Cholesterol turnover

With investigations of phytochemicals and functional foods, the outcome measure is generally going to be a biomarker of disease, such as serum cholesterol level as a marker of heart disease risk, or indicators of bone turnover as markers of osteoporosis risk. Alternatively, markers of exposure may also indicate the benefit from a functional food by demonstrating bioavailability, such as increased serum levels of vitamins or carotenoids. Some components will be measurable in both ways. For instance, effects of a folic acid-fortified food could be measured via decrease in plasma homocysteine levels, or increase in red blood cell folate. 

The answer is a. (Katzung, p 590.) Bile acids are absorbed primarily in the ileum of the small intestine. Cholestyramine binds bile acids, preventing their reabsorption in the jejunum and ileum. Up to 10-fold greater excretion of bile acids occurs with the use of resins. The increased clearance leads to increased cholesterol turnover of bile acids. Low-density lipoprotein receptor upregulation results in increased uptake of LDL. This does not occur in homozygous familial hypercholesterolemia because of lack of functioning receptors. 

Cholesterol transport and regulation in the central nervous system is distinct from that of peripheral tissues. Blood-borne cholesterol is excluded from the CNS by the blood-brain barrier. Neurons express a form of cytochrome P-450, 46A, that oxidizes cholesterol to 24(S)-hydroxycholesterol [11] and may oxidize it further to 24,25 and 24,27-dihydroxy products [12]. In other tissues hydroxylation of the alkyl side chain of cholesterol at C22 or C27 is known to produce products that diffuse out of cells into the plasma circulation. Although the rate of cholesterol turnover in mature brain is relatively low, 24-hydroxylation may be a principal efflux path to the liver because it is not further oxidized in the CNS [10]. 

Lund, E. G., Xie, C., Kotti, T., Turley, S. D., Dietschy, J. M. and Russell, D. W. Knockout of the cholesterol 24-hydroxy-lase gene in mice reveals a brain-specific mechanism of cholesterol turnover. /. Biol. Chem. 278 22980-22988, 2003. 

A few enzymes, such as the previously mentioned CNP, are believed to be fairly specific for myelin/oligodendro-cytes. There is much more in the CNS than in peripheral nerve, suggesting some function more specialized to the CNS. In addition, a unique pH 7.2 cholesterol ester hydrolase is also enriched in myelin. On the other hand, there are many enzymes that are not myelin-specific but appear to be intrinsic to myelin and not contaminants. These include cAMP-stimulated kinase, calcium/calmodulin-dependent kinase, protein kinase C, a neutral protease activity and phosphoprotein phosphatases. The protein kinase C and phosphatase activities are presumed to be responsible for the rapid turnover of MBP phosphate groups, and the PLP acylation enzyme activity is also intrinsic to myelin. 

Myelin components exhibit great heterogeneity of metabolic turnover. One of the novel characteristics of myelin demonstrated in early biochemical studies was that its overall rate of metabolic turnover is substantially slower than that of other neural membranes [1]. A standard type of experiment was to evaluate lipid or protein turnover by injecting rat brains with a radioactive metabolic precursor and then follow loss of radioactivity from individual components as a function of time. Structural lipid components of myelin, notably cholesterol, cerebro-side and sulfatide, as well as proteins of compact myelin, are relatively stable, with half-lives of the order of many months. One complication in interpreting these studies is that the metabolic turnover of individual myelin components is multiphasic - consisting of an initial rapid loss of radioactivity followed by a much longer slower loss. 

Ma YL, Bryant HU, Zeng Q, Palkowitz A, Jee WSS, Turner CH, et al. (2002) Long-term dosing of arzoxifene lowers cholesterol, reduces bone turnover, and preserves bone quality in ovariectomized rats. J Bone Miner Res 17 2256-2264... 

In preclinical models of postmenopausal osteoporosis, lasofoxifene inhibited bone turnover and prevented bone loss throughout the skeleton (Maeda et al. 2004). The primary indication of lasofoxifene is the treatment and prevention of postmenopausal osteoporosis. In preclinical models, lasofoxifene inhibited breast tumor formation and reduced serum cholesterol (Maeda et al. 2004). Lasofoxifene-treated animals did not differ from ovariectomized controls with respect to endometrial thickness and superficial and basal endometrial gladular epithelial luminal area (Maeda et al. 2004 Ke et al. 2004). 

Ma L, Palkowitz A, Bryant HU, Rowley E, Adian MD, Cole HW, Shetler P, Smith S, Turner CH, Yao W, et al. (1998) Long-term dosing of LY353381HC1 preserves bone quality, reduces turnover and lowers cholesterol levels in ovariectomized rats. Bone... 

In addition to more rapid absorption of lipids in animals fed casein, another mechanism that may be operative is decreased clearance of circulating lipids. Rabbits fed a casein-based semipurified diet excreted significantly less cholesterol but more bile acids in their feces than animals fed a commercial diet (18). The total sterol excretion in feces of the animals fed the casein diet was half that of the rabbits fed the stock diet. Huff and Carroll (19) found that rabbits fed soy protein had a much faster turnover rate of cholesterol and a significantly reduced rapidly exchangeable cholesterol pool compared with rabbits fed casein. Similar studies performed in our laboratory revealed that the mean transit time for cholesterol was 18.4 days in rabbits fed soy protein, 36.8 days in rabbits fed casein, 33.7 days in rabbits fed soy plus lysine, and 36.3 days in rabbits fed casein plus arginine. These data suggest that addition of lysine to soy protein... 

OH is a major pathway for cholesterol turnover in mouse and human brain... 

