Another aspect of the carbohydrate-lipid relationship which has received considerable attention lately is the influence of FFA on glucose metabolism. The term "glucose-fatty acid cycle" has been coined (389).
In the uncontrolled diabetic, the plasma FFA are generally raised and may be elevated even when the blood glucose is normal (173, 174). Since the entry of glucose into cells is impaired in diabetes, it was thought that a reduction in FFA esterification was entirely responsible for the increased efflux of FFA (133). However Randle et al. (389) have suggested that the increased concentrations of plasma FFA preceded and were responsible for the development of hyperglycemia. The situation in the mild diabetic may be analogous to that of starvation in which a rise in
plasma FFA certainly precedes carbohydrate intolerance (174, 390).
Randle et al. (389) cite experimental evidence to show that high concentra-tions of FFA interfere with several phases of glucose metabolism such as glucose phosphorylation, glycolysis, glycogen metabolism, and pyruvate oxidation. This could be demonstrated in tissues from starved or diabetic animals and from animals treated with corticosteroids or growth hormone.
They postulate that FFA may, in fact, be insulin antagonists.
Their conclusion, that in diabetes there may be excessive lipolysis of triglyceride in adipose tissue, has been supported by the finding of increased lipolytic activity in the plasma of diabetic patients (390a).
Carlson and Ostman (179) have reported an increased rate of FFA release from adipose tissue of diabetic subjects. It must be stressed, however, that these are preliminary studies and require extensive confirmation, but there is little doubt that FFA suppress the uptake and oxidation of glucose by tissues such as the heart; this is discussed fully in Section VIII,C.
In addition, it has been demonstrated that, when plasma FFA are ele-vated with noradrenaline, the rate of removal of intravenously injected glucose is significantly reduced (391). There are also a number of dis-orders (such as hyperthyroidism, acromegaly, and pheochromocytoma) in which raised plasma FFA levels are associated with impaired glucose tolerance.
C. Obesity
This section is confined to an aspect of obesity about which there appears to be agreement. Measurements of plasma FFA before and after procedures which normally alter the FFA concentration indicate that obese subjects respond abnormally. This has been thought to reflect abnormal insulin and growth hormone metabolism.
In the grossly obese subject, the plasma FFA concentration following an overnight fast is higher than in normal subjects, but fails to rise as much as in nonobese subjects during prolonged starvation (392-394). In moderate obesity however, the postabsorptive FFA concentration has been reported to be less than normal, and an inverse relationship between body fatness and plasma FFA has been demonstrated (395). Stressful situations lead to small increments in plasma FFA in overweight subjects (395).
Several lines of evidence suggest that these responses are produced by abnormalities in insulin and growth hormone metabolism. The metab-olism of FFA, glucose, and potassium in the forearm of these subjects resembles that seen in insulin-treated normal controls (149). Beck et al.
(394) demonstrated differences between obese and nonobese subjects in insulin secretion after glucose, and Bolinger et al. (396) reported the
presence of insulin-like activity in the urine of obese subjects. An abnor-mal rise in plasma insulin-like activity following a glucose meal in obese diabetics has been ascribed to the obesity (373), and Shapiro and co-work-ers (397) have failed to observe the expected rise in R.Q. when insulin was injected into obese subjects. The latter finding may reflect abnormal substrate utilization (the resting R.Q. in the obese subjects was also abnormally low) or diminished sensitivity to insulin.
Plasma growth hormone levels, on the other hand, are abnormally low in gross obesity (394) and do not show the usual rise during fasting (398). Low levels of growth hormone may be partly responsible for the diminished response of plasma FFA to prolonged fasting and stress, and Grasso et ah (399) were unable to produce a rise in plasma FFA when human growth hormone was injected into these subjects.
X. ALCOHOL-INDUCED HYPERLIPEMIA
An association between alcoholism, fatty liver, and hyperlipemia has been recognized for a long time (400, 401). It has been shown more recently that the administration of alcohol to man or to an animal regularly leads to an increase in plasma lipids and triglyceride in particu-lar. This has greatly stimulated research in this field and has indirectly led to an increase in knowledge of lipoprotein transport.
A rise in the plasma triglyceride concentration may result from an increased fatty acid synthesis, an increased FFA mobilization from adi-pose tissue, an increased rate of fatty acid esterification in the liver, an increase in the transfer of triglyceride from liver to plasma, or a dimin-ished utilization of fatty acid or triglyceride. Each and every one of these mechanisms has been implicated in the pathogenesis of alcohol-induced hyperlipemia, although it is agreed that not all are of equal importance (402).
In man the plasma triglyceride concentration is rapidly raised by the consumption of alcohol (403-405). The rise in triglycerides is predom-inantly within very low-density lipoproteins (405), and lactescence of the plasma has been described (401, 404).
