Oxysterols

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Oxysterols may be formed by cooking food that contains cholesterol, through cholesterol oxidation. Oxysterols from ordinary foodstuff are absorbed in the human intestinal tract.[1] Endogenously, they may be formed enzymatically, or through oxidation as well.[2](Full Free Text) Oxysterols are widely distributed in nature, being found in the blood and tissues of animals and man.[3] Some oxysterols are essential for the normal physiology of the hepatic, central nervous and vascular systems [4], as well as in inflammation and immunity.[5][6] In healthy people, endogenously formed oxysterols (7α-OHC, 24-OHC, 27-OHC) are most abundant (relative to all oxysterols).[7] Many oxysterols are cytotoxic. Most research suggests that certain oxysterols may cause cell death, and have been strongly implicated in the pathogenesis of atherosclerosis.[8]

Oxidation

  • In water, cholesterol oxidizes more rapidly. But at 125°C, autoxidation of cholesterol also occurs in the dry state.[9] Heating at 100°C for 8 hours, 5% of cholesterol was oxidized. The identified oxidation products (52% of total) were: 7-ketoC (42%), 7β-OHC (20%), β-epoxyC (16%), α-epoxyC (12%), 7α-OHC (7%) and 25β-OHC (3%). A diet enriched with such oxidized cholesterol resulted in a 100% increase in fatty streak lesions in the aorta.[10] (free full text)
  • Heat-treatment of cholesterol caused 30% oxidation; the major oxidation products: 7β-OHC, 7-keto-C, α-epoxyC and β-epoxyC. In the rats given the oxidized cholesterol, 6% of the oxysterol load was absorbed and incorporated into lymph chylomicrons, resulting in a twofold increase in the cholesterol and triglyceride content. [11]
  • Besides heat, cholesterol may also be oxidized (endogenously) by reactive agents such as copper, myoglobin and peroxynitrite, yielding 7-keto-C, 7β-OHC, 7α-OHC, β-epoxyC and α-epoxyC.[12]
  • Fatty streaks in the aorta may contain 7-ketoC, 7β-OHC, β-epoxyC, α-epoxyC, 7α-OHC and 27-OHC, which are hardly (or not at all) present in normal aorta.[13]
  • Cholesterol incorporated in a membrane is relatively protected aginst oxidation.[14] Normally, unoxidized cholesterol levels are over 1000-fold greater than oxysterol levels. In atherosclerotic plaque, the cholesterol:oxysterol ratio is much lower.[15]
  • Serum cholesterol is increased after consuming unoxidized cholesterol, similar to partially (5%) oxidized cholesterol, but only the oxidized cholesterol (25 mg/day) diet resulted in a 100% increase in fatty streak lesions in the aorta.[16]
  • Oxysterols are found in the human atheroma [17], and accumulate in macrophage foam cells. [18] Oxysterols are generally toxic to endothelial cells [19] and macrophages.[20]

