Mouse plasma cholesterol

Cholesteryl esters are quantitatively minor constituents (5-15% of total lipids) of VLDLs but the amount of cholesteryl esters relative to TG in VLDLs increases when rats are fed a high cholesterol diet. The esterification of cholesterol is mediated by two distinct acyl-CoA cholesterol acyltransferases (ACATs) [11]. Inhibition of cholesterol esterification with an ACAT inhibitor in hepatocytes decreased apo B secretion in some studies but not in others. For example, severe reduction in cholesteryl ester content of hepatoma cells decreased apo B secretion, whereas increased cholesteryl ester content did not stimulate apo B secretion. In mouse liver and intestine, the majority of cholesteryl esters are made by ACAT2. Nevertheless, normal quantities of apo B-containing lipoproteins are produced in mice lacking ACAT2 despite the absence of essentially all hepatic ACAT activity. However, ACAT2-deficient mice exhibit reduced intestinal absorption of cholesterol and are resistant to diet-induced hypercholesterolemia (R.V. Farese, 2(X)0). Thus, the observed reduction of plasma cholesterol in response to ACAT inhibitors is probably due to decreased cholesterol absorption rather than decreased VLDL secretion. 

Specific inhibitors of the lipid transfer activity of MTP have been developed as a potential treatment for atherosclerosis based on the premise that inhibition of MTP reduces VLDL secretion. Indeed, MTP inhibitors effectively reduce plasma cholesterol levels by up to 80% in rats, hamsters, and rabbits [13]. However, heterozygosity for MTP deficiency in humans does not diminish plasma lipids or lipoproteins, indicating that a modest reduction in MTP activity does not limit VLDL production. On the other hand, adenovirus-mediated over-expression of MTP in mouse liver increased the secretion, and plasma levels, of TG, apo B100, and apo B48 (D.J. Rader, 1999). MTP inhibitors are not currently used therapeutically, probably because they induce some storage of TG in the liver (steatosis) as a result of the blockage in VLDL secretion. 

The two hypocholesterolemic agents, XLVIII [158] and XLIX [159], are even more remote in their structural relationship to triparanol. Ehmination of the NH-Hnkage in the diarylamine series led to biphenyl analogs of which the most active compound was the basic ether, L. This drug caused a 20% lowering of serum cholesterol when administered to rats orally at 0.0003% of diet [160]. The hypohpidemic activity of boxidine (L) has been studied in the rat, mouse, male monkey and dog. The fall in plasma cholesterol levels caused by oral administration of the drug was partially compensated by the appearance of 7-dehydrocholesterol in the blood [161]. 

Lee M, Calabresi L, Chiesa G, Franceschini G, Kovanen FT. Mast cell chymase degrades apoE and apoA-n in apoA-I-knockout mouse plasma and reduces its ability to promote cellular cholesterol eSiax.Arterioscler Thromb Vase Biol2002 22 1475-1481. 

Orotic acid in the diet (usually at a concentration of 1 per cent) can induce a deficiency of adenine and pyridine nucleotides in rat liver (but not in mouse or chick liver). The consequence is to inhibit secretion of lipoprotein into the blood, followed by the depression of plasma lipids, then in the accumulation of triglycerides and cholesterol in the liver (fatty liver) [141 — 161], This effect is not prevented by folic acid, vitamin B12, choline, methionine or inositol [141, 144], but can be prevented or rapidly reversed by the addition of a small amount of adenine to the diets [146, 147, 149, 152, 162]. The action of orotic acid can also be inhibited by calcium lactate in combination with lactose [163]. It was originally believed that the adenine deficiency produced by orotic acid was caused by an inhibition of the reaction of PRPP with glutamine in the de novo purine synthesis, since large amounts of PRPP are utilized for the conversion of orotic acid to uridine-5 -phosphate. However, incorporation studies of glycine-1- C in livers of orotic acid-fed rats revealed that the inhibition is caused rather by a depletion of the PRPP available for reaction with glutamine than by an effect on the condensation itself [160]. 

Fig. 3. (A) Intracellular unesterified cholesterol accumulation in a lesional foam cell. Electron micrograph of the cytoplasm of a foam cell isolated ftom an advanced aortic atherosclerotic lesion in a cholesterol-fed rabbit. The cell was treated with filipin, which forms spicules with unesterified cholesterol. Multiple spicules are observed in vesicles, shown to be lysosomes (depicted by arrows). D , neutral lipid droplet. Bar 0.5 pm. From [34]. Lab. Invest. 41 160-167. (B) Extracellular cholesterol crystals in an advanced atherosclerotic lesion. The section is from the proximal aorta of a fat-fed apolipoprotein E knockout mouse. This mouse model is often used to study atherosclerosis in vivo because the high plasma levels of remnant lipoproteins resulting from absence of apolipoprotein E leads to a much greater degree of atherosclerosis lesion development than observed in wild-type mice. The arrows depict the areas of cholesterol crystals. Reproduced with permission from the publisher.

Figure 1.5. Correlation between the total amount of protein adsorbed and circulation time before plasma clearance of large unilamellar vesicles (LUVs) containing trace amounts of [3H]cholesteryl-hexadecyl ether administered intravenously in CDl mice at a dose of about 20 pmol of total lipid per 100 g of mouse weight. Results are shown for liposomes containing SM PC ganglioside GMl (72 18 10) (open square), PC CH (55 45) (filled circle), PC CH plant PI (35 45 20) (filled square), SM PC (4 1) (open triangle), PC CH dioleoylphosphatidic acid (DOPA) (35 45 20) (open diamond), and PC CH DPG (35 45 20) (open circle) (SM, sfingomyelin PC, phosphatidyl choline CH, cholesterol PI, phosphatdylinositol DPG, diphosphatidyl glycerol) (data from ref. (55))...

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