
Anti-inflammatory Functions
HDL has anti-inflammatory functions in both endothelial cells and leukocytes. During inflammation, several leukocyte adhesion molecules are activated which promotes the binding of leukocytes and formation of atheroma. HDL has been shown to inhibit the activation of vascular cell adhesion molecule (VCAM-1,[9] interleukin-1-induced expresion of E-selectin,[10] interleukin-8, intracellular adhesion molecule (ICAM)-1, neutrophils,[11] monocytes,[12] and also prevents the binding of T-lymphocytes to monocytes thereby preventing the formation of proinflammatory cytokines.[13]
Metabolic Functions
In a study to determine the effects and mechanisms of HDL on glucose metabolism, 13 type 2 diabetic patients received intravenous reconstituted HDL. The result proved a reduction in the plasma glucose of the patients due to an increase in plasma insulin in addition to the activation of AMP-activated protein kinase in skeletal muscle. These findings suggest a role for HDL-raising therapies beyond atherosclerosis to address type 2 diabetes mellitus.[14]
Anti-apoptotic Functions
Plasma HDLs in-vitro was shown to offer some cytoprotection against oxidized LDL-causing apoptosis and generation of reactive oxygen species.[15]
Vasodilatory Functions
HDL has been shown to restore endothelial dysfunction which is implicated in the pathogenesis of type 2 diabetes. In a study, reconstituted HDL was infused in patients with type 2 diabetes and the vascular function (forearm blood flow) was assessed at 4 hours and 7 days post-infusion. HDL was found to increase the forearm blood flow in diabetic patients as compared to the controlled group, probably due to its effect on increasing nitric oxide bioavailability.[16]
References
- ↑ Calkin, AC.; Drew, BG.; Ono, A.; Duffy, SJ.; Gordon, MV.; Schoenwaelder, SM.; Sviridov, D.; Cooper, ME.; Kingwell, BA. (2009). "Reconstituted high-density lipoprotein attenuates platelet function in individuals with type 2 diabetes mellitus by promoting cholesterol efflux". Circulation. 120 (21): 2095–104. doi:10.1161/CIRCULATIONAHA.109.870709. PMID 19901191. Unknown parameter
|month=ignored (help) - ↑ Lerch, PG.; Spycher, MO.; Doran, JE. (1998). "Reconstituted high density lipoprotein (rHDL) modulates platelet activity in vitro and ex vivo". Thromb Haemost. 80 (2): 316–20. PMID 9716159. Unknown parameter
|month=ignored (help) - ↑ Brill, A.; Fuchs, TA.; Chauhan, AK.; Yang, JJ.; De Meyer, SF.; Köllnberger, M.; Wakefield, TW.; Lämmle, B.; Massberg, S. (2011). "von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models". Blood. 117 (4): 1400–7. doi:10.1182/blood-2010-05-287623. PMID 20959603. Unknown parameter
|month=ignored (help) - ↑ Fleisher, LN.; Tall, AR.; Witte, LD.; Miller, RW.; Cannon, PJ. (1982). "Stimulation of arterial endothelial cell prostacyclin synthesis by high density lipoproteins". J Biol Chem. 257 (12): 6653–5. PMID 7045092. Unknown parameter
|month=ignored (help) - ↑ Viswambharan, H.; Ming, XF.; Zhu, S.; Hubsch, A.; Lerch, P.; Vergères, G.; Rusconi, S.; Yang, Z. (2004). "Reconstituted high-density lipoprotein inhibits thrombin-induced endothelial tissue factor expression through inhibition of RhoA and stimulation of phosphatidylinositol 3-kinase but not Akt/endothelial nitric oxide synthase". Circ Res. 94 (7): 918–25. doi:10.1161/01.RES.0000124302.20396.B7. PMID 14988229. Unknown parameter
|month=ignored (help) - ↑ Kita T, Kume N, Minami M, Hayashida K, Murayama T, Sano H; et al. (2001). "Role of oxidized LDL in atherosclerosis". Ann N Y Acad Sci. 947: 199–205, discussion 205-6. PMID 11795267.
