Liver triglyceride synthesis

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. 

Dihydroxyacetone phosphate (DHAP) is used in liver and adipose tissue for triglyceride synthesis. 

This is the accumulation of triglycerides in hepatocytes, and there are a number of mechanisms underlying this response as is discussed below (see the sect. "Mechanisms of Toxicity"). The liver has an important role in lipid metabolism, and triglyceride synthesis occurs particularly in zone 3. Consequently, fatty liver is a common response to toxicity, often the result of interference with protein synthesis, and may be the only response as after exposure to hydrazine, ethionine, and tetracycline, or it may occur in combination with necrosis as with carbon tetrachloride. It is normally a reversible response, which does not usually lead to cell death, although it can be very serious as is the case with tetracycline-induced fatty liver in humans. Repeated exposure to compounds, which cause fatty liver, such as alcohol, may lead to cirrhosis. 

The decreased returh of bile acids to the liver also will produce an increase in triglyceride synthesis ahd a transient rise in VLDL levels. Subsequent compensatory mechanisms will increase VLDL removal, most likely through the ihcreased LDL receptors, and return VLDL levels to predrug levels. For those patiehts with preexisting hypertriglyceridemia, the compehsatory mechanisms are inadequate, and a persistent rise in VLDL levels occurs (7). 

Nicotinic acid exerts a variety of effects on lipoprotein metabolism (7,16,49). One of its most important actions is the inhibition of lipolysis in adipose tissue. This initial inhibition, like those of previously discussed antihyperlipidemic agents, produces a sequence of events that ultimately result in the lowering of plasma triglycerides and cholesterol. Impaired lipolysis decreases the mobilization of free fatty acids, thus reducing their plasma levels and their delivery to the liver. In turn, this decreases hepatic triglyceride synthesis and results in a decreased production of VLDL. Enhanced clearance of VLDL through stimulation of lipoprotein lipase also has been proposed to contribute to the reduction of plasma VLDL levels. Because LDL is derived from VLDL (Fig. 30.5), the decreased production of VLDL ultimately leads to a decrease in LDL levels. The sequential nature of this process has been clinically demonstrated. The reduction in triglyceride levels occurs within several hours after ... 

Most of the fat is stored in the adipose tissue. Avian adipose tissue has limited ability for de novo triglyceride synthesis (see Section 4.3), and most of the lipid accumulated is either of dietary origin or as the result of de novo synthesis in the liver. 

The liver is the most important organ involved in fatty acid and triglyceride synthesis. It is able to modify body fats by lengthening or shortening and saturating or unsaturating the fatty acid chains. The only fatty acids that cannot be synthesized by the body are those that are polyunsaturated. However, linoleic acid (two double bonds) and linolenic acid (three double bonds) from the diet can be converted to other polyunsaturated fatty acids. This utilization of linoleic and linolenic acids as sources of other polyunsaturated fatty acids is the basis for classifying them as essential fatty acids for humans (Section 8.2). 

Fish/fish oil consumption has also been shown to affect plasma lipid and lipoprotein levels (for review, see Herold and Kinsella, 1986). The most consistent effect is a substantial reduction in plasma triglyceride following (0-3 fatty acid-rich diets. This is associated with reduced plasma VLDL since this lipoprotein fraction is the major carrier of triglyceride in the blood. The mechanism of this (o-3 fatty acid effect may involve inhibition of triglyceride synthesis in the liver, as well as a recluction in the formation of VLDL apoproteins (see Weaver and Holub, 1988). The effect of fish/fish oil feeding on plasma total cholesterol levels have been variable, with either no change or only a moderate decrease observed. Similarily, effects on LDL-cholesterol and HDL-cholesterol are variable. 

The formation of triglycerides from free fatty acids in subcellular preparations of intestinal mucosa was shown to require the presence of ATP, Coenzyme A and Mg++. Addition of L-a-glycerophosphate to the incubation mixture increased the synthesis manyfold (Dawson and Isselbacher 1960 Clark and Htoscher 1960, 1961). These requirements are similar to those found for triglyceride synthesis in liver particles (see chapter III 2) and it was therefore considered likely that triglyceride synthesis in the intestine proceeds by the same reaction steps as in liver. 

It seems well established that fatty livers produced by starvation, diabetes or the administration of anterior pituitary hormones are primarily due to an increased mobilization of fatty acids from adipose tissue (see chapter III 2) (Barrett et al. 1938 Stetten and Salcedo 1944). The rate of hepatic triglyceride synthesis is directly proportional to the level of free fatty acids in the blood (Feigelson et al. 1961), and increased mobilization will therefore residt in accelerated triglyceride synthesis. 

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