Liver lipoprotein synthesis

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. 

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. 

VLDL is assembled in liver cells from lipid obtained via degradation of lipoproteins, synthesis from dietary carbohydrate and protein, and from fat mobilized from adipose tissue. VLDL is also rich in triglyceride (about 50%) and contains a substantial portion of cholesterol mainly as cholesterol ester. VLDL transports about 15% of the total cholesterol found in the blood. The apohpoproteins present on the surface of VLDL are apo BlOO, Cn and E. VLDL circulates in the blood and is acted upon by lipoprotein lipase in the same manner as for chylomicrons. The resulting VLDL remnants are LDL. 

According to recent papers, the action of liver poisons like carbon tetrachloride and white phosphorus in the induction of fatty livers is similar to that indicated for ethionine. Here too the fatty liver is associated with low plasma lipid levels. A short time after the injection of carbon tetrachloride into the animal, marked dilatations of the cystemae of the endoplasmic reticulum are discemable (Smuck-LER and Bend ITT 1963). This is the site of protein and lipoprotein synthesis and of the presumed triglyceride secretory mechanism (Byers and Friedman 1960). Reck-NAGEL and Lombardi (1961) have suggested that this structure is the key focus of carbon tetrachloride action and its destruction the cause of fat accumulation. 

Another treatment for cholesterol is niacin. The use of niacin predates the statins. Niacin is also known as nicotinic acid or vitamin B3. The name, niacin comes from nicotinic ac id and vitamin and was coined to avoid confusion and so that people would not think that the vitamin contained nicotine or that tobacco products contained vitamins. Niacin inhibits lipoprotein synthesis by preventing the secretion of very low density lipoprotein from the liver. Very low density lipoprotein is a precursor of low density lipoproteins (LDL). However there are several adverse side effects with niacin including flushing, warm skin, itching rash, constipation, nausea, hearthum, and problems with liver function. Because of these side effects, niacin is often used in a controlled release form [17] and even in this form is unsuitable for many patients. 

Endogenous liver triglyceride synthesis can occur in conditions when there is an excess of free fatty acids reaching the liver, e.g. diabetes, or when there is excessive hepatic de novo free fatty acid synthesis. Triglycerides synthesized in this way are incorporated into pre- -lipoproteins. 

A toxicant that reduces lipoprotein synthesis needed to transport high-energy lipids from the liver... 

Jones, A. L., Ruderman, N. B., and Herrera, M. G., 1968, Electron microscopic and biochemical study of lipoprotein synthesis in the isolated perfused rat liver, /. Lipid Res. 8 429. 

Fibric acid derivatives, the third group of antihyperlipi-demic drugs, work in a variety of ways. Clofibrate (Atromid-S), acts to stimulate the liver to increase breakdown of very-low-density lipoproteins (VLDL) to low-density lipoproteins (LDL), decreasing liver synthesis of... 

The second type of fatty liver is usually due to a metabolic block in the production of plasma lipoproteins, thus allowing triacylglycerol to accumulate. Theoretically, the lesion may be due to (1) a block in apolipoprotein synthesis, (2) a block in the synthesis of the lipoprotein from lipid and apolipoprotein, (3) a failure in provision of phospholipids that are found in lipoproteins, or (4) a failure in the secretory mechanism itself. 

Figure 25-6. The synthesis of very low density lipoprotein (VLDL) in the liver and the possible loci of action of factors causing accumulation of triacylglycerol and a fatty liver. (EFA, essential fatty acids FFA, free fatty acids ...

The liver plays a decisive role in the cholesterol metabolism. The liver accounts for 90% of the overall endogenic cholesterol and its esters the liver is also impli-cated in the biliary secretion of cholesterol and in the distribution of cholesterol among other organs, since the liver is responsible for the synthesis of apoproteins for pre-p-lipoproteins, a-lipoproteins, and P-lipoproteins which transport the secreted cholesterol in the blood. In part, cholesterol is decomposed by intestinal micro-flora however, its major part is reduced to coprostanol and cholestanol which, together with a small amount of nonconverted cholesterol, are excreted in the feces. 

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],... 

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