Analysis of the fatty acid composition of the newly synthesized triglyceride has revealed increments in oleate and linoleate, which indi-cates that the percursor fatty acids had been derived predominantly from adipose tissue. This has been demonstrated in the rat (406-408) and in man (404). It is consistent with an increased rate of mobilization of FFA or an increased rate of esterification of FFA which had been deposited in the liver. Moreover, experimental procedures that prevent FFA mobilization will also prevent alcohol-induced fatty livers (402).
An increase in the rate of mobilization of FFA from adipose tissue in
response to alcohol has not been incontrovertibly demonstrated. In man, Schapiro et al. (404) found a consistent elevation of plasma FFA during prolonged ingestion of large quantities of alcohol. This has not been observed during shorter periods of administration, when falls in plasma FFA have, in fact, occurred (403, 405). Moreover, alcohol appears to reduce the rise in plasma FFA induced by smoking cigarettes (409). In rats, both increments (410-412) and unchanged FFA levels have been reported (413). Measurements of FFA turnover have not shown any change with alcohol (407). In man, the turnover rate of FFA following alcohol ingestion has been measured by injecting intravenously 1 4 C-la-beled palmitic acid and found to be a little less than during fasting, but considerably greater than when isocaloric amounts of glucose are ingested (405). Bouchier and Dawson (414) also observed a fall in FFA levels following intravenously administered alcohol, but reported an exagger-ated rebound when the infusion was stopped. These discrepancies may be related to the dose and duration of administered alcohol (404).
Nevertheless, striking increments in plasma triglyceride occur even in the absence of increased FFA mobilization, and previously cited evidence indicates that FFA originating in the adipose tissue provide the major source of precursor fatty acid for triglyceride synthesis. This suggests that an increase in fatty acid esterification within the liver is a major factor in the pathogenesis of alcohol-induced hyperlipemia. Maling et al. (415) have shown that alcohol may specifically stimulate the forma-tion of triglyceride at the expense of phospholipid. Recent studies in man (405), the rat (407), and the rabbit (416) have measured the incorporation of labeled fatty acid into triglycerides of liver and plasma during both short and prolonged periods of alcohol ingestion. In each study a sig-nificantly greater fraction of administered labeled fatty acid was incorpor-ated into hepatic and plasma triglyceride when alcohol was fed. In man, Nestel and Hirsch (405) have shown that the fractional rate of transfer of triglyceride from liver to plasma was similar during fasting and with alcohol; since the absolute amount of triglyceride secreted into the plasma was much greater with alcohol, it is apparent that triglyceride turnover was stimulated by alcohol.
Increased hepatic esterification of FFA derived in normal or increased amounts from adipose tissue is, therefore, the likeliest explanation for alcohol induced hyperlipemia. Other mechanisms are probably also oper-ative but appear to be of lesser importance.
Diminished utilization of triglyceride by extrahepatic tissues has been suggested by the finding of decreased postheparin lipolytic activity in plasmas from alcohol-fed subjects (417). This may have merely reflected the depression of lipoprotein lipase which follows withdrawal of dietary
fat (120). Alcohol has also been shown to stimulate de novo synthesis of fatty acids (418, 419) and cholesterol (420). However, the fatty acids thus produced are dissimilar to those found predominating in the intact alcohol-fed animal (408). Moreover, other substances that also stimulate hepatic lipogenesis do not produce overproduction of triglyceride (419).
Similarly, although alcohol in vitro suppresses fatty acid oxidation (418), equivalent inhibition with other agents does not result in accumulation of triglyceride.
At very high levels of blood alcohol the triglyceride concentration of plasma may become abnormally low (404). This is consistent with the observation that triglyceride secretion by perfused rat livers may be inhibited by high concentrations of alcohol (421) and may be analogous to other agents, such as ethionine, (317) which suppress lipoprotein synthesis.
Recent studies by Lieber et al. (422) have also revealed that different factors may operate when alcohol is given for long rather than for short periods. They found that a single dose of alcohol led to the accumulation in the liver of fat which had been derived from adipose fatty acids. On the other hand, when alcohol was consumed for many days the fatty acids found in the liver resembled those derived from endogenous syn
thesis; when specific fats were fed together with the alcohol, much of the fat in the liver was clearly of dietary origin.
REFERENCES 1. D. S. Goodman, Λ Am. Chem. Soc. 8 0 , 3887 (1958).
2. F. R. N. Gurd, in "Lipide Chemistry" (D. Hanahan, ed.), p. 260. Wiley, New York, 1960.
2a. R. B. Alfin-Slater and R. Shull, in "Newer Methods of Nutritional Biochem
istry" (A. A. Albanese, ed.), Vol. I, p. 369. Academic Press, New York, 1963.
3. D. S. Fredrickson and R. S. Gordon, Physiol. Rev. 3 8 , 585 (1958).
4. F. T. Lindgren and Α. V. Nichols, in "The Plasma Proteins" (F. W. Putnam, ed.), Vol. 2, p. 1. Academic Press, New York, 1960.
