Cholesterol Exogenous

Gustafsson has reported that Ca " and Mg " have different effects on mitochondrial 26-hydroxylation of endogenous cholesterol, exogenous cholesterol and 5j8-cholestane-3o,7a,12a-triol [132]. He concluded that there might be different transport mechanisms for the two substrates through the mitochondrial membranes. This was later supported by studies by Pedersen et al., showing that the stimulatory effect of Mg was similar for hydroxylation of several substrates catalysed by a partially purified system [133]. 

Anion exchange resins are basic polymers with a high affinity for anions. Because different anions compete for binding to them, they can be used to sequester anions. Clinically used anion exchange resins such as cholestyramine are used to sequester bile acids in the intestine, thereby preventing their reabsorption. As a consequence, the absorption of exogenous cholesterol is decreased. The accompanying increase in low density lipoprotein (LDL)-receptors leads to the removal of LDL from the blood and, thereby, to a reduction of LDL cholesterol. This effect underlies the use of cholestyramine in the treatment of hyperlipidaemia. 

Synthesis of endogenic cholesterol is also controlled by exogenous cholesterol supplied in food the more dietary cholesterol is digested, the less endogenic cho-lesterol is produced in the liveV. Exogenous cholesterol inhibits the activity of hydroxymethylglutaryl-CoA reductase and the cyclization of squalene to lanosterol. 

The answer is a. (Hardman, pp 885-887.) Lovastatin decreases cholesterol synthesis in the liver by inhibiting HMG-CoA reductase, the rate-limiting enzyme in the synthetic pathway This results in an increase in LDL receptors in the liver, thus reducing blood levels for cholesterol. The intake of dietary cholesterol must not be increased, as this would allow the liver to use more exogenous cholesterol and def eat the action of lovastatin. 

LCAT acts preferentially on lipids transported by HDL (so-called a-LCAT activity), but also on lipids transported by apoB-containing lipoproteins (so-called jS-LCAT activity) [58, 85]. In practice, LCAT activity is measured either as the activity required to esterify radioactive cholesterol that has been exogenously incorporated into native HDL or into artificial HDL-like particles (a-LCAT activity) or which has been equilibrated with endogenous lipoproteins of the plasma sample (cholesterol esterification rate, CER) [21, 58, 85]. Several variations of these assays have been reported, some of which are available as commercial test kits (e.g., Roar Biomedical, New York, USA). In addition, LCAT concentration can be determined by either laboratory-made tests or by a commercial ELISA kits [57]. However, the decrease in LCAT concentration is difficult to judge since it also decreases secondary to HDL deficiency due to causes other than LCAT deficiency. Plasma from patients with LCAT deficiency fails to esterify radioactive cholesterol provided by any substrate. By contrast, plasmas of patients with fish-eye disease show a near-normal cholesterol ester-fication rate but have a selective inability to esterify radioactive cholesterol provided to plasma with native HDL or reconstituted HDL (a-LCAT activity) [58, 85]. 

In adipose tissue, TAG is stored in the cytosol of the cells in a nearly anhydrous form. It serves as "depot fat," ready for mobilization when the body requires it for fuel. Little TAG is stored in the liver. Instead, most is exported, packaged with cholesteryl esters, cholesterol, phospholipid, and protein (apolipoprotein B-100, see p. 229) to form lipoprotein particles called very low density lipoproteins (VLDL). Nascent VLDL are secreted into the blood where they mature and function to deliver the endogenously-derived lipids to the peripheral tissues. [Note Recall that chylomicrons deliver primarily dietary (exogenously-derived) lipids.] Plasma lipoproteins are discussed in Chapter 18, p. 225. 

The two significant sources of cholesterol in body are endogenously synthesized cholesterol and exogenous or dietary cholesterol. Efforts to inhibit the absorption of dietary cholesterol have primarily focused on the inhibition of ACAT, a major enzyme associated with cholesterol esterification. Inhibition of this enzyme blocks the absorption of intestinal cholesterol and may also inhibit cholesteryl ester deposition in the vascular wall in the form of fatty streaks associated with atherosclerotic plaque. 

Plasma Lipoproteins. The plasma lipids are transported by four major lipoprotein classes. The plasma lipoproteins are synthesized and secreted only in the intestine and liver. Chylomicrons, the richest in triglyceride, are synthesized in the small intestine and transport dietary (exogenous) triglyceride and cholesterol. Very low density (prebeta) lipoproteins (VLDL)... 

The presence of lipids in the GI tract stimulates gall bladder contracts and biliary and pancreatic secretions, including bile salts, phospholipids, and cholesterol. These products, along with the gastric shear movement, form a crude emulsion, which promotes the solubilization of the coadministered lipophilic drug. Exogenous surface-active agents incorporated into the formulation may further stimulate the solubilization of the lipophilic compound. 

Numerous studies have pointed to an important role for cholesterol during proliferation and progression of cancer (e.g., ref. 612-615). Rapidly dividing cancer cells have two major routes to fulfill their need for cholesterol to form new cell membrane endogenous synthesis of cholesterol and/or receptor-mediated uptake of exogenous LDL particle-associated cholesterol and cholesterol esters (ref. 612,613,615). Each LDL particle contains a cholesterol ester core surrounded by a polar shell of phospholipids (primarily phosphoglycerides), free cholesterol, and apolipoprotein B (ref. 616-618). Once bound to its cell surface receptor, LDL is internalized by receptor-mediated endocytosis and degraded in lysosomes, and the subsequently released cholesterol may be used for membrane synthesis by the tumor (ref. 619). 

P.J. Pussinen, B. Karten, A. Wintersperger, H. Reicher, M. McLean, E. Malle and W. Sattler, The human breast carcinoma cell line HBL-100 acquires exogenous cholesterol from high-density lipoprotein via CLA-1 (CD-36 and LIMPII analogous 1)-mediated selective cholesteryl ester uptake, Biochem. J. 349 (2000) 559-566. 

Nguyen, T.T. 1999. The cholesterol-lowering action of plant stanol esters. J. Nutr. 129, 2109-2112. Ni, W., Yoshida, S., Tsuda, Y., Nagao, K., Sato, M., and Imaizumi, K. 1999. Ethanol-extracted soy protein isolate results in elevation of serum cholesterol in exogenously hypercholesterolemic rats. Lipids 34, 713-716. 

---