to accompany the nephrotic state. Moribund 

 BHE rats, regardless of diet, frequently exhibited 

 a hypercholesterolemia generaUy associated with 

 damaged kidneys. Blood sera from these rats 

 were often obviously lipemic. In many ways the 

 picture seen in these moribund rats was similar 

 to that observed in experimentally induced 

 nephrotic rats. 



Heymann and Lund (90) showed that a con- 

 dition simulating the nephrotic syndrome of 

 childhood can be produced in rats by the in- 

 jection of rabbit anti-rat kidney serum (AKS) 

 prepared by immunizing rabbits against rat 

 kidney. This procedure has been used rather 

 extensively to study the factors involved in 

 chronic nephrosis in this animal. Heymann, 

 Matthews, Lemm, and others (91) observed no 

 evidence of a disturbed clearance of fat from blood 

 when intravenous injections of C 14 labeled tri- 

 laurin were given to nephrotic rats. Rosenman, 

 Friedman, and Byers (163) reported that the 

 hypercholesterolemia observed was not due to 

 increased intestinal absorption, to decreased rate 

 of excretion, nor to increased cholesterol synthesis. 

 The elevated blood cholesterol present in these 

 rats was endogenous in origin, and the authors 

 have suggested biliary obstruction as the cause. 

 Friedman, Rosenman, and Byers (71) found that 

 the nephrotic rat was unable to remove either 

 endogenously or exogenously derived lipid from 

 plasma with its usual efficiency. A progressive 

 fall in plasma albumin was found to follow the 

 injection of AKS and was associated with a rise 

 in plasma triglycerides, phospholipids, and total 

 cholesterol. Heymann and Hackel (88, 89) in- 

 dicated a possible involvement of both the kidney 

 and liver in the mechanism eliciting hyper- 

 lipemia. Bilateral nephrectomy (88) prevented 

 the development of hyperlipemia, and it was 

 suggested that a "hyperlipemia inducing" agent 

 may be secreted by the nephrotic kidney. Sub- 

 total hepatectomy (89) resulted in reduced hyper- 

 lipemia. Ehrich, Forman, and Seifer (55) re- 

 ported an increased kidney weight, an increased 

 adrenal weight, and extensive proteinuria in 

 rats receiving a large dosage of AKS. 



Lewis and Heymann (115) analyzed the serum 

 lipoproteins in these rats and found the greatest 

 increment in the low density fractions. They 

 were similar in type to those of nephrotic children. 

 Heymann, Matthews, Lemm, and others (91) sug- 

 gested that the hyperlipemia observed was due to 

 increased mobilization of lipid rather than to a 

 deposit of lipid in tissues. Marsh and Drabkin 

 (12 If) provided evidence indicating that fat was 

 mobilized from body stores. 



There appears to be little information on the 

 production by dietary means of hypercholester- 

 olemia and hyperlipemia in rats associated with 

 kidney damage. According to Blatherwick and 

 Medlar (30), diet alone will produce nephritis and 

 will also determine its severity. They observed 

 marked involvement of the kidney when rats were 



fed a diet containing 75 percent liver. Some kid- 

 ney damage was also found when the level of liver 

 fed was 30 percent. Fatty infiltration of the liver, 

 high liver and plasma cholesterol, and increased 

 urinary protein were observed. An average 

 plasma cholesterol of 88 mg./lOO ml. was observed 

 in stock rats without nephritis. Values over 146 

 mg./lOO ml. were considered hypercholesteremic. 

 On liver diet, the mean value was 126 mg./lOO ml. 

 without nephritis and 219 mg./lOO ml. was con- 

 sidered the upper level for normal rats. Higher 

 values were associated with extensive kidney dam- 

 age. Fatty infiltration of the liver was observed 

 even though kidneys still appeared normal in rats 

 fed the high level of liver. 



The fatty infiltration of the liver, the high 

 plasma cholesterol, and the increased urinary pro- 

 tein obtained by Blatherwick and Medlar (30) 

 when rats were fed a diet containing high levels of 

 liver were strikingly similar to the results reported 

 here for BHE rats fed diets containing 25 percent 



egg. 



Summary. — The results of the investigations re- 

 ported in this bulletin provide further evidence 

 that many factors influence blood cholesterol levels, 

 and emphasize the statement made by Portman 

 and Stare (153) that it is unwise to place too much 

 emphasis on the effect of a single factor in the con- 

 trol of serum cholesterol unless that factor is 

 evaluated under a wide range of conditions. 



From the long-term studies with BHE rats, the 

 relation of serum cholesterol levels to age was 

 found to differ with diet. High levels were rarely 

 seen in healthy BHE rats that were maintaining 

 then- weight on the stock diet and there was little 

 evidence that cholesterol levels were influenced by 

 age. Cholesterol levels were generally low in rats 

 under 400 days old that were maintaining their 

 weight on the semipurified diet or on modifications 

 of this diet, SPM, SPB, and SPPB, containing 

 milk, beef, or peanut butter. In the sera of older 

 rats, elevated cholesterol levels were observed on 

 all of these diets except the stock diet; the highest 

 value observed in the absence of dietary cholesterol 

 was for rats fed SPPB diet. The increased serum 

 cholesterol in the older rats was generally accom- 

 panied by kidneys showing evidence of degenera- 

 tive changes even in rats that appeared healthy at 

 the time of sacrifice. 



Although serum cholesterol values tended to 

 be high in moribund rats, relatively low cholesterol 

 levels were found in several rats that survived 

 over 700 days. Cholesterol values obtained for 

 individual rats at intervals throughout life are 

 needed to determine whether we are measuring 

 changes in cholesterol level that are due to aging 

 processes or whether these changes may be the 

 result of the development of some pathological 

 condition. 



In the presence of dietary cholesterol, with 

 egg as the source, elevated cholesterol values 

 were observed in relatively young BHE rats. 

 The values for rats between 200 and 400 days 



85 