Bogdanovic N, Bretillon L, Lund EG, Diczfalusy U, Lannfelt L, et al. 2001. On the turnover of brain cholesterol in patients with Alzheimer s disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells. Neurosci Lett 314 45-48. 

The HDLs also originate in the liver. They return the excess cholesterol formed in the tissues to the liver. While it is being transported, cholesterol is acylated by lecithin cholesterol acyltransferase (LCAT). The cholesterol esters formed are no longer amphipathic and can be transported in the core of the lipoproteins. In addition, HDLs promote chylomicron and VLDL turnover by exchanging lipids and apoproteins with them (see above). 

Wolfe has presented an excellent description of the systematic application of stable and radioactive isotope tracers in determining the kinetics of intestinal fat absorption, hepatic triglyceride synthesis, lipid mobilization, triglyceride-fatty acid recycling, and cholesterol turnover. 

Pheromone (sex attractant). Ether extract of the stem, produced equivocal effect on Aspiculuris tetraptera, female and male Dacus dorsalis, male Mediterranean fruit flies, and male and female melon flies " k Pheromone (signaling). Ether extract of the stem, produced equivocal effect on Aspiculuris tetraptera, female and male Dacus dorsalis, male Mediterranean fruit flies, and male and female melon flies " k Phospholipidemic effect. Oil, administered to phospholipids transfer protein knockout (PLTPO)-deficient mice, produced an increase of phospholipids and free cholesterol in the VLDL-LDL region of PLTPO mice. Accumulation of phospholipids and free cholesterol was dramatically increased in PLTPO/HLO mice compared to PLTPO mice. Turnover studies indicated that coconut oil was associated with delayed catabolism of phospholipids and phospho-lipids/free cholesterol-rich particles. Incubation of these particles with hepatocytes of coconut-fed mice produced a reduced removal of phospholipids and free cholesterol by SRBI, even though SRBI protein expression levels were unchanged . 

OE149 VanTol, A., A. E. H. Terpsta, P. Van Der Berg, and A. C. Beynen. Dietary corn oil versus olive oil enhances HDL protein turnover and lowers HDL cholesterol levels in hamsters. Atherosclerosis 1999 147(1) 87-94. 

Huff, M.W. and Carroll, K.K. 1980. Effects of dietary protein on turnover, oxidation, and absorption of cholesterol, and on steroid excretion in rabbits. J. Lipid Res. 21, 546-558. 

Kelley, JJ. and Tsai, A.C. 1978. Effect of pectin, gum arabic and agar on cholesterol absorption, synthesis, and turnover in rats. J. Nutr. 108, 630-639. 

Fawcett et al. proposed four hypothetical pathways leading to suicide in clinical depression an acute pathway involving severe anxiety/agitation associated with high brain corticotrophin-releasing factor levels, trait baseline and reactivity hopelessness, severe anhedonia, and trait impulsiveness associated with low brain serotonin turnover, with low total cholesterol as a... 

The elucidation of the molecular genetics RXI has had a major impact on our understanding of stratum corneum turnover. Individuals with RXI lack an enzyme, cholesterol sulfatase,3,4 which catalyzes the transformation of cholesterol sulfate (CS) to cholesterol and free sulfate. As a result there is an accumulation of CS in the stratum corneum intercellular space. Possible mechanisms by which this change in intercellular lipid composition of the stratum corneum can cause disturbances in desquamation, leading to ichthyosis, will be discussed later. 

Newborn babies have a low plasma LDL cholesterol, between 25 and 50 mg/100 ml (K36), a level similar to that found in many animal species (C2, M35). Goldstein and Brown have hypothesized that the marked rise which occurs in industrialized man, with LDL-cholesterol levels of over 100 mg/100 ml, may be attributed to suppression of LDL receptors as a result of environmental factors (B55, G19). They adduce evidence from studies on LDL turnover performed by Bilheimer and others that indicates that dogs, baboons, and humans each produce about 15 mg LDL cholesterol per kilogram body weight per day, but the very marked differences in plasma LDL-cholesterol levels in these species is the result of a fractional catabolic rate lower in the baboon than in the dog and much lower in man (G19). Miller also summarizes evidence from others suggesting that the slow rise in plasma LDL concentration seen with age in men and women is associated with a corresponding fall in the fractional catabolic rate of LDL, and he hypothesizes that the decrease in efficiency of LDL clearance with advancing age is a consequence of a decrease in either the number or the function of LDL (B-100,E) receptors (M33). 

G24. Goodman, D. S., The in vivo turnover of individual cholesterol esters in human plasma lipoproteins. J. Clin. Invest. 43, 2026-2036 (1964). 

Fig. 5. Pattern of product formation during single turnover cycles of anaerobic reduction/oxygenation of the cytochrome P-450,.,. - cholesterol - adrenodoxin complex. The results are expressed as a percentage conversion of the total [14C]cholesterol added to the incubation. Cholesterol, o 22-hydroxy-cholesterol, 20,22-dihydroxycholesterol. a pregnenolone, (from Ref. 38, with permission).

Raloxifene Like tamoxifen, which is also a SERM (see p 266), raloxifene s [ra LOCKS ih feen] actions are mediated through the estrogen receptors, and it has both estrogenic and antiestrogenic effects. Its clinical use is based on its ability to decrease bone resorption and overall bone turnover. However, unlike estrogen and tamoxifen, it apparently has little to no effect on the endometrium, and therefore may not predispose to uterine cancer. Raloxifene lowers total cholesterol and LDL in the serum, but has no effect on HDL or triglycerides. [Note Whether the latter... 

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