List of Important Oxysterols

  • 4-beta-hydroxycholesterol (4β-OHC) - a minor product of endogenous cholesterol conversion.[21] (free full text)
  • 5 alpha,6 alpha-epoxycholesterol (α-epoxyC) - is cytotoxic [22]
  • 5 beta,6 beta-epoxycholesterol (β-epoxyC) - is cytotoxic [23], and its levels are dramatically increased in hypercholesterolemic plasma samples.[24]
  • 5 alpha,6 beta-epoxycholesterol (5α,6β-diOHC)
  • 7-hydroperoxycholesterol (7-OOHC) - this primary 7- oxidation product of cholesterol is the most cytotoxic oxygenated lipid present in oxidized LDL.[25]Free Full PDF It is rapidly decomposed into 7α-OHC, 7β-OHC and 7-ketoC, which may be found in relatively high concentrations in foam cells and fatty streaks.[26] (free full pdf)
  • 7-alpha-hydroxycholesterol (7α-OHC) - mostly the first step in endogenous bile synthesis [27] (full free text), but also a decomposition product of 7-OOHC. The mean levels of 7α-OHC in subjects with severe coronary atherosclerosis were significantly higher than in controls.[28]
  • 7-alpha-hydroxy-4-cholesten-3-one (7α-OHC4)
  • 7-beta-hydroxycholesterol (7β-OHC) - 7β-OHC is cytotoxic [29], and its serum levels significantly associate with progression of carotid atherosclerosis.[30]
  • 7-ketocholesterol (7-ketoC) = 7-oxocholesterol - is the most abundant oxysterol of nonenzymatic origin in atherosclerotic plaques.[31](free full pdf) It is cytotoxic [32], rather stable [33] and its levels are dramatically increased in hypercholesterolemic plasma samples.[34]
  • 7-dehydrocholesterol (7-DHC)
  • 24,25-epoxycholesterol (24,25-epoxyC) - is formed endogenously in any cell that may form cholesterol. It elicits effects on multiple levels of cellular cholesterol homeostasis [35](free full text) and regulates cholesterol synthesis in the liver [36](free full text)[37] and neuronal cells.[38] It may accumulate in the liver [39] (free full pdf) Without 24,25-epoxyC, acute cholesterol synthesis is exaggerated.[40]
  • 22-hydroxycholesterol (22-OHC)
  • 24-hydroxycholesterol (24 OHC) - In humans, 24-hydroxycholesterol is predominantly formed in the brain [41][42] (free full texts), and eventually 'leaks' into the blood, prior to ending up as bile acid or being excreted.[43] (free full pdf)
  • 25-beta-hydroxycholesterol (25β-OHC)
  • 25-hydroxycholesterol (25-OHC) - is enzymatically formed, and endogenously present in very low concentrations.[44](free full text) [45](free full pdf). 25-OHC is cytotoxic [46] and has marked antiviral activity against pathogenic enveloped and non-enveloped viruses.[47](full free text)
  • 26-hydroxycholesterol (26-OHC), which includes 27-hydroxycholesterol (27-OHC) = (25R)-26-Hydroxycholesterol [48] - 5% to 10% of the total conversion of cholesterol into bile acids starts with the conversion of cholesterol into 27-OHC.[49][50] (free full texts) Accumulation of cholesterol in atheromas (macrophages, endothelial cells) is counteracted by conversion of cholesterol into 27-OHC, which is transported to the liver.[51](free full pdf) [52](Free full text) This explains the abundant presence of 27-OHC in atheromas.[53] The levels of 26-OHC in atherosclerotic aorta of human subjects increase with severity of the disease.[54][55] 27-OHC has remarkable antiviral activity.[56]

HDL / LDL

HDL and LDL are lipoproteins transporting cholesterol, and oxysterols. Natural oxysterols that are intermediates in cholesterol synthesis (24S- and 27-hydroxycholesterol) are transported with both HDL and LDL [57]. Cholesterol oxidation products are not equally distributed among plasma lipoproteins.[58][59] Oxidized fatty acids in the diet contribute to serum lipoprotein oxidation. Oxidized fatty acids in the diet accelerate atherosclerosis in cholesterol-fed rabbits.[60] Elevated levels of oxidized LDL correlate with subclinical atherosclerosis and predict future cardiovascular events [61]Free Full Text [62]Free Full Text Elevated LDL levels represent one of the most important risk factors for atherosclerosis, cardiovascular morbidity and mortality. Both native and oxidized LDL are potent growth factors and regulate several other growth factors, for several cell types. Furthermore, the mitogenic effects of oxLDL may be mediated through lysophosphatidylcholine (LPC), lysophosphatidic acid (LPA), lactosylceramide (LacCer) sphingosine-1-phosphate (S1P) and sphingosylphosphorylcholine (SPC). [63] LDL is more oxidised in the plasma of dementia patients although total cholesterol levels remained unchanged. Oxidized LDL disrupts blood brain barrier function.[64] Oxidized β-VLDL leads to increased lipid accumulation in smooth muscle cells.[65][66] Macrophages cannot limit the uptake of lipids. The uptake of oxidized LDL by macrophages is a key initial event in atherogenesis. (oxy)cholesterol efflux from macrophages is attributed to HDL (facilitated by apolipoprotein E and inhibited by some oxysterols [67]). HDL protects macrophages from apoptosis induced by loading with free cholesterol or oxidized LDL. [68] Full Free Text

