Effects of Lipoproteins

The characteristic effect of inhibitors of HMG-CoA reductase is a profound reduction in LDL cholesterol. The maximal doses of the most effective drugs in this class, simvastatin and atorvastatin, produce reductions by about half in the plasma levels of this atherogenic lipoprotein (Heinonen et al., 1996 Ose et al., 1998 Stein et al., 1998b). The full 

Accompanying these changes is a large reduction in apolipoprotein B, the principal protein of both LDL and very low density lipoprotein (VLDL). The fact that apolipoprotein B falls nearly as much as LDL 

Mechanisms of the Cholesterol-Lowering Effects of Reductase Inhibitors 

A diet low in saturated fat and cholesterol has been the traditional mainstay of therapy and should continue to accompany statin therapy, as the effects are additive (Hunninghake et al., 1993). However, perhaps 

It is well established that HMG-CoA reductase inhibitors and bile acid sequestrants can be used together safely, with a greater reduction in LDL cholesterol than is obtainable when either drug is used alone. Unfortunately, bile acid sequestrants are often poorly tolerated, which limits the usefulness of this combination. Relatively low doses of niacin, when used in combination with statins, produce a very attractive effect on the lipoprotein profile (Gardner et al., 1996 Stein et al., 1996) the ability of niacin to substantially increase HDL cholesterol is additive, with the profound reduction in LDL cholesterol produced by the statin, and there is also a moderate reduction in triglycerides. However, 

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H32. Hodenberg, E. von, and Kreuzer, J., Effects of lipoprotein(a) on success rate of thrombolytic therapy in acute myocardial infarction. Am. J. Cardiol. 67, 1349-1353 (1991). 

Angles-Cano, E., Hervio, L., Rouy, D., Fournier, C., Chapman, J. M., Laplaud, M., and Koschinsky, M. L. (1994). Effects of lipoprotein (a) on the binding of plasminogen to fibrin and its activation by fibrin-bound tissue-type plasminogen activator. Chem. Phys. Lipids 67-68, 369-380. 

T7. Thanabalasingham, S., Thompson, G. R., Trayner, T. I., Myant, N. B., and Soutar, A. K., Effect of lipoprotein concentration and lecithin cholesterol acyltransferase activity on cholesterol esterification in human plasma after plasma exchange. Eur. J. Clin. Invest. 10, 45-48 (1980). 

Since the beneficial effects of lipoprotein were thought to be related to phospholipid content, a lipid emulsion with 10% phospholipids was developed and tested in animal as well as human studies (Gordon et al., 2003). 

Markscheid, L., and E. Shafrir Assimilation of lipoprotein triglyceride (TG) in vitro Comparison of various adipose tissues and lipoproteins and effect of lipoprotein lipase (LL) inhibitors. Israel J. Chem. 1, 205—207 (1963). 

The effect of lipoprotein fractions on adhesiveness and aggregation of blood platelets. 

The effect of statins on plasma lipids and lipoproteins is rapidly seen and fully achieved after 4-6 weeks of treatment. The effect persists unchanged during continued use for several years, but after stopping the diug, LDL-cholesterol rapidly increases to pretreatment levels. Treatment with statins is therefore usually continued indefinitely and not as a short-term cure. Finally, it is generally advisable to use the statins that have documented their efficacy in clinical trials (evidence-based medicine). 

The effect of a statin is usually determined by measuring fasting plasma lipids and lipoproteins after 4-6 weeks of treatment. Liver enzymes and eventually creatine kinase (in case of myositis liver enzymes are usually also elevated) are measured simultaneously to exclude side effects related to liver and muscles. After the treatment goal has been reached, blood sampling is usually performed 1-2 times a year. 

Systemic treatment of 13-cis retinoic acid frequently leads to cheilitis and eye irritations (e.g., unspecific cornea inflammation). Also other symptoms such as headache, pruritus, alopecia, pains of joints and bone, and exostosis formation have been reported. Notably, an increase of very low density lipoproteins and triglycerides accompanied by a decrease of the high density lipoproteins has been reported in 10-20% of treated patients. Transiently, liver function markers can increase during oral retinoid therapy. Etretinate causes the side effects of 13-cis retinoid acid at lower doses. In addition to this, generalized edema and centrilobulary toxic liver cell necrosis have been observed. 

The reason for the cholesterol-lowering effect of polyunsaturated fatty acids is still not fully understood. It is clear, however, that one of the mechanisms involved is the up-regulation of LDL receptors by poly-and monounsaturated as compared with saturated fatty acids, causing an increase in the catabolic rate of LDL, the main atherogenic lipoprotein. In addition, saturated fatty acids cause the formation of smaller VLDL particles that contain relatively more cholesterol, and they are utilized by extrahepatic tissues at a slower rate than are larger particles—tendencies that may be regarded as atherogenic. 

