XI. THE RELATION OF FATTY LIVERS TO FASTING KETONURIA IN THE RAT*

BY HARRY J. DEUEL, JR., LOIS F. HALLMAN, AND

SHEILA MURRAY

(From the Department of Biochemistry, University of Southern California School of Medicine, Los Angeles)

(Received for publication, March 13, 1937)

There can be no question but that fat is the chief source of the ketone bodies which are excreted in the urine under a variety of circumstances. In the rat, however, no appreciable ketonuria occurs during fasting, although large quantities of fat are present in the carcass and must represent the principal source of energy during the period of inanition. Moreover, the administration of comparatively large amounts of such neutral fat as tributyrin or tricaproin is not followed by a marked ketonuria (1) in such ani- mals, although, when the sodium salts or the ethyl esters of the even chain fatty acids are fed, a considerable ketonuria results

c&3). The fat present in the liver above the amount which may be

considered the 6lBment constant of Terroine must represent the chief source of ketone bodies during fasting. That this is true seems especially evident when one realizes that the liver is the principal site of ketone body synthesis (4). In the rat, however, no appreciable increase in lipid content follows inanition; this phenomenon probably explains the absence of well defined fasting ketosis in this species (5).

There have been no extensive studies designed to ascertain whether a correlation exists between high liver fat and ketonuria

*This work was assisted by a research grant from the Rockefeller Foundation.

A preliminary report of some of these data was given at the meeting of the American Society of Biological Chemists at Memphis, April 21-24, 1937.

257

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258 Studies on Ketosis. XI

in the rat. The present study was made on rats in which the fatty livers were produced by high fat, high carbohydrate, low protein diets similar to those employed by Best and Channon (6). It was also of interest to determine whether the sex differ-

TABLE I

Liver Glycogen, Water, and Lipids in Unfaded Male and Female Rats for 14 Days on Various High Fat Diets (Group A)

Previous diet

Stock diet. . . . . .

Butter Fat It.. .

<‘ iI II...

Cod liver oil.. .

Coconut oil. . . .

Cholesterol-Larc I. . . . . . . . . . . .

Cholesterol-Larc 11s. . . . . . . . . . .

-

1

-_

1

1

-

No. of ex- periments -

3 z -

15

10

15

14

15

15

5 -

16

10

20

lb

15

15

5 - -

Liver lipids

-l-l-l-l- P@ PC Per

cent cent

4.11 ! 1 I I cent

4.11 67.5 68.44.28 8.63

3.84 4.76 54.0 54.23.45 3.92

4.86 5.34 50.0 48.63.05 6.08

4.18 3.82 64.9 67.85.86 6.06

5.34 5.32 52.9 53.13.70 2.75

6.20 6.68 49.4 47.32.11 3.69

1.43 34.92 37.92

4.56 4.30 57.8 60.43.22 1.67 18.21 16.17

2 3 5 $ z --- zzt per cent per cent 2.29 3.76 3.79

1.93 23.07 27.28

1.51 32.35 35.26

3.36 11.80 7.26

2.71 28.42 28.82

* Ratio of mean difference to probable error of mean difference of the average of males compared with the mean of females. When this value exceeds 3.00, the differences are considered significant.

t No yeast used in this series. Crystalline vitamin B1, kindly supplied by Merck and Company, given daily by stomach tube in a dose of 0.01 mg. daily.

# High protein diet (20 per cent casein) at expense of glucose.

ences in ketonuria noted earlier (2) are related to such differences in liver lipid; and finally a comparison has been made in the ke- tonuria resulting after fatty livers had been produced by the administration of various fats.