5. D. G. Cornwell and F. A. Kruger, / . Lipid Res. 2, 110 (1961).
6. O. F. de Lalla and J. W. Gofman, in "Blood and Other Body Fluids" (D. S.
Dittmer, ed.). Federation of American Societies for Experimental Biology, Washington, D.C., 1961.
7. R. L. Searcy and L. M. Bergquist, "Lipoprotein Chemistry in Health and Disease." Thomas, Springfield, Illinois, 1962.
8. J. L. Oncley, in "Lipid Transport" (H. C. Meng, ed.), p. 70. Thomas, Spring
field, Illinois, 1964.
9. D. B. Zilversmit, in "Biochemical Problems of Lipids" (A. C. Frazer, ed.), p. 257. Elsevier, Amsterdam, 1963.
10. H. G. Kunkel and R. Trautman, J. Clin. Invest. 3 5 , 641 (1956).
11. E. Gordis, Proc. Soc. Exptl. Biol. Med. 1 1 0 , 657 (1962).
12. R. J. Havel, Metab., Clin. Exptl. 1 0 , 1031 (1961).
13. R. J. Havel, H. A. Eder, and J. H. Bragdon, J. Clin. Invest. 34, 1345 (1955).
14. D. Gitlin, D. G. Cornwell, D. Nakasato, J. L. Oncley, W. L. Hughes, and C. A. Janeway, J. Clin. Invest. 37, 172 (1958).
15. B. Shore and V. Shore, J. Atherosclerosis Res. 2, 104 (1962).
16. A. Gustafson, P. Alaupovic, and R. H. Furman, Biochemistry 5, 632 (1965).
17. Α. V. Nichols and L. Smith, J. Lipid Res. 6, 206 (1965).
18. R. S. Lees and F. T. Hatch, J. Lab. Clin. Med. 61, 518 (1963).
19. E. L. Bierman, D. Porte, D. D. O'Hara, M. Schwartz, and F. C. Wood, J.
Clin. Invest. 44, 261 (1965).
20. R. I. Levy, R. S. Lees, and D. S. Fredrickson, J. Clin. Invest. 44, 1068 (1965).
21. R. I. Levy and D. S. Fredrickson, / . Clin. Invest. 44, 426 (1965).
22. G. B. Phillips, Proc. Soc. Exptl. Biol. Med. 100, 19 (1959).
23. J. A. Glomset, Biochim. Biophys. Acta 70, 389 (1963).
24. K. G. Pinter and D. B. Zilversmit, Biochim. Biophys. Acta 59, 116 (1962).
25. J. H. Bragdon, Arch. Biochem. Biophys. 75, 528 (1958).
26. M. L. Peterson, "The Transport of Fat in Man. A Study of Chylomicrons."
Rockefeller Inst., New York, 1960.
27. K. J. Isselbacher and D. M. Budz, Nature 200, 364 (1963).
28. M. Rodbell, D. S. Fredrickson, and K. Ono, J. Biol. Chem. 2 3 4 , 567 (1959).
29. F. T. Hatch, L. M. Hagopian, J. J. Rubenstein, and G. P. Canellos, Circulation 28, 659 (1963).
30. Η. B. Salt, Ο. H. Wolff, J. K. Lloyd, A. S. Fosbrooke, A. H. Cameron, and D. V. Hubble, Lancet I I, 325 (1960).
31. B. Borgstrom, J. Clin. Invest. 39, 801 (1960).
32. L. Swell, E. C. Trout, J. R. Hopper, H. Field, and C. R. Treadwell, J. Biol.
Chem. 232, 1 (1958).
33. O. Minari and D. B. Zilversmit, / . Lipid Res. 4, 424 (1963).
34. J. M. Johnston and J. H. Bearden, Arch. Biochem. Biophys. 90, 57 (1960).
35. Μ. I. Gurr, W. F. R. Pover, J. N. Hawthorne, and A. C. Frazer, in "Biochemical Problems of Lipids" (A. C. Frazer, ed.), p. 236. Elsevier, Amsterdam, 1963.
36. D. B. Zilversmit, C. Entenman, and I. L. Chaikoff, Λ Biol. Chem. 172, 637 (1948).
37. J. R. Senior, J. Lipid. Res. 5, 495 (1964).
38. F. H. Mattson and R. A. Volpenhein, / . Biol. Chem. 239, 2772 (1964).
39. J. R. Senior and K. J. Isselbacher, J. Clin. Invest. 42, 187 (1963).
40. B. Clark and G. Hubscher, Biochim. Biophys. Acta 46, 479 (1961).
41. J. R. Senior and K. J. Isselbacher, J. Biol. Chem. 237, 1454 (1962).
42. J. M. Johnston, J. Biol. Chem. 234, 1065 (1959).
43. A. M. Dawson and K. J. Isselbacher, Λ Clin. Invest. 39, 730 (1960).
44. A. M. Dawson and K. J. Isselbacher, J. Clin. Invest. 39, 150 (1960).
45. B. Bloom, I. L. Chaikoff, and W. O. Reinhardt, Am. J. Physiol. 166, 451 (1951).
46. B. Borgstrom, Acta Physiol. Scand. 34, 71 (1955).
47. Ε. H. Ahrens and N. Spritz, in "Biochemical Problems of Lipids" (A. C.
