Humans fatty acid synthesis

Hudgins LC et al Human fatty acid synthesis is stimulated by a eucaloric low fat, high carbohydrate diet. J Clin Invest 1996 97 2081. 

Fatty Acid Synthesis. In human fatty acids synthesis is highly active in liver, mammary glands and brain. Fatty acid biosynthesis occurs in the cytosol through a series of reactions where acetyl-CoA (synthesized from pyruvate, the end product of glucose metabolism) and Malonyl-CoA are linked to form palmitoyl-CoA. During this elongation process, NADPH supplies electrons to Malonyl-CoA [20, 23]. 

COMPARTMENTALIZED PYRUVATE CARBOXYLASE DEPENDS ON METABOLITE CONVERSION AND TRANSPORT The second interesting feature of pyruvate carboxylase is that it is found only in the matrix of the mitochondria. By contrast, the next enzyme in the gluconeogenic pathway, PEP carboxykinase, may be localized in the cytosol or in the mitochondria or both. For example, rabbit liver PEP carboxykinase is predominantly mitochondrial, whereas the rat liver enzyme is strictly cytosolic. In human liver, PEP carboxykinase is found both in the cytosol and in the mitochondria. Pyruvate is transported into the mitochondrial matrix, where it can be converted to acetyl-CoA (for use in the TCA cycle) and then to citrate (for fatty acid synthesis see Figure 25.1). /Uternatively, it may be converted directly to 0/ A by pyruvate carboxylase and used in glu-... 

Insulin also plays a role in fat metabolism. In humans, most fatty acid synthesis takes place in the liver. The mechanism of action of insulin involves directing excess nutrient molecules toward metabolic pathways leading to fat synthesis. These fatty acids are then transported to storage sites, predominantly adipose tissue. Finally, insulin stimulates the uptake of amino acids into cells where they are incorporated into proteins. 

The synthesis of fatty acids in humans takes place in the liver and adipose tissue. The rates of synthesis are normally relatively low in adults in developed countries, probably because the normal diet contains such a high proportion of fat which reduces the activities of enzymes involved in fatty acid synthesis by decreasing expression... 

Insulin is a polypeptide hormone that consists of two peptide chains bonded by two disulfide bonds. The two chains are designated A and B. The A chain consists of 21 amino acids with a third internal disulfide bond, and the chain contains the remaining 30 amino acids. All vertebrates produce insulin and the structure is similar in these species. For example, the insulin produced in humans and porcine species differs by only one amino acid, and humans and bovine insulin differ by three amino acids. Insulin plays a crucial role in several physiological processes. These include the regulation of sugar in the body, fatty acid synthesis, formation of triglycerides, and amino acid synthesis. 

Increased synthesis of lipid or uptake. Increased synthesis of lipid may be the cause of fatty liver after hydrazine administration as this compound increases the activity of the enzyme involved in the synthesis of diglycerides. Hydrazine also depletes ATP and, however, inhibits protein synthesis. Large doses of ethanol will cause fatty liver in humans, and it is believed that this is partly due to an increase in fatty acid synthesis. This is a result of an increase in the NADH/NAD"1" ratio and therefore of the synthesis of triglycerides. Changes in the mobilization of lipids in tissues followed by uptake into the liver can also be another cause of steatosis. 

Increased synthesis of fatty acids De novo synthesis of fatty acids from acetyl CoA in adipose tissue is nearly undetectable in humans, except when refeeding a previously fasted individual. At other times, fatty acid synthesis in adipose tissue is not a major pathway (see Figure 24.5, G). Instead, most of the fatty acids added to the lipid stores of adipocytes are provided by dietary fat (in the form of chylomicrons), with a lesser amount is supplied by VLDL from the liver (see p. 229). 

Biotin is important in a number of metabolic reactions, especially in fatty acid synthesis. The biotin supply of the human organism is only partly derived from the diet. 

Effects of compounds that inhibit enzymes of fat metabolism have been reported in recent literature. Changes in fatty acid oxidation have been inversely correlated to changes in food intake using rodent models as well as human subjects. After administration of compounds that directly inhibit fatty acid oxidation or inhibit fatty acid synthesis, significant increases or decreases in food intake, respectively,... 

The answer is d. (Murray, pp 230-267. Scriver, pp 2297-2326. Sack, pp 121-138. Wihon, pp 287-320.) In humans, the end product of fatty acid synthesis in the cytosol is palmitic acid. The specilicity of cytosolic multienzyme, single-protein fatty acid synthetase is such that once the C16 chain length is reached, a thioesterase clips off the fatty acid. Elongation as well as desaturation of de novo palmitate and fatty acids obtained from the diet occur by the action of enzymes in the membranes of the endoplasmic reticulum. 

The liver is the major organ for fatty-acid synthesis in humans. 

Pizer, E. S., Jackisch, C., Wood, F. D., Pasternack, G. R., Davidson, N. E. and Kuhajda, F. P., Inhibition of fatty acid synthesis induces programmed cell death in human breast cancer cells. Cancer Res 56 (1996a) 2745-2747. 

Swinnen, J. V., Vanderhoydonc, F., Elgamal, A. A., Eelen, M., Vercaeren, I., Ionian, S., Van Poppel, H., Baert, L., Goossens, K., Heyns, W. and Verhoeven, G., Selective activation of the fatty acid synthesis pathway in human prostate cancer, Int J Cancer 88 (2000b) 176-179. 

In addition to the provision of fatty acids for triacylglycerol synthesis, the low but regulated rates of lipogenesis may be critical for overall control of fatty acid metabolism in humans. As discussed above, malonyl-CoA, which is the product of the ACC reaction and the only free intermediate of fatty acid synthesis, inhibits CPT-1 activity, and thereby prevents transport of fatty acids into mitochondria. Thus, the dual role of malonyl-CoA as an intermediate of fatty acid synthesis and as a regulator of fatty acid oxidation, prevents the operation of the futile cycle, in tissues where both fatty acid synthesis and oxidation can be active. 

In addition to stimulating the synthesis and release of LPL, insulin stimulates glucose metabolism in adipose cells. Insulin leads to the activation of the glycolytic enzyme phosphofructokinase-1 by an activation of PFK-2, which increases fructose 2,6-bisphosphate levels. Insulin also stimulates the dephosphorylation of pyruvate dehydrogenase, so that the pyruvate produced by glycolysis can be oxidized in the TCA cycle. Furthermore, insulin stimulates the conversion of glucose to fatty acids in adipose cells, although the liver is the major site of fatty acid synthesis in humans. 

Since one of the metabolic changes associated with some types of obesity in human beings and rodents is increased fatty acid synthesis, inhibitors of lipogenesis are sought as antiobesity agents. This area has been reviewed recently. ... 

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