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Deuel, Hallrnan, and Murray 259

General Procedure

Male and female rats, 3 to 4 months old, from our stock colony and previously on our stock diet (3) were used. They were placed in separate cages and fed on the diet under investigation for 14

TABLE II Water and Lipids in Male and Female Rats Fasted 3 Days Following 1.J Days

on Various High Fat Diets (Group B)

No. of ox- Body periments weight jj~~JyPe~e~~~~ Liver water Liver lipids

Previous diet .2 22 2

3 2

8 0 3 2 4 s 22 3 .2 1 c ZG $3 f ii 2 4 z

~__~~ -__

gm. gm. Per cent gt per cent per cent

Stock diet., 10 10 164 120 3.23 3.53 68.4 69.5 3.95 3.61 -29 -24 -0.88 -0.68+0.9+1.1+0.19 -0.18

Butter Fat I*... 10 10 155 111 3.74 4.07 54.2 59.6 23.76 19.99 -24 -18 -O.lO-0.69+0.2+6.4+0.69 -7.29

“ “ II... 10 9 177 133 4.27 5.19 52.2 51.9 30.59 30.38 -10 -24 -0.69 -0.16+2.2+3.3 -1.76 -4.88

Cod liver oil.. 10 10 127 102 3.33 3.36 67.2 70.2 8.44 4.22 -14 -16 -0.80-0.46+2.3+2.4 -3.26 -3.04

Coconut oil.. 10 10 128 104 4.53 4.20 55.8 61.6 25.49 17.28 -25 -17 -0.79 -1.12+2.1+8.0-1.30-10.46

Cholesterol- Lard I.. . . . . . 10 10 172 117 5.40 6.24 47.6 47.3 36.44 37.64

-0.80 -0.44 -1.8 0.0+1.62 -0.28 Cholesterol-

Lard IIt...... 5 5 196 127 3.82 4.13 55.4 57.8 23.90 18.10 -24 -22 -0.74-0.17 -2.4+0.6+6.49 +I.98

The values in bold-faced type represent the change in mean when com- pared with the averages for unfasted rats (Group A, Table I). The loss in body weight in the present series is for rats fasting for 3 days.

* No yeast used in this series. Crystalline vitamin B1, kindly supplied by Merck and Company, given daily by stomach tube in a dose of 0.01 mg.

t High protein diet (20 per cent casein) at expense of glucose.

days. At the conclusion of this period they were divided into two groups. The first, Group A, was sacrificed immediately; glycogen, water, fat, and proteinlwere determined in the liver of the unfasted

1 The results on liver protein will be reported in a later communication.

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260 Studies on Ketosis. XI

rats which consisted of an equal number of each sex. Group B, which was composed of litter mates of the animals used in Group A, was fasted for 3 days, during which the urine was collected by the procedure usually employed in our studies on ketonuria. Nitrogen and acetone bodies were determined on the urine by the Kjeldahl procedure and the Van Slyke technique respectively. Sodium chloride solution was administered by stomach tube twice

TABLE III Water and Lipids in Livers of Male and Female Rata Fasted 6 Days

Following 14 Days on Various High Fat Diets (Group C)

No. of ex- periments

-

Stockdiet.... 5 5

Butter Fat II. 5 5

Codliveroil... 4 5

Coconut oil.. . 15 13

Cholesterol- Lard I...... 5 5

I I

Body Liver, per cent weight of body weight 1 Liver water 1 Liver lipids

gm. gm. c;;t per cent per cent per cent

169 118 2.80 3.49 70.1 72.2 4.31 4.07 -4.0 -30 -1.31 -0.62 +2.6 +3.8 +0.66 +0.28 163 115 4.95 4.41 53.7 58.4 31.68 22.38

-22 -24 +O.OS -0.93 +3.7 +9.8 -0.67 -12.60 163 114 3.13 3.30 66.0 70.7 12.09 5.94

-22 -20 -1.00 -0.62 +l.l +2.9 +0.29 -1.32 163 124 3.35 4.02 60.8 63.6 19.85 16.85*

-27 -19 -1.99 -1.30 +7.9+10.6 -8.67 -12.17

i43 115 5.04 5.23 50.1 50.4 34.32 34.36 -23 -24 -1.16 -1.46+0.7 +3.1-0.60 -3.66

The values in bold-faced type represent the change in mean when com- pared with the averages of the corresponding values of unfasted rats (Group A, Table I). The loss in body weight is for the rats in the present series on fasting for 5 days.