Frazer, ed.), p. 304. Elsevier, Amsterdam, 1963.
48. J. Fernandes, J. H. Van de Kamer, and H. A. Weijers, J. Clin. Invest. 34, 1026 (1955).
49. R. Blomstrand, N. A. Thorn, and Ε. H. Ahrens, Am. J. Med. 24, 958 (1958).
50. S. A. Hashim, Η. V. Roholt, V. K. Babayan, and Τ. B. Van Itallie, New Eng. J. Med. 270, 756 (1964).
51. R. Blomstrand and Ε. H. Ahrens, / . Biol. Chem. 2 3 3 , 321 (1958).
52. R. Blomstrand, J. Gurtler, and B. Werner, J. Clin. Invest. 44, 1766 (1965).
53. J. H. Bragdon and A. Karmen, J. Lipid Res. 1, 167 (1960).
54. R. Blomstrand and O. Dahlback, J. Clin. Invest. 3 9 , 1185 (1960).
55. H. J. Kayden, A. Karmen, and A. Dumont, J. Clin. Invest. 4 2 , 1373 (1963).
56. A. Karmen, Η. M. Whyte, and D. S. Goodman, J. Lipid Res. 4 , 312 (1963).
57. Η. M. Whyte, A. Karmen, and D. S. Goodman, J. Lipid Res. 4 , 322 (1963).
58. S. L. Palay and L. J. Karlin, J. Biophys. Biochem. Cytol. 5 , 373 (1959).
59. F. S. Sjostrand, in "Biochemical Problems of Lipids" (A. C. Frazer, ed.), p. 91. Elsevier, Amsterdam, 1963.
60. J. R. Casley-Smith, Λ Cell Biol. 1 5 , 259 (1962).
61. D. G. Cornwell, F. A. Kruger, and Η. B. Robinson, J. Lipid Res. 3 , 65 (1962) . 62. V. P. Dole and J. T. Hamlin, Physiol Rev. 4 2 , 674 (1962).
63. D. S. Robinson, Advan. Lipid Res. 1, 134 (1963).
64. I. A. D. Bouchier and B. Bronte-Stewart, Lancet I, 363 (1961).
65. M. L. Mashford and P. J. Nestel, Circulation Res. 9 , 7 (1961).
66. M. C. Balodimos, J. J. Ball, and R. H. Williams, Metab., Clin. Exptl. 1 1 , 365 (1962).
67. N. R. Di Luzio and S. J. Riggi, RES: J. Reticuloendothelial Soc. 1 , 136 (1964).
68. E. L. Bierman and J. T. Hamlin, Proc. Soc. Exptl Biol. Med. 1 0 9 , 747 (1962).
69. N. R. Di Luzio and E. L. Bierman, Proc. Soc. Exptl Biol Med. 1 1 6 , 1045 (1964).
70. E. L. McCandles and D. B. Zilversmit, Am. J. Physiol. 1 9 3 , 294 (1958).
71. R. J. Havel and J. C. Clarke, Clin. Res. 6 , 264 (1958).
72. P. J. Nestel, R. J. Havel, and A. Bezman, / . Clin. Invest. 4 2 , 1313 (1963).
73. D. S. Fredrickson, D. L. McCollester, R. J. Havel, and K. Ono, in "Chemistry of Lipids as related to Atherosclerosis" (I. H. Page, ed.), p. 205. Thomas, Springfield, Illinois, 1958.
74. W. J. Lossow, N. Brot, and I. L. Chaikoff, J. Lipid Res. 3 , 207 (1962).
75. F. T. Lindgren, Ν. K. Freeman, Α. V. Nichols, and J. W. Gofman, Proc. 3rd Intern. Conf. Biochem. Probl. Lipids, Brussels, 1956 p. 224.
