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HANDBOOK OF PHYSIOLOGY 



CIRCULATION II 



hormones, and by a variety of other influences. In 

 fasting states and when carbohydrate utilization is de- 

 creased, serum levels of these low-density lipoproteins 

 tend to increase; however, appreciable rises in concen- 

 tration of such molecules occur only after the fast has 

 been sustained. Ordinarily, such a rise in circulating 

 beta lipoproteins is preceded by an increase in plasma 

 levels of free fatty acids. 



There is some evidence that lipoprotein interconver- 

 sions occur and that, as fatty acids are split off a low- 

 density lipoprotein molecule, its density progressively 

 increases. When heparin is administered, thereby stim- 

 ulating lipoprotein lipase activity, the interconversion 

 process is greatly accelerated (62). 



Free Fatty Acids 



The free fatty acids comprise less than 10 per cent 

 of the total fatty acids found in plasma. Strictly speak- 

 ing, these acids are not "free" since they circulate 

 bound to albumin. Each molecule of albumin can 

 bind two or more molecules of long-chain fatty 

 acid (83). 



The free fatty acids represent one important form in 

 which fatty acids are transported from sites of storage 

 (fat depots) to working cells (see above). They do not 

 appear to derive directly from dietary fat. However, 

 dietary fatty acids with chain lengths of C10 or less, a 

 very small fraction of fat in the diet, may enter the 

 circulation from the gut via the portal vein in the 

 "free" form (28), although their esterification with 

 glycerol by the intestinal mucosa may also occur (160). 

 Actually, the level of circulating free fatty acids falls 

 after a normal meal. On the other hand, during the 

 course of clearing of alimentary lipemia, a variable 

 fraction of the circulating free fatty acids may originate 

 from chylomicron triglyceride (71). 



Studies of the distribution of C 14 -labeled palmitate 

 (bound to albumin) in rats 15 min after intravenous 

 injection have disclosed a general uptake of the label 

 by various organs and by muscle. Liver lipids were 

 particularly active, whereas adipose tissue had no 

 detectable activity (53). If such experiments can be 

 considered representative of the behavior of free fatty 

 acids under normal circumstances, it would seem that 

 the plasma free fatty acids are removed rapidly in 

 various parts of the body, with subsequent oxidation 

 or esterification, depending upon metabolic circum- 

 stances. 



There is growing evidence that the free fatty acids 

 constitute an important source of the body's energy 

 in the fasting state; they are released in increasing 



amounts by the adipose tissue and used very rapidly 

 at times when carbohydrate utilization is diminished 

 (52). Experimentally induced elevation of the blood 

 sugar or of blood amino acids (94) results in a recipro- 

 cal drop in plasma levels of free fatty acids. 



Calculations suggest that the circulating free fatty 

 acids probably do not supply more than 50 per cent 

 of the energy in the fasting state; hence, it may be 

 suspected that another important source of energy 

 during fasting is esterified fatty acid (71). Isotope 

 studies have shown that the fatty acid turnover is much 

 more rapid in triglyceride than in cholesteryl ester 

 and phospholipid (13). Thus, the serum glycerides 

 may well function as a major vehicle for transport of 

 esterified fatty acid to sites of utilization. 



Ordinarily, in the postabsorptive state, triglyceride 

 moieties travel in the blood as parts of low-density 

 lipoprotein molecules that are neither large nor nu- 

 merous enough to affect the gross clarity of the serum. 

 However, under conditions of metabolic stress, and in 

 certain disorders, lipoproteins of very low density 

 appear in the circulation in quantities sufficient to 

 render the plasma lactescent. It is unlikely that such 

 particles can be released directly from the fat depots 

 and evidence is accumulating that they originate from 

 the liver. 



Role of the Liver 



The liver plays a major role in the synthesis and 

 disposal of lipids and lipoproteins. With the exception 

 of the chylomicrons, it appears that lipoprotein 

 manufacture takes place principally, if not exclu- 

 sively, in the liver. The various factors that influence 

 hepatic synthesis of lipoproteins are not well under- 

 stood. The process whereby the intestinal mucosa 

 handles dietary fats and transforms them into chylo- 

 microns, some of which are removed by the liver, has 

 been discussed already. Adipose tissue releases fat in 

 the form of free fatty acids "bound" to albumin. These 

 acids also are extracted in appreciable quantities by 

 the liver. Carbohydrate and protein can be converted 

 into fat by the liver. In short, the liver is presented 

 with lipid from several sources, and can itself synthe- 

 size lipid, including cholesterol and phospholipid. 

 Thus, the lipoproteins that the liver manufactures 

 and sends out to the circulation are made from a 

 variety of building blocks and are subject to a variety 

 of metabolic influences including diet and hormones. 

 These concepts concerning the origin of serum lipids 

 are shown in schematic form in figure 5. In the case 

 of certain lipids, such as cholesterol, the liver is the 



