Lipoprotein biosynthesis

Chronic malabsorption does not fully explain the different extents of fat-soluble vitamin deficiencies associated with ABL. More specifically, why are plasma vitamin E levels more severely affected than those of vitamins A or K The answer for this can be traced to apoB lipoprotein biosynthesis and catabolism (Fig. 27-2). Just as observed for lipids, hydrophobic, fat-soluble vitamins require apoB lipoproteins as vehicles for plasma transport. The reliance of each fat-soluble vitamin on apoB lipoproteins varies, and this variable dependency is directly related to the severity of symptoms observed in ABL. 

In contrast to the in vitro results, Boren et al. (1992) have shown that lipoprotein biosynthesis occurred cotranslationally in HepG2 cells, that is, while the C-terminal portion of apoB was still being synthesized on the ribosome, the N-terminal portion was already incorporated into a small lipoprotein. 

Fig. 15. One version of the two-step model for lipoprotein biosynthesis. This model (Alexander et al., 1976) proposes that VLDL-sized emulsion particles lacking apoB were synthesized in the smooth ER (SER) and that these particles subsequently migrated to the junction between the smooth and the rough ER (RER), where the apoB was incorporated into the surface monolayer of the nascent VLDL. In this review it is suggested that the primary lipoprotein, shown in Fig. 14, is the vehicle that transports the apoB to the emulsion particle and merges with it to complete the assembly of the VLDL. Reproduced from the Journal of Cell Biology (Alexander et al., 1976), by copyright permission of the Rockefeller University Press.

Plasma lipoprotein biosynthesis has also been reported to occur in vitro by cells of intestinal mucosa (Rodbell and Fredrickson, 1959 Hatch et al., 1963 Isselbacher and Budz, 1963) and aortic tissue (Hollander,... 

The relevance of the results obtained in vitro, in either liver slices or perfusates, to the general problem of lipoprotein biosynthesis in the intact animal remains to be established. In vivo synthesis of the protein moiety of serum 3-lipoprotein was studied in roosters by administration of S -methionine (Florsheim et al., 1963), followed by measurements of specific radioactivity of plasma 3-lipoprotein separated by dextran sulfate. Under these experimental conditions, enhancement of methionine incorporation was noted after pharmacological doses of ethanol, estrogens, and triiodothyronine. No significant effect was obtained after administration of epinephrine, cortisone, and thyroxine preparations. 

Havel RJ (1980) Lipoprotein biosynthesis and metabolism. Ann NY Acad Sci 348 16-29 Heras H, Pollero RJ (1989) Blood lipids of the small octopus. Octopus tehuelchus (Mollusca, Cephalopoda) at different stages of sexual maturation. Comp Biochem Physiol 92A 571-575 Heras H, Pollero RJ (1990) Occurrence of plasma lipoproteins in octopods — partial characterization and interorgan transport of lipids. J Exp Mar Biol Ecol (in press)... 

We turn now to the biosynthesis of lipid structures. We begin with a discussion of the biosynthesis of fatty acids, stressing the basic pathways, additional means of elongation, mechanisms for the introduction of double bonds, and regulation of fatty acid synthesis. Sections then follow on the biosynthesis of glyc-erophospholipids, sphingolipids, eicosanoids, and cholesterol. The transport of lipids through the body in lipoprotein complexes is described, and the chapter closes with discussions of the biosynthesis of bile salts and steroid hormones. 

Vance DE Glycerolipid biosynthesis in eukaryotes. In Biochem-istry of Lipids, Lipoproteins and Membranes. Vance DE, Vance JE (editors). Elsevier, 1996. 

As indicated in Table 1, statins, which block cholesterol biosynthesis by inhibition of hepatic HMGCoA reductase, have been used extensively to reduce LDL-C levels. At most therapeutic doses, statins marginally increase HDL levels by 5-10% [3,16]. The HDL elevation observed with statins has been highly variable and not easily extrapolated from the effects on LDL. A recent study (STELLAR) demonstrated increased HDL elevation with the use of rosuvastatin compared to simvastatin, pravastatin or atorvastatin (10% vs. 2-6%) [16,24], Although the mechanism of HDL elevation by statins is not clearly understood, it is proposed that statins enhance hepatic apoA-I synthesis [25] and decrease apoB-containing lipoproteins [26]. A number of clinical trials have demonstrated that statins reduce the risk of major coronary events. However, it is not clear if the statin-induced rise in HDL levels is an independent contributor to the reduced risk of coronary events. The observed small increase in HDL and adverse side effect profile related to liver function abnormalities and muscle toxicity limits the use of statins as monotherapy for HDL elevation [27],... 

Apparently the acceleration of de novo purine biosynthesis by orotic acid results from a release of feedback inhibition imposed by hepatic purine nucleotides. In a related study, it was found that orotic acid feeding can prevent hyperlipaemia, which normally follows the administration of Triton WR-1339, a surface active agent [152]. The influence of orotic acid on lipid metabolism can be readily shown by the fact that depression of serum lipoproteins and milk production were observed in lactating goats when an aqueous suspension of orotic acid was administered orally [164]. 