76. J. E. French and B. Morris, J. Physiol {London) 1 3 8 , 326 (1957).
77. B. Borgstrom and P. Jordon, Acta Soc. Med. Upsalien. 6 4 , 185 (1959).
78. R. J. Havel and D. S. Fredrickson, / . Clin. Invest. 3 5 , 1025 (1956).
79. R. J. Havel and A. Goldfien, / . Lipid Res. 2 , 389 (1961).
80. P. J. Nestel, M. A. Denborough, and J. O'Dea, Circulation Res. 1 0 , 786 (1962).
81. P. J. Nestel, J. Clin. Invest. 4 3 , 943 (1964).
82. L. A. Carlson and D. Hallberg, Acta Physiol. Scand. 5 9 , 52 (1963).
83. D. Hallberg, Acta Physiol Scand. 6 2 , 407 (1964).
84. P. Belfrage, B. Borgstrom, and T. Olivecrona, Acta Physiol. Scand. 5 8 , 111 (1963).
85. D. F. Brown, A. S. Heslin, and J. T. Doyle, New Engl. J. Med. 2 6 4 , 733 (1961).
86. M. A. Denborough, Clin. Sci. 2 5 , 115 (1963).
87. J. H. Bragdon and R. S. Gordon, J. Clin. Invest. 3 7 , 574 (1958).
88. B. Morris and M. W. Simpson-Morgan, J. Physiol (London) 1 6 9 , 729 (1963).
89. P. J. Nestel, R. J. Havel, and A. Bezman, J. Clin. Invest. 4 1 , 1915 (1962).
90. B. Borgstrom and T. Olivecrona, J. Lipid Res. 2 , 263 (1961).
91. J. E. French and B. Morris, J. Physiol (London) 1 4 0 , 262 (1958).
92. T. Olivecrona, J. Lipid Res. 3 , 439 (1962).
93. R. E. Kay and C. Entenman, J. Biol Chem. 2 3 6 , 1006 (1961).
94. M. Heimberg, I. Weinstein, H. Klausner, and M. L. Watkins, Am. J. Physiol.
2 0 2 , 353 (1962).
95. M. A. Mishkel and B. Morris, Quart. J. Exptl. Physiol. 4 9 , 21 (1964).
96. T. Olivecrona and P. Belfrage, Biochim. Biophys. Acta 9 8 , 81 (1965).
97. C. Green and J. A. Webb, Biochim. Biophys. Acta 8 4 , 404 (1964).
98. H. S. Bennett, J. H. Luft, and J. C. Hampton, Am. J. Physiol. 1 9 6 , 381 (1959).
99. J. M. Felts, Ann. N.Y. Acad. Sci., 1 3 1 , 24 (1965).
100. G. E. Palade, Circulation 2 4 , 368 (1961).
101. E. D. Korn, J. Biol. Chem. 2 1 5 , 1 (1955).
102. D. S. Fredrickson, D. L. McCollester, and K. Ono, J. Clin. Invest. 37, 1333 (1958).
103. A. Bezman, J. M. Felts, and R. J. Havel, J. Lipid Res. 3 , 427 (1962).
104. P. J. Nestel and R. J. Havel, Proc. Soc. Exptl. Biol. Med. 1 0 9 , 985 (1962).
105. C. A. Stern, J. M. Iacono, and J. F. Mueller, Proc. Soc. Exptl. Biol. Med.
1 1 0 , 366 (1962).
106. J. D. Schnatz, J. W. Ormsby, and R. H. Williams, Am. J. Physiol 2 0 5 , 401 (1963).
107. A. Cherkes and R. S. Gordon, J. Lipid Res. 1 , 97 (1959).
108. C. H. Hollenberg, J. Clin. Invest. 3 9 , 1282 (1960).
109. A. A. Alousi and S. Mallov, Am. J. Physiol. 2 0 6 , 603 (1964).
110. D. S. Robinson and P. M. Harris, Quart. J. Exptl. Physiol. 4 4 , 80 (1959).
111. J. R. E. Fraser, R. R. H. Lovell, and P. J. Nestel, Clin. Sci. 2 0 , 351 (1961).
112. M. Rodbell, J. Biol. Chem. 2 3 9 , 753 (1964).
113. R. E. Condon, H. Tobias, and D. V. Dhatta, / . Clin. Invest. 4 4 , 860 (1965).
114. V. S. Le Quire, R. L. Hamilton, R. Adams, and J. M. Merrill, Proc. Soc.
Exptl. Biol. Med. 1 1 4 , 104 (1963).
115. R. J. Havel, Am. J. Clin. Nutr. 6 , 662 (1958).
116. L. A. Carlson and L. B. Wadstrom, Clin. Chim. Acta 2 , 9 (1957).
117. Η. B. Jones, J. W. Gofman, F. T. Lindgren, Τ. B. Lydon, D. M. Graham, B. Strisower, and Α. V. Nichols, Am. J. Med. 1 1 , 358 (1951).
118. E. L. Bierman, E. Gordis, and J. T. Hamlin, J. Clin. Invest. 4 1 , 2254 (1962).
119. R. J. Havel and R. S. Gordon, J. Clin. Invest. 3 9 , 1777 (1960).
120. D. S. Fredrickson, K. Ono, and L. L. Davis, J. Lipid Res. 4 , 24 (1963).
121. P. Kuo, D. R. Bassett, and R. Lopez, Circulation 2 8 , 664 (1963).
122. D. Porte, D. D. O'Hara, and R. H. Williams, Clin. Res. 1 3 , 108 (1965).
123. R. J. Havel and M. Petersen, Circulation 1 8 , 496 (1958).
124. P. J. Nestel, J. Atherosclerosis Res. 4 , 193 (1964).
125. Y. Yoshitoshi, C. Naito, H. Okaniwa, M. Usui, T. Mogani, and T. Tomono, J. Clin. Invest. 4 2 , 707 (1963).
126. J. Boberg and L. A. Carlson, Clin. Chim. Acta 1 0 , 420 (1964).
127. D. Porte and R. H. Williams, Proc. Soc. Exptl. Biol. Med. 1 1 8 , 639 (1965).
128. B. Shore and V. Shore, Am. J. Physiol. 2 0 1 , 915 (1961).
129. W. C. Vogel and E. L. Bierman, Federation Proc. 2 4 , 439 (1965).
130. J. M. Barry, W. Bartley, J. L. Linzell, and D. S. Robinson, Biochem. J.
8 9 , 6 (1963).