* Two abnormally high results were excluded from the average.

daily (1 cc. per 100 sq.cm. of surface area) to produce a diuresis. At the conclusion of the experiments on ketonuria, the animals were sacrificed and the livers removed to determine the lipid, water, and protein1 contents. In Group C the ketosis tests were continued for 5 days, after which the animals were killed and simi- lar analyses made. Amytal was employed throughout as an anes- thetic when the animals were sacrificed.

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Deuel, Hallman, and Murray 261

The glycogen was determined by the method of Good, Kramer, and Somogyi (7). Liver water was ascertained by drying the liver to a constant weight in a vacuum oven heated to 50’. The deter- mination of liver lipid was made on the dried sample by extraction with ether on the Bailey-Walker apparatus, followed by a re- extraction of the liver which was powdered after the first extrac- tion.

TABLE IV

Average Body Weight and Food Consumption of Rats on Various High Fat Diets

Diet

Butter Fat I

‘L I* II

Cod liver oil

Coconut oil

Cholesterol- Lard I

Cholesterol- Lard II

Body weight at start of diet IFood consumption per 100 gm. per day

Males T Females Males I Females

-2 Pa v 4 2 4 g 8 g

-_- gm. gm. gm.

208 210 -33 -31 200 203 205 -6 -16 -22 190 180 221

-31 -39 -3E lb1 172 203

-27 -30 -13 192 205 188

-19 -22 -22 198 210 +5 +17

-- gm. gm. gm. gm. gm.

143 149 5.184.02 -16 -20 152 170 1514.694.46 -8 -13 -12 149 140 1533.693.38

-25 -22 -32 160 140 1585.067.39’

-20 -19 -13 139 141 1484.66 3.9; -9-14 -9 148 142 4.18 4.5(

t10 +7

0 4 a z 4 4 6 g g

--- gm. gm. gm.

4.71 7.16

1.594.92 4.16

3.034.56 4.62

3.646.12*8.98’

k.565.39 4.12

5.07 4.95

- V

9

9

Pm.

1.48

1.07

I.87

1.34

The values under the average body weight represent the mean change in body weight during the 14 day period when the diet was ingested. The number of experiments in each group is the same as in the experiments recorded in Tables I to III.

* Maximum values; a considerable amount was spilled from the cups.

In general the diets had the following composition, which is similar to those employed by Channon and coworkers: casein 5 per cent, glucose (cerelose) 48 per cent, fat under investigation 40 per cent, irradiated yeast3 2 per cent, salt mixture (8) 5 per cent.

* Vitamin-free, from the Casein Manufacturing Company of America. 3 Specially high in vitamin G, furnished by Standard Brands, Inc.

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262 Studies on Ketosis. XI

TABLE V

Acetone Bodies in Urine of Fasting Male and Female Rats Previously on High Fat Diets, Receiving Sodium Chloride Solution

Previous diet

Stock diet (con- trols)

Butter Fat It

Butter Fat II

Cod liver oil

Coconut oil

Cholesterol-Lard I’

Cholesterol-Lard TT

-

-

(

(

(

(

(

(

(

-

Acetone bodies, gm. per sg. m.

1st day 1 2nd day / 3rdday 1 4th day

).040.040.030.010.050.100.170.1: (15) (15) (15) (15) (15) (15) (5) (5) ).030.381.103.291.382.43 (10) (10) (10) (10) (10) (10) 3.34 6.96 3.10 ).060.531.802.731.882.951.462.1t (14) (13) (15) (14) (15) (14) (4) (5) 3.49 2.82 3.64 2.87 3.150.312.994.121.873.051.773.0~ (15) (14) (14) (14) (15) (15) (5) (5) 1.71 2.86 3.87 3.81 ).250.412.833.031.842.151.652.41 (15) (14) (15) (15) (15) (15) (5) (5)

2.74 ).120.512.443.102.793.001.571.1~ (14) (14) (15) (13) (15) (12) (5) (5) 8.38 2.27 0.81 1.000.000.170.230.331.46 (5) (5) (5) (5) (5) (5)

Acetonuria ~ for 100 gm.

