Lipoprotein synthesis

IL-1 (17.5) Monocyte/macrophage, lymphocyte, neutrophil, endothelium, fibroblast keratinocyte Activation of T cells, B cells, natural killer cells, osteoblasts, and endothelium. Induces fever, sleep, anorexia, ACTH release, hepatic acute phase protein synthesis and HSPs. Leads to myocardial depression, hypercoagulability, hypotension/sbock, and death. Simulates production of TNF, IL-6, and IL-8 and stress hormone release. Suppression of cytochrome P-450, thyro-globulin, and lipoprotein synthesis. Procoagulant activity. Antiviral activity. 

Peroxisome-proliferator activated receptors (PPARs) are lipid-activated transcription factors exerting several functions in development and metabolism. PPARa is implicated in the regulation of lipid metabolism, lipoprotein synthesis, and inflammatory response in liver and other tissues. 

The increased degradation of fat that occurs in insulin deficiency also has serious effects. Some of the fatty acids that accumulate in large quantities are taken up by the liver and used for lipoprotein synthesis (hyperlipidemia), and the rest are broken down into acetyl CoA. As the tricarboxylic acid cycle is not capable of taking up such large quantities of acetyl CoA, the excess is used to form ketone bodies (acetoacetate and p-hydroxy-butyrate see p. 312). As H"" ions are released in this process, diabetics not receiving adequate treatment can suffer severe metabolic acidosis (diabetic coma). The acetone that is also formed gives these patients breath a characteristic odor. In addition, large amounts of ketone body anions appear in the urine (ketonuria). 

Lecithin plays an important role in the transport of fats and cholesterol from the liver to sites where they can be either used or stored. Since fats do not dissolve in water solutions like blood plasma, they are transported in spherical particles called lipoproteins. These particles can mix with water solutions because the water-friendly proteins, cholesterol and phospholipids are on the outside surface. The nonpolar fats associated with them make up the core, which is unexposed to water. Because lecithin is required for lipoprotein synthesis, a lecithin deficiency results in fats accumulating in the liver and leads to liver damage. Lecithin deficiency also leads to increased amounts of cholesterol in the blood and atherosclerosis, a disease in which narrowing of the arteries is caused primarily by the deposit of fats from the bloodstream. 

In the liver, cholesterol has three major fates conversion to bile acids, secretion into the blocKlstream (packaged in lipoproteins), and insertion into the plasma membrane. Conversion of cholesterol to cholic acid, one of the bile acids, requires about 10 enzymes. The rate of bile synthesis is regulated by the first enzyme of the pathway, cholesterol la-hydioxylase, one of the cytochrome P450 enzymes (see the section on Iron in Chapter 10), Cholesterol, mainly in the form of cholesteryl esters, is exported to other organs, after packaging in particles called very-low-density lipoproteins. Synthesis of cholesteryl esters is catalyzed by acyl CoA cho-Jesteroi acy(transferase, a membranc bound enzyme of the ER, Free cholesterol is used in membrane synthesis, where it appears as part of the walls of vesicles in the cytoplasm. These vesicles travel to the plasma membrane, where subsequent fusion results in incorporation of their cholesterol and phospholipids into the plasma membrane. 

Levy E, Mehran M, Seidman E. Caco-2 cells as a model for intestinal lipoprotein synthesis and secretion. FASEB J 1995 May 9(8) 626- 635. 

Lipoprotein synthesis Reduction of LDL inhibitor cholesterol levels... 

Alteration of tissue fatty acid concentration by oxidized fats may indicate the impairment of transport and enzyme systems by effects on lipoprotein synthesis and function (31). Clark et al. (49) showed that lipoproteins are susceptible to alterations of both structure and function by reaction with agents that pro-... 

Woo W, Gibbs DL, Hooper PL, et al. 1983. The effect of dietary zinc on high-density lipoprotein synthesis. Nutr Rep Int 27 499-502. 

Sparks, J.D. Sparks, C.E. (1994) Biochim. Biophys. Acta, 1215, 9-32. Insulin regulation of triacyl-glycerol-rich lipoprotein synthesis and secretion. 

Much evidence, nevertheless, shows that the acceleration of hepatic fatty acid oxidation under ketogenic conditions entails important intracellular adaptive changes at steps subsequent to fatty acid activation. A set of these adaptations enhance the proportion of extramitochondrial fatty acyl-CoA being directed to the mitochondrial oxidative route over that being channeled for triacylglycerol and lipoprotein synthesis. Opposite changes in the... 

Fatty liver developed in rats fed a diet containing orotic acid is characterized by the deposition of droplets of triglycerides in the tubules of the endoplasmic reticulum [297,298]. The reticulum breaks down into individual vesicles which contain lipid droplets 0.2-0.S im in diameter which accumulate the apolipoproteins of low and very low density lipoproteins. The liver otherwise appears to be functionally normal, unlike that of animals receiving other lipotrophic agents. The administration of orotic acid has a specific effect on lipoprotein synthesis without overall inhibition of protein synthesis. The effect is selective for hepatic but not intestinal P-lipoprotein production and triglyceride transport [299]. 

The liver is an important organ for lipoprotein metabolism. It is not only a major site of lipoprotein synthesis, but also the most important site of lipoprotein catabolism. Most of the apolipoproteins, as well as the cholesterol and cholesterylester moieties of all circulating plasma lipoproteins, are catabolized in the liver. This makes sense because the liver is the only organ capable of degrading substantial amounts of cholesterol. The resulting bile acids are secreted in the bile, together with undegraded cholesterol. A small part of the bile acids and cholesterol escapes the enterohepatic circulation and forms the major route of cholesterol excretion from the body. 

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