In adipose tissue, the effect of the decrease in insulin and increase in glucagon results in inhibition of lipo-genesis, inactivation of lipoprotein lipase, and activation of hormone-sensitive lipase (Chapter 25). This leads to release of increased amounts of glycerol (a substrate for gluconeogenesis in the liver) and free fatty acids, which are used by skeletal muscle and liver as their preferred metabolic fuels, so sparing glucose. 

HININGER I, CHOPRA M, THURNHAM D I, LAPORTE F, RICHARD M J, FAVIER A and ROUSSEL A-M (1997) Effect of increased fruit and vegetable intake on the susceptibility of lipoprotein to oxidation in smokers , Eur J Clin Nutr, 51, 601-6. 

VAN DEN BERG H and VAN VLIET T (1998) Effects of simultaneous, single oral doses of 3-carotene, with lutein or lycopene on the (3-carotene and retinyl ester responses in the triacylglycerol-rich lipoprotein fractions in men. Am J Clin Nutr 68(1) 82-89. 

CROUSE J R 3" , MORGAN T, TERRY J G, ELLIS J, viTOLiNS M and BURKE G L (1999) A randomised trial comparing the effect of casein with that of soy protein containing varying amounts of isoflavones on plasma concentrations of lipids and lipoproteins. Arch Intern Med. 159 (17) 2070-76. 

HODGSON J M, MORI T A, PUDDEYI B, CROFT K D, BEILIN L J (1999) / vitro antioxidant activity of black and green tea effect on lipoprotein oxidation in human sermn, Journal of Science in Food and Agriculture, 79, 561-6. 

Kim, H.S. and Lee, B.M., Protective effects of antioxidant supplementation on plasma lipid peroxidation in smokers, J. Toxicol. Environ. Health A, 63, 583, 2001. Gaziano, J.M. et al.. Supplementation with beta-carotene in vivo and in vitro does not inhibit low density lipoprotein oxidation. Atherosclerosis, 112, 187, 1995. Sutherland, W.H.F. et al.. Supplementation with tomato juice increases plasma lycopene but does not alter susceptibility to oxidation of low-density lipoproteins from renal transplant recipients, Clin. Nephrol, 52, 30, 1999. 

Using human hepatoma-derived cell lines Kong et al. [268] showed that berberine increased mRNA and protein as well as the function of hepatic linear low density lipoprotein receptor (LDLR). It does not stimulate the transcription of LDLR, as the LDLR promoter activity was not increased by this compound. Post-transcriptional regulation appears to be the main working mechanism underlying the effect of this alkaloid on LDLR expression. It was proposed that berberine can be used as a monotherapy to treat hypercholes-terolemic patients [268]. Very recently it was observed [269] that berberine reduces cholesterol and Upid accumulations in plasma as well as Uver. 

Carew, T.E., Schwenke, D.C. and Steinberg, O. (1987). Antiatherogenic effect of probucol unrelated to its hyper-cholesterolaemic effect evidence that antioxidants in vim can selectively inhibit low density lipoprotein degradation in macroph -rich fatty streaks slowing the progression of atherosclerosis in the WHHL rabbit. Proc. Natl Acad. Sci. USA 84, 7725-7729. 

Bowry, V.W. and Stocker, R. (1993). Tocopherol-mediated peroxidation. The prooxidant effect of vitamin E on the radical-initiated oxidation of human low-density lipoprotein. J. Am. Chem. Soc. 115, 6029-6044. 

In addition to effects on bone, raloxifene may have effects in breast tissue and on the cardiovascular system. A secondary end point of the MORE trial evaluated the effects of raloxifene on the primary prevention of breast cancer and found a significant reduction in all types of breast cancer.33 Raloxifene decreases total and low-density lipoprotein (LDL) cholesterol,34 and studies are evaluating its effect on reducing the risk of cardiovascular disease.35... 

Han KH, Han KO, Green SR, Quehenberger O. Expression of the monocyte chemoattractant protein-1 receptor CCR2 is increased in hypercholesterolemia. Differential effects of plasma lipoproteins on monocyte function. J Lipid Res 1999 40(6) 1053-1063. 

Mensink, R. P., Katan, M. B., Effect of a diet enriched with monounsaturated or polyunsaturated fatty acids on levels of low-density and high-density lipoprotein cholesterol in healthy women, N Engl J Med, 321, 436, 1989... 

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