5th day rat* ~-

22 s i 3 74 2 c $ %

---- Trig. mg.

J.300.35 0.8 1.1 (5) (5)

24.7 57.0

1.911.8336.656.5 (4) (5)

1.052.6448.371.2 (5) (5)

1.731.6846.551.6 (5) (5)

).820.6252.260.8 (5) (5)

5.0 16.7

The figures in parentheses are the number of experiments included in the average.

The figures in bold-faced type represent the ratio of mean difference to probable error of mean difference for the average of males compared with the mean of tht same group of females. The ratio for the 4th day is based on the combine\1 average of the 4th and 5th days respectively.

* Average for 2nd and 3rd days only. t No yeast used in this series. Crystalline vitamin Br, kindly supplied

by Merck and Company, given daily by stomach tube in a dose of 0.01 w.

In the experiments with cholesterol (Eastman) lard was employed to make the food cohere. This comprised 40 per cent of the diet. 2 per cent of cholesterol was added at the expense of the cerelose.

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Deuel, Hallman, and Murray 263

Results

The summary of the analyses on Group A of the glycogen, fat,, and water in the livers of control rats (on the stock diet) and of those previously on the special high fat diet is presented in Table I. Table II gives the results on Group B, while Table III records the mean values for Group C. In Table IV are shown data as to food consumption, etc., for the animals whose experiments are recorded in the other protocols.

The studies on ketonuria made on rats previously on the various high fat diets are recorded in Table V. The analyses of the livers

TABLE VI

Average Nitrogen, in Gm. per Sq. M., in Urine of Fasting Male and Female Rats Following Various Diets

Stock Diet.. . . . Butter Fat I.....

‘I “ II.... Cod liver oil.. . . Coconut oil.. . . . . Cholesterol-Lard

I . . . . . . . . . . . . . . Cholesterol-Lard

Males Females

Previous diet 1st 2nd 3rd 4th 5th 1st 2nd 3rd 4th 5th day day day day day day day day day day

__---- --- --

4.19 4.41 3.51 3.28 2.86 4.52 4.37 3.76 3.25 3.10 2.42 2.78 2.84 2.67 3.27 3.30 2.55 2.87 3.01 3.11 2.79 2.57 3.13 2.71 3.08 2.86 2.81 3.23 2.95 2.71 2.52 2.68 3.13 2.85 2.52 2.57 2.89 3.05 3.05 2.57 2.19 2.67 3.03 2.97 2.48 2.10

2.43 3.10 3.05 3.03 3.18 2.75 3.05 3.04 3.10 2.89

4.58 3.64 3.24 4.31 3.71 3.35

The values are averages of a similar number of experiments in each case as those reported in Table V.

II.............

of the animals used in these tests following the 3 day fast are recorded in Table II, while the values for those undergoing the 5 day tests are given in Table III. The values for urine nitrogen are given in Table VI.

DISCUSSION

The extent to which a ketonuria develops during fasting in the rat is principally related to the nature of the previous diet. In rats previously receiving our stock diet (which contains 5.40 per cent of fat), there was no appreciable ketonuria during a 5 day period of fasting. Such results are in harmony with our earlier

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Studies on Ketosis. XI

work (2), although it was found that the incorporation of 5 per cent of desiccated liver in such a diet was followed by the appear- ance of definite amounts of the acetone bodies during inanition (9). The fasting ketonuria in these rats on the liver diet could be abolished by returning them for 60 days to a similar liver-free regime.

On the other hand a considerable ketonuria which reaches a maximum on the 2nd or 3rd fast day occurs when the rats have been on a high fat diet of such a nature that a deposition of liver fat has resulted. Such a condition persists for at least 5 days, although the quantity of acetone bodies is considerably reduced from the maximum level by that time. In all the experiments recorded here the average value for the excretion of ketone bodies is higher with the females. In most instances the variations are statistically significant. Although such a sex difference in fasting ketonuria has previously been noted between normal men and women (10) as well as in fasting rats and guinea pigs fed sodium acetoacetate (2), this is the first instance in which such a sex variation has been found in rats when the material is not derived from exogenous sources.