131. D. B. Zilversmit, Federation Proc. 2 4 , 342 (1965).
132. P. J. Nestel and R. 0 . Scow, J. Livid Res. 5 , 4 6 ( 1 9 6 4 ) . 133. B. Jeanrenaud, Metab., Clin. Exptl. 1 0 , 5 3 5 ( 1 9 6 1 ) . 134. M. Vaughan, / . Lipid Res. 2 , 293 ( 1 9 6 1 ) .
135. I . B. Fritz, Physiol. Rev. 4 1 , 5 2 ( 1 9 6 1 ) .
136. D . Steinberg, in "Control of Lipid Metabolism" (J. M. Grant, ed.), p. 1 1 1 . Oxford Univ. Press, London and New York, 1963.
137. A. E. Renold and G. F. Cahill (eds.), "Adipose Tissue." Am. Physiol. Soc, Baltimore, Maryland, 1964.
138. D . S. Fredrickson and R. S. Gordon, J. Clin. Invest. 3 7 , 1 5 0 4 ( 1 9 5 8 ) . 139. S. R. Lipsky, A. Haavik, C. L. Hopper, and R. W. McDivitt, J. Clin. Invest.
3 6 , 2 3 3 ( 1 9 5 7 ) .
140. D . T. Armstrong, R. Steele, N. Altszuler, A. Dunn, J. S. Bishop, and R.
C. de Bodo, Am. J. Physiol. 2 0 1 , 9 ( 1 9 6 1 ) .
141. Μ. B. Fine and R. H. Williams, Am. J. Physiol. 1 9 9 , 4 0 3 ( 1 9 6 0 ) .
142. W. T. McElroy, W. L. Seifert, and J. J. Spitzer, Proc. Soc. Exptl. Biol. Med.
1 0 4 , 2 0 ( 1 9 6 0 ) .
143. P. J. Nestel and D . Steinberg, J. Lipid Res. 4 , 461 ( 1 9 6 3 ) .
144. A. Gousios, J. M. Felts, and R. J. Havel, Metab., Clin. Exptl. 1 2 , 7 5 ( 1 9 6 2 ) . 145. J. J. Spitzer, M. Gold, and B. J. Branson, Proc. Soc. Exptl. Biol. Med, 1 1 8 ,
149 ( 1 9 6 5 ) .
146. S. Laurell, Acta Physiol. Scand. 4 7 , 2 1 8 ( 1 9 5 9 ) .
147. R. J. Havel, J. M. Felts, and C. M. Van Duyne, J. Lipid Res. 3 , 297 ( 1 9 6 2 ) . 148. Μ. E. Rothlin and R. J. Bing, J. Clin. Invest. 4 0 , 1380 ( 1 9 6 1 ) .
149. D . Rabinowitz and K. L. Zierler, / . Clin. Invest. 4 1 , 2 1 7 3 ( 1 9 6 2 ) .
150. J. P. Dustin, D . S. Fredrickson, P. Laudat, and K. Ono, Federation Proc.
2 0 , 2 7 0 ( 1 9 6 1 ) .
151. P. J. Nestel, A. Bezman, and R. J. Havel, Am. J. Physiol. 2 0 3 , 9 1 4 ( 1 9 6 2 ) . 152. P. J. Nestel, Metab., Clin. Exptl. 1 4 , 1 ( 1 9 6 5 ) .
153. J. J. Spitzer and M. Gold, Proc. Soc. Exptl. Biol. Med. 1 1 0 , 6 4 5 ( 1 9 6 2 ) . 154. Y. Stein and B. Shapiro, Am. J. Physiol. 1 9 6 , 1238 ( 1 9 5 9 ) .
155. P. V. Harper, W. B. Neal, and G. R. Hlavacek, Metab. Clin. Exptl. 2 ,
6 9 ( 1 9 5 3 ) .
156. S. O. Byers and M. Friedman, Am. J. Physiol. 1 9 8 , 6 2 9 ( 1 9 6 0 ) . 157. L. A. Carlson and B. Olhagen, Λ Clin. Invest. 3 8 , 8 5 4 ( 1 9 5 9 ) . 158. L. A. Carlson and L-G. Ekelund, Λ Clin. Invest. 4 2 , 7 1 4 ( 1 9 6 3 ) .
159. S. J. Friedberg, R. F. Klein, D. L. Trout, M. D. Bogdonoff, and Ε. H. Estes, J. Clin. Invest. 4 0 , 1846 ( 1 9 6 1 ) .