- ↑ Parthasarathy S, Barnett J, Fong LG (1990). "High-density lipoprotein inhibits the oxidative modification of low-density lipoprotein". Biochim Biophys Acta. 1044 (2): 275–83. PMID 2344447.
- ↑ Galle, J.; Ochslen, M.; Schollmeyer, P.; Wanner, C. (1994). "Oxidized lipoproteins inhibit endothelium-dependent vasodilation. Effects of pressure and high-density lipoprotein". Hypertension. 23 (5): 556–64. PMID 8175161. Unknown parameter
|month=ignored (help) - ↑ Dimayuga, P.; Zhu, J.; Oguchi, S.; Chyu, KY.; Xu, XO.; Yano, J.; Shah, PK.; Nilsson, J.; Cercek, B. (1999). "Reconstituted HDL containing human apolipoprotein A-1 reduces VCAM-1 expression and neointima formation following periadventitial cuff-induced carotid injury in apoE null mice". Biochem Biophys Res Commun. 264 (2): 465–8. doi:10.1006/bbrc.1999.1278. PMID 10529386. Unknown parameter
|month=ignored (help) - ↑ Cockerill, GW.; Huehns, TY.; Weerasinghe, A.; Stocker, C.; Lerch, PG.; Miller, NE.; Haskard, DO. (2001). "Elevation of plasma high-density lipoprotein concentration reduces interleukin-1-induced expression of E-selectin in an in vivo model of acute inflammation". Circulation. 103 (1): 108–12. PMID 11136694. Unknown parameter
|month=ignored (help) - ↑ Murphy, AJ.; Woollard, KJ.; Suhartoyo, A.; Stirzaker, RA.; Shaw, J.; Sviridov, D.; Chin-Dusting, JP. (2011). "Neutrophil activation is attenuated by high-density lipoprotein and apolipoprotein A-I in in vitro and in vivo models of inflammation". Arterioscler Thromb Vasc Biol. 31 (6): 1333–41. doi:10.1161/ATVBAHA.111.226258. PMID 21474825. Unknown parameter
|month=ignored (help) - ↑ Murphy, AJ.; Woollard, KJ.; Hoang, A.; Mukhamedova, N.; Stirzaker, RA.; McCormick, SP.; Remaley, AT.; Sviridov, D.; Chin-Dusting, J. (2008). "High-density lipoprotein reduces the human monocyte inflammatory response". Arterioscler Thromb Vasc Biol. 28 (11): 2071–7. doi:10.1161/ATVBAHA.108.168690. PMID 18617650. Unknown parameter
|month=ignored (help) - ↑ Carpintero, R.; Gruaz, L.; Brandt, KJ.; Scanu, A.; Faille, D.; Combes, V.; Grau, GE.; Burger, D. (2010). "HDL interfere with the binding of T cell microparticles to human monocytes to inhibit pro-inflammatory cytokine production". PLoS One. 5 (7): e11869. doi:10.1371/journal.pone.0011869. PMID 20686620.
- ↑ Drew, BG.; Duffy, SJ.; Formosa, MF.; Natoli, AK.; Henstridge, DC.; Penfold, SA.; Thomas, WG.; Mukhamedova, N.; de Courten, B. (2009). "High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus". Circulation. 119 (15): 2103–11. doi:10.1161/CIRCULATIONAHA.108.843219. PMID 19349317. Unknown parameter
|month=ignored (help) - ↑ de Souza, JA.; Vindis, C.; Nègre-Salvayre, A.; Rye, KA.; Couturier, M.; Therond, P.; Chantepie, S.; Salvayre, R.; Chapman, MJ. (2010). "Small, dense HDL 3 particles attenuate apoptosis in endothelial cells: pivotal role of apolipoprotein A-I". J Cell Mol Med. 14 (3): 608–20. doi:10.1111/j.1582-4934.2009.00713.x. PMID 19243471. Unknown parameter
|month=ignored (help) - ↑ van Etten, RW.; de Koning, EJ.; Verhaar, MC.; Gaillard, CA.; Rabelink, TJ. (2002). "Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate". Diabetologia. 45 (7): 1004–10. doi:10.1007/s00125-002-0862-1. PMID 12136399. Unknown parameter
|month=ignored (help)