ABCA-1 and ABCG-1 proteins mediate the efflux of oxysterols (and cholesterol) from macrophages [69] (for transportation to the liver), which in turn is mediated by HDL. The effect of ABCA-1 and ABCG-1 proteins is inhibited by AGEs and ALEs (Maillard reaction products), thus inhibiting the protective effect of HDL.[70] Free Full Text Oxidized LDL also inhibits the protective effect of HDL, by inhibiting PON-1 (human serum paraoxonase, which is associated to HDL) PON-1 can eliminate oxidized LDL (by hydrolysis of oxLDL-lipid peroxides) [71], similar to PAF acetylhydrolase (which is also associated to HDL). [72] Full Free Text HDL inhibits LDL oxidation, as about 45% of the total plasma oxysterols (plus 35-40% of the total plasma lipoxidation products) is associated with HDL transporters, accounting for the protective effect of HDL. [73]

Sphingomyelin & Calcification

  • Aging is the single most important risk factor for cardiovascular diseases, and increased vessel rigidity appears to be a major hallmark of cardiovascular aging.[74]
  • Sphingomyelin in arterial tissue (and relative to lecithin) increases with age.[75]
  • Oxysterols promote atherosclerosis through sphingomyelin-mediated arterial calcification and thromboxane-mediated interruption of blood flow. [76]
  • Oxidized LDL induces an immediate and oscillatory increase in intracellular calcium.[77]
  • oxidized LDL-induced apoptosis of endothelial cells is calcium-dependent.[78]
  • Oxidative modification of LDL results in the production of lipid peroxides and the conversion of phosphatidylcholine to lysophosphatidylcholine.[79]
  • In bone tissue, locally synthesized (Smpd3 encoded-) sphingomyelinase stimulates bone calcification. Sphingomyelinase cleaves sphingomyelin to generate bioactive lipid metabolites (ceramide).[80]
  • Lowering plasma sphingomyelin reduces atherosclerotic lesions. [81]
  • Plasma sphingomyelin concentration is an independent predictor of coronary artery disease.[82] [
  • Inhibiting sphingomyelin synthesis decreases atherosclerosis in mice.[83]
  • the plasma from cardiac catheterized patients suffering from chest pains contained higher levels of oxysterols.[84]
  • the plasma of patients with cardiovascular disease contains excess concentration of oxysterols, resulting in more calcium in endothelial cells.[85]
  • Oxysterols (25- and 26-hydroxycholesterol) have an injurious effect on arterial cells. [86]
  • Oxysterols (7 alpha OHC, 7 beta OHC, alpha epoxyC, beta epoxyC, 7ketoC, 26OHC, TriolC) replace cholesterol in the cell membrane, increasing calcium influx.[87]
  • 27OHC decreases phosphatidylethanolamine and AA, and increases sphingomyelin, LA and calcium.[88]
  • The arteries from patients who had had coronary artery bypass operations, contained elevated concentrations of oxysterols and sphingomyelin, increasing calcium influx into endothelial cells. The phospholipd sphingomyelin fraction in replaced arteries was 48.2%, compared to 24% in healthy arteries, and to 10% in arterial tissue from umbilical cords. [89]
  • the newborn human placenta contained only about 10% sphingomyelin and 50% phosphatidylcholine.Full Free Text
  • Depending on the oxidation rate and the ratio of oxysterols plus thiobarbituric acid reactive substances (TBARS) versus lysolecithin (obtained from phosphatidylcholine, inhibiting thromboxane synthesis), [90] oxidized LDL may stimulate thromboxane release by platelets [91], increasing blood clotting.

