Cholesterol forward

Often you need to carry forward data to a specific time point due to holes or sparseness of data. The previous example on determining baseline cholesterol level provides an excellent context for this problem. Assume that you have several cholesterol readings of HDL, LDL, and triglycerides for patients before they take an experimental pill designed to reduce cholesterol levels. For each cholesterol parameter, you want the last observation carried forward so long as the measures occur within a five-day window before the pill is taken. Here are some sample data that illustrate the problem ... 

If the cholesterol measurement is non-missing and was taken within the five days prior to drug dosing, then the cholesterol values are valid values for baseline. Note that because the cholesterol data are sorted chronologically (as mentioned in note 1), the last non-missing value within the five-day window is carried forward in time as... 

To explain the relationship between Lp(a) concentrations and risk of atherosclerosis, several hypothesis could be brought forward first, Lp(a) affects the metabolism of cholesterol and LDL secondly, Lp(a) plays a role in foam-cell and plaque formation thirdly, Lp(a) interacts with the activation of plasminogen to plasmin, the key step in the fibrinolytic system (L10, M27). Such activation can occur in two different localizations, i.e., on fibrin and its proteolytic residues, and on the surface of endothelial and monocytic cells. 

FIGURE 1.11. The derivation of the chemical formulae of steroids resulting from Bernal s X-ray crystallographic work. I and II had been put forward as possible fcrmulae, but III seemed to provide a better fit to the experimental data on molecular ine from refractive index data combined with unit cell dimensions. Bernal listed ses 8.5 x7.0 xl8 A for I, 11.0 x7.5 xl5 A for II, 7.5 x4.5 x20 A for III (from models built to scale), and 7.2 x5.0 x 17-20 A from observed data from X-f .y studies and refractive index measiu-ements. The correct formula, which is very iiiniiar to formula III, is shown in formula IV (cholesterol). The crystal structure of cholesteryl iodide is shown as V. (The value of the parameter x reported for C15 apparently should be 0.585, not that reported in ref. 85.) Iodine atom, filled circle. 

HDL is antiatherogenic and removes cholesterol from peripheral cells and tissues for eventual transport to hepatocytes and excretion in the bile directly or after conversion into bile acids. The efflux of cholesterol from peripheral cells is mediated by the ATP-binding cassette (ABC) transporter protein (discussed later). The flux of cholesterol transport from extrahepatic tissues (e.g., blood vessel wall) toward liver for excretion is known as the reverse cholesterol transport pathway. In contrast, the forward cholesterol pathway involves the transport of cholesterol from liver to the peripheral cells and tissues via the VLDL IDL LDL pathway. It should be noted, however, that the liver plays a major role in the removal of these lipoproteins. Thus, the system of reverse cholesterol transport consisting of LCAT, CETP, apo D, and their carrier lipoproteins is critical for maintaining cellular cholesterol homeostasis. The role of CETP is exemplified in clinical studies involving patients with polymorphic... 

A question of some importance is whether cholesterol in biomembranes can affect the function of membrane proteins. Several systems have now been examined and a number of conflicting ideas have been put forward. Let us first consider what is known about intrinsic protein-cholesterol interactions. 

Cellular cholesterol levels are regulated, not only by feedback inhibition of cholesterol synthesis, but also by feed-forward regulation of cholesterol metabolism. Excess cholesterol is metabolized to oxysterols. In addition to blocking SCAP-facilitated proteolysis of SREBP and thereby downregulating endogenous cholesterol synthesis and LDL receptor levels, oxysterols also activate bile acid synthesis (Chapter 15) and cholesterol esterification, which further reduces the cellular content of unesterified cholesterol. 

Plate 17. Summary of major forward and reverse lipid transport pathways through the extracellular compartment that link the liver and intestine with peripheral tissues. FC, unesterified cholesterol. For other abbreviations see list of abbreviations. (See page 536 in this volume.)... 

Reverse lipid transport is the movement of lipids, mainly cholesterol and phospholipids, from peripheral tissues, through the extracellular compartment, to the liver for catabolism. Unlike the forward transport of lipids, that involves mainly TG packaged into lipoproteins inside hepatic and intestinal cells, the cholesterol and phospholipids contributing to reverse transport are assembled into lipoproteins extracellularly, as the result of events in the plasma. 

The impact of novel medicines for unmet medical needs brought forward by the pharmaceutical industry in the last thirty years is tremendous drugs for metabolic diseases (cholesterol, hypertension, diabetes), HIV treatments, new antibiotics, treatments for rheumatoid arthritis, schizophrenia, etc. These medicines have profoundly transformed the treatment paradigm in their respective fields, with a major impact of extending and enhancing human life. 

To date, no plausible explanation has been forwarded as to why such increase in cholesterol production should occur. Here, we propose an explanation, which suggests that the cholesterol variations can be attributed to the fluctuations in the amount of the active species of the enzyme. 

De Kruijff and Demel [154] also constructed space-filling models for cholesterol, distearoyl lecithins and a range of polyenes, enabling them to put forward a series of models capable of explaining many of the properties of polyenes. 

Function Transport dietary TAG and cholesterol from the intestines to the periphery Forward transport of endogenous TAG and cholesterol from liver to periphery Precursor of LDLs Cholesterol transport 1 Reverse transport of cholesterol from periphery to the liver 2 Stores apoprotein C2 and apoprotein E which it supplies to chylomicrons and VLDLs 3 Scavenges and recycles apolipoproteins released from chylomicrons and VLDL following lipoprotein lipase activity in the capillaries... 

Forward transport of cholesterol from the liver to peripheral tissues... 

Figure 39.2 Forward transport of cholesterol to the peripheral tissues and its excretion as bile salts.

VLDL and LDL metabolism I forward cholesterol transport Lipids and iipid metaiwiism 87... 

LPL is the major enzyme responsible for the hydrolysis of circulating TAG moiety of both classes of TAG-rich lipoproteins the chylomicrons and VLDL, generating FFA, that are either oxidized in the muscles or reesterified in the adipose tissues, and glycerol that is returned to the liver. LPL plays a central role in overall lipoprotein metabolism, where (1) the successive interaction of VLDL with LPL generates the LDL that are involved in forward cholesterol transport and (2) the remnant lipoprotein particles so formed from LPL catalysis contributes to the maturation of HDL precursors, the latter of which is then involved in reverse cholesterol transport [21, 22], Perturbation in LPL activity could therefore lead to significant metabolic consequences, and LPL has been implicated in pathophysiological conditions characterized... 

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