Cholesterol is present in all animal tissues, and particularly in neural tissue. It is a major constituent of cellular membranes, in which it regulates fluidity (see p. 216). The storage and transport forms of cholesterol are its esters with fatty acids. In lipoproteins, cholesterol and its fatty acid esters are associated with other lipids (see p.278). Cholesterol is a constituent of the bile and is therefore found in many gallstones. Its biosynthesis, metabolism, and transport are discussed elsewhere (see pp. 172, 312). 

As precursors for the biosynthesis of fats (lipogenesis), the adipocytes use triacylglycerols from lipoproteins (VLDLs and chylomicrons see p. 278), which are formed in the liver and intestines and delivered by the blood. Lipoprotein lipase [1], which is located on the inner surface of the blood capillaries, cleaves these triacylglycerols into glycerol and fatty acids, which are taken up by the adipocytes and converted back into fats. 

The cholesterol required for biosynthesis of the steroid hormones is obtained from various sources, it is either taken up as a constituent of LDL lipoproteins (see p. 278) into the hormone-synthesizing glandular cells, or synthesized by glandular cells themselves from acetyl-CoA (see p. 172). Excess cholesterol is stored in the form of fatty acid esters in lipid droplets. Hydrolysis allows rapid mobilization of the cholesterol from this reserve again. 

Partial summary of lipoprotein metabolism in humans. I to VII are sites of action of hypolipidemic drugs. I, stimulation of bile acid and/or cholesterol fecal excretion II, stimulation of lipoprotein lipase activity III, inhibition of VLDL production and secretion IV, inhibition of cholesterol biosynthesis V, stimulation of cholesterol secretion into bile fluid VI, stimulation of cholesterol conversion to bile acids VII, increased plasma clearance of LDL due either to increased LDL receptor activity or altered lipoprotein composition. CHOL, cholesterol IDL, intermediate-density lipoprotein. 

Menendez, R., S. I. Fernandez, A. Del Rio, et al. Policosanol inhibits cholesterol biosynthesis and enhances low density lipoprotein processing in cultured human fibroblasts. Biol Res... 

Fig. 5.1.3 Sterol analysis in patients with defective cholesterol biosynthesis. Gas chromatography-mass spectrometry analysis of trimethylsilyl derivatives of sterols extracted from primary skin fibroblasts of a control subject, a Smith-Lemli-Opitz syndrome (SLOS) patient, and a Con-radi-Hunermann syndrome (CDPX2) patient, and lymphoblasts of a desmosterolosis patient cultured in lipoprotein-deficient medium reveals the accumulation of sterol intermediates indicative of a defect in cholesterol biosynthesis. Similar spectra can be obtained by sterol analysis of the plasma of such patients...

As an alternative, primary skin fibroblasts or lymphoblasts of patients suspected to be affected with a cholesterol biosynthesis defect can be cultured for 3-7 days in medium supplemented with fetal calf serum depleted of lipoproteins to induce cholesterol biosynthesis, whereupon the specific defect can be determined by sterol analysis using GC-MS as described above. This procedure will readily identify patients affected with Smith-Lemli-Opitz syndrome, desmosterolosis, lathosterolosis, hydrops-ectopic calcification-motheaten (HEM) skeletal dysplasia and most patients with Conradi-Hunermann syndrome (CDPX2). Patients with congenital hemidys-plasia with ichthyosiform nevus and limb defects (CHILD) syndrome may not be identified with this assay, but they can be readily diagnosed on the basis of their typical clinical presentation. 

Plasma cholesterol may arise from the diet or from endogenous biosynthesis. In either case, cholesterol is transported between tie tissues in combination with protein and phospholipids as lipoproteins. 

Other Acylglycerols. If some of the DGs in freshly drawn milk are involved in biosynthesis, it is possible that they are enantiomeric and are probably the sn-1,2 isomer. If so, the constituent fatty acids are long chain. Their configuration can be determined by stereospecific or other analyses, but it is difficult to accumulate enough material for analysis. Nevertheless, Lok (1979) isolated the DGs from freshly extracted cream as the trityl derivatives. Trityl chloride reacts selectively with primary hydroxyls. The stereochemical configuration of the DGs was identified as sn-1,2 therefore, these residual DGs were most likely intermediates of biosynthesis. If the DGs were products of lipol-ysis, they would be a mixture of 1,2/2,3 isomers in a ratio of about 1 2, since milk lipoprotein lipase preferentially attacks the sn-1 position of TGs (Jensen et al. 1983). 

From Lanosterol to Cholesterol Takes Approximately 20 Steps Summary of Cholesterol Biosynthesis Lipoprotein Metabolism... 

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