160. D. Steinberg, M. Vaughan, and S. Margolis, J. Biol. Chem. 2 3 6 , 1931 ( 1 9 6 1 ) . 161. M. A. Rizack, Λ Biol. Chem. 2 3 6 , 657 ( 1 9 6 1 ) .
162. M. Vaughan, J. Berger, and D . Steinberg, J. Biol. Chem. 2 3 9 , 4 0 1 ( 1 9 6 4 ) . 163. E. Gorin and E. Shafrir, Biochim. Biophys. Acta 8 4 , 2 4 ( 1 9 6 4 ) .
164. M. Vaughan and D . Steinberg, / . Lipid Res. 4 , 193 ( 1 9 6 3 ) .
165. B. Leboeuf, R. B. Flinn, and G. F. Cahill, Proc. Soc. Exptl. Biol. Med. 1 0 2 ,
527 ( 1 9 5 9 ) .
166. M. Vaughan, D. Steinberg, and R. Pittman, Biochim. Biophys. Acta 8 4 , 1 5 4
( 1 9 6 4 ) .
167. V. P. Dole, / . Clin. Invest. 3 5 , 1 5 0 ( 1 9 5 6 ) .
168. R. S. Gordon and A. Cherkes, Λ Clin. Invest. 3 5 , 2 0 6 ( 1 9 5 6 ) . 169. L. A. Carlson and L. Oro, Metab., Clin. Exptl. 1 2 , 1 3 2 ( 1 9 6 3 ) . 170. S. Laurell, Acta Physiol. Scand. 4 1 , 1 5 8 ( 1 9 5 7 ) .
171. L. Rubin and F. Aladjem, Am. J. Physiol. 178, 263 (1954).
172. R. J. Havel, A. Naimark, and C. F. Borchgrevink, J. Clin. Invest. 42, 7 (1963).
173. E. L. Bierman, V. P. Dole, and Τ. N. Roberts, Diabetes 6, 475 (1957).
174. C. Ν. T. Hales and P. J. Randle, Lancet I, 790 (1963).
175. C. R. Ford, R. Stevens, R. E. Bolinger, and J. H. Morris, Proc. Soc. Exptl.
Biol. Med. 113, 177 (1963).
176. S. S. Chernick and R. 0 . Scow, Am. J. Physiol. 196, 125 (1959).
177. E. P. Joslin, W. R. Bloor, and H. Gray, / . Am. Med. Assoc. 69, 375 (1917).
178. E. L. Bierman, J. Amaval, and B. Belknap, Diabetes 15, 675 (1966).
179. L. A. Carlson and J. Ostman, Acta Med. Scand. 174, 215 (1963).
180. Μ. E. Tarrant, R. Mahler, and J. Ashmore, J. Biol. Chem. 239, 1714 (1964).
181. M. Gold and J. J. Spitzer, Federation Proc. 24, 342 (1965).
182. A. Gousios and J. M. Felts, Circulation 28, 729 (1963).
183. R. J. Havel, in "Lipid Pharmacology" (R. Paoletti, ed.), p. 357. Academic Press, New York, 1964.
184. R. J. Havel and A. Goldfien, J. Lipid Res. 1, 102 (1959).
185. E. Shafrir and D. Steinberg, J. Clin. Invest. 39, 310 (1960).
186. R. J. Havel, L. A. Carlson, L-G. Ekelund, and A. Holmgren, Metab. Clin.
Exptl. 13, 1402 (1964).
187. D. Steinberg, P. J. Nestel, E. Buskirk, and R. H. Thompson, J. Clin. Invest.
43, 167 (1964).
188. P. S. Mueller and D. Horwitz, J. Lipid Res. 3, 251 (1962).
189. J. H. Hagen and P. B. Hagen, in "Actions of Hormones on Molecular Pro
cesses" (G. Litwak and D. Kritchevsky, eds.), p. 268. Wiley, New York, 1964.
190. L. A. Carlson, R. J. Havel, L-G. Ekelund, and A. Holmgren, Metab. Clin.
Exptl. 12, 837 (1963).
191. L. A. Carlson, Acta Med. Scand. 173, 719 (1963).
192. P. J. Nestel, J. Clm. Invest. 43, 77 (1964).
193. P. V. Cardon and R. S. Gordon, / . Psychosomatic Res. 4, 5 (1959).
194. M. D. Bogdonoff, Ε. H. Estes, and D. L. Trout, Proc. Soc. Exptl. Biol. Med.
100, 503 (1959).
195. M. D. Bogdonoff, A. M. Weissler, and F. L. Marritt, J. Clin. Invest. 39, 959 (1960).
196. J. T. Hamlin, R. B. Hickler, and R. C. Hoskins, Λ Clin. Invest. 39, 606 (1960).
197. L. A. Carlson and S.-O. Liljedahl, Acta Med. Scand. 173, 25 (1963).
198. A. Kershbaum, S. Bellett, E. R. Dickstein, and L. J. Feinberg, Circulation Res. 9, 631 (1961).
199. W. R. Harlan, J. Laszlo, M. D. Bogdonoff, and Ε. H. Estes, J. Clin. Endocrinol.
Metab. 23, 33 (1963).