Sphingosine-1-phosphate (S1P)

  • Sphingomyelin deposition and metabolism occurs in the atherosclerotic plaque, leading to the formation of sphingosine-1-phosphate (S1P). S1P receptor 2 (S1PR2) is expressed in bone marrow-derived macrophages and in macrophage-like foam cells in atherosclerotic plaques. S1PR2 retains macrophages in atherosclerotic plaques. S1PR2 signaling in the plaque macrophage regulates macrophage retention and inflammatory cytokine secretion, thereby promoting atherosclerosis. [92] Full Free Text
  • Macrophages internalize oxidized LDL immune complexes (oxLDL-IC) and transform into activated foam cells. S1P may be generated extracellularly in response to oxidized LDL immune complexes.[93]
  • oxLDL induces the immediate activation of sphingosine kinase (SK), which can increase sphingosine-1-phosphate (S1P) levels by phosphorylating sphingosine. Both S1P and oxLDL block macrophage apoptosis and producing calcium oscillations. [94] Full Free Text
  • S1P is mainly released from activated platelets. release of S1P from activated platelets was increased by enhanced platelet sensitivity in hypercholesterolemia, which potentiated the ox-LDL-induced VSMC proliferation via EDG-1 receptor pathway.[95]
  • Sphingosine-1-phosphate (SPP) is a major (and potent) Full Free Text polar sphingolipid metabolite (from ceramides, derived from sphingomyelin) released from activated platelets that (also) acts as an intracellular lipid messenger, regulating calcium mobilisation.[96]
  • S1P is a mediator in inflammation and atherogenesis.[97]
  • S1P acts via multiple signaling pathways. S1P induces vasoconstriction in vivo. S1P can act through both receptors and a novel intracellular pathway to activate store-operated calcium entry (SOCE) in vascular smooth muscle cells. Because S1P-induced SOCE contributes to vessel constriction and is increased in proliferative VSMCs, it is likely that S1P/SOCE signaling in proliferative VSMCs may play a role in vascular dysfunction such as atherosclerosis.[98] Full Free Text
  • TNFalpha rapidly triggers S1P generation and activation of SPHK. Moreover, our data shows that SPHK1 is the isoform activated by TNFalpha, and plays an essential role on the TNFalpha-triggered intracellular Ca2+ signals.[99]
  • The endothelium can evoke relaxations (dilatations) of the underlying vascular smooth muscle, by releasing vasodilator substances, particularly nitric oxide (NO), synthesized by nitric oxide synthase (eNOS). The release of NO is down-regulated by oxidative stress and oxidized LDL.[100] S1P inhibits IL-1beta induction of NO production and iNOS expression in rat vascular smooth muscle cells through multiple mechanisms, playing an important role in the ptrogression of atherosclerosis.[101]
  • oxLDL induces neutral sphingomyelinase activity, evoking sphingomyelin turnover to ceramide.[102] Full Free Text oxLDL increased the activities of both acidic and alkaline ceramidases as well as sphingosine kinase, elevating S1P. [103] Full Free Text

Thromboxane

  • Depending on the oxidation rate and the ratio of oxysterols plus thiobarbituric acid reactive substances (TBARS) versus lysolecithin (obtained from phosphatidylcholine, inhibiting thromboxane synthesis), [104] oxidized LDL may stimulate thromboxane release by platelets [105], increasing blood clotting.
  • Low concentrations of oxLDL inhibit thromboxane release by platelets and intracellular calcium.[106]
  • Elevated oxLDL triggers platelet activation.[107]
  • Aggregating platelets at sites of atherosclerotic injury release thromboxane A2(TXA2). Even low concentration of TXA2 released from aggregating platelets may potentiate the mitogenic effect of oxLDL at sites of vascular damage.[108]
  • Selenoproteins in the vascular wall protect against oxysterol-induced vascular damage. When selenium (glutathione peroxidase) deficient, oxysterols elevate plasma thromboxane.[109]

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Author

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Author of this article is Thijs Klompmaker, born in 1966