200. F. X. Hausberger, Z. Mikroscop.-Anat. Forsch. 36, 231 (1934).
201. R. Paoletti, R. L. Smith, R. P. Maickel, and Β. B. Brodie, Biochem. Biophys.
Res. Commun. 5, 424 (1961).
202. Η. M. Goodman and E. Knobil, Proc. Soc. Exptl. Biol. Med. 102, 493 (1959).
203. E. Shafrir, Κ. E. Sussman, and D. Steinberg, J. Lipid Res. 1, 459 (1960).
204. C. Rich, E. L. Bierman, and I. L. Schwartz, J. Clin. Invest. 38, 275 (1959).
205. D. Rabinowitz, G. A. Klassen, and K. L. Zierler, J. Clin. Invest. 44, 51 (1965).
206. S. M. Glick, J. Roth, R. S. Yalow, and S. A. Berson, J. Clin. Invest. 42.
935 (1963).
207. I . A. Mirsky, in "Adipose Tissue" (A. E. Renold and G. F. Cahill, eds.), p. 407. Am. Physiol. Soc, Baltimore, Maryland, 1964.
208. D. Steinberg, M. Vaughan, P. J. Nestel, O. Strand, and S. Bergstrom, J. Clin.
Invest. 43, 1533 (1964).
209. S. Bergstrom, L. A. Carlson, and L. Oro, Acta Physiol. Scand. 6 0 , 170 (1964).
210. S. Bergstrom, L. A. Carlson, L-G. Ekelund, and L. Oro, Proc. Soc. Exptl. Biol.
Med. 1 1 8 , 110 (1965).
211. A. Dury, Circulation Res. 5 , 47 (1957).
212. E. Shafrir, Κ. E. Sussman, and D. Steinberg, J. Lipid Res. I, 109 (1959).
213. E. Feigelson, W. Pfaff, A. Karmen, and D. Steinberg, J. Clin. Invest. 4 0 , 2171 (1961).
214. L. A. Carlson and S-O. Liljedahl, Acta Med. Scand. 1 7 3 , 787 (1963).
215. R. Lundolt and Ε. B. Astwood, Am. J. Physiol. 2 0 0 , 841 (1961).
216. D. Rudman, F. Seidman, S. J. Brown, and R. L. Hirsch, Endocrinology 7 0 , 579 (1962).
217. S. B. Penick, Clin. Res. 1 0 , 402 (1962).
218. A. Kershbaum, S. Bellett, R. F. Caplan, and L. J. Feinberg, Circulation 2 4 , 970 (1961).
219. S. M. Grundy and A. C. Griffin, J. Am. Med. Assoc. 1 7 1 , 1794 (1959).
220. M. Friedman, R. H. Rosenman, and V. Carroll, Circulation 1 7 , 852 (1958).
221. C. B. Thomas and E. A. Murphy, J. Chronic Diseases 8 , 661 (1958).
222. P. T. Wertlake, A. A. Wilcox, Μ. I . Haley, and J. E. Peterson, Proc. Soc.
Exptl. Biol. Med. 9 7 , 163 (1958).
223. M. Friedman and R. H. Rosenman, / . Am. Med. Assoc. 1 6 9 , 1286 (1959).
224. J. H. Bragdon, R. J. Havel, and E. Boyle, J. Lab. Clin. Med. 4 8 , 36 (1956).
225. J. W. Farquhar, R. C. Gross, R. M. Wagner, and G. M. Reaven, J. Lipid Res.
6, 119 (1965).
226. D. S. Goodman and T. Shiratori, J. Lipid Res. 5 , 307 (1964).
227. E. L. Bierman and D. E. Strandness, / . Clin. Invest. 4 4 , 1028 (1965).
228. L. J. Gidez, P. S. Roheim, and H. A. Eder, Federation Proc. 2 1 , 289 (1962).
229. C. Waterhouse, J. H. Kemperman, and J. M. Stormont, J. Lab. Clin. Med.
6 3 , 605 (1964).
230. E. J. Masoro, J. Lipid Res. 3 , 149 (1962).
231. R. P. Eaton, D . Steinberg, and M. Berman, / . Clin. Invest. 4 4 , 1042 (1965).
232. N. Baker and M. C. Schotz, / . Lipid Res. 5 , 188 (1964).
233. J. W. Farquhar, R. C. Gross, P. W. Wright, and G. M. Reaven, J. Clin.
Invest. 4 4 , 1046 (1965).
234. P. J. Nestel, Clin. Sci. 31, 31 (1966).
235. R. C. Gross, Ε. H. Eigenbrodt, G. M. Reaven, and J. W. Farquhar, Clin.
235. R. C. Gross, Ε. H. Eigenbrodt, G. M. Reaven, and J. W. Farquhar, Clin.