The extent of the ketonuria is not definitely related to the fat level but may possibly be altered by the type of liver fat laid down. Thus, a higher level of ketonuria was noted in the animals pre- viously receiving the cod liver oil than in those on the butter fat diet; the liver fat was 3 to 5 times as great in the butter fat group as was found in the animals fed cod liver oil (butter fat, males 32.35 per cent, females 35.26 per cent; cod liver oil, males 11.80 per cent, females 7.26 per cent). Moreover, although the level of ketonuria was invariably higher in the female rats, the greater level cannot be traced to the liver fat. It is true that in the majority of experiments the liver fat is somewhat higher in the female group. However, owing to considerable variations in the individual experiments such differences are not statistically sig- nificant. It is of interest to note that Campbell (11) has also reported that the fat deposition in the livers of female guinea pigs receiving anterior pituitary extracts was greater than in the male animals. In the group of experiments with cod liver oil, in which much higher liver fat was noted in the males, the female animals still excreted significantly greater amounts of the acetone bodies.

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Deuel, Hahnan, and Murray 265

That a qualitative difference according to sex exists in the type of fat present in the livers seems to be suggested by the results obt’ained following a 3 or 5 day fast. That the lipids in this organ of the female are much more labile than those of the male is indi- cated by the constant results on the decrease in liver fat in Groups B and C (recorded in Tables II and III). In all cases the fall in liver fat from the level in unfasted animals is much greater in the females. Thus, on Butter Fat I there is a decline of 7.69 per cent in the female group after 3 days of fasting, while there is an in- crease of 0.69 per cent in the males. In the coconut oil tests, the drop for a 3 day fast is 10.45 per cent in the females as contrasted with a fall of only 1.30 per cent in the males. In those experi- ments on Cholesterol-Lard II in which an increase in liver fat re- sults after 3 days in both the males and females, the rise is con- siderably less in the latter group. In the animals on Butter Fat II, a decrease in 12.50 per cent was noted after a 5 day fast, while there was very little change in the case of the male animals (-0.67 per cent). The only divergent group in which the decrease in fat in the females was less than in the males was in the 3 day tests on cod liver oil. However, the level in the females had dropped to the value of 4.22 per cent and this is approximately the level of the 618ment constant of Terroine. It approximates the value found in the animals on the stock diet (3.79 per cent). The values noted in this experiment also probably would have been in harmony with the rest had not the fat level of the female livers approached what one might consider as an “irreducible minimum” of liver fat.

The rate of disappearance of liver fat is definitely the slowest in the rats which have been fed on a diet high in cholesterol. After a 3 day fast the fat in the liver of the males had increased 5.49 per cent (Cholesterol-Lard II), while that in the females was 1.93 per cent higher.

The levels of liver fat are somewhat higher than those reported by Channon and Wilkinson (12). These investigators give mean figures of 30.67 per cent for the butter fat, 20.54 per cent for the coconut oil, and 7.18 per cent for the cod liver oil tests. The reason why the cod liver oil diet fails to bring about a better fat deposition in the liver is obscure. Higher values are noted in some cases in individual experiments. A liver fat as high as 22.94 per cent was obtained in one of our tests on male rats. It is

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266 Studies on Ketosis. XI

probable that the low values may largely be ascribed to the low food intake of the rats receiving the cod liver oil diet, as suggested by Channon and Wilkinson.

A consistent sex difference in liver glycogen of the unfasted rats was noted in the present experiments. In all cases except the tests with coconut oil, the liver glycogen of the male rats was significantly higher than that of the females. The mean value of liver glycogen in the females after Butter Fat II was only 49.5 per cent of that found in the males, while a maximum of 73.4 per cent of the level found in males was obtained in the female rats previously fed coconut oil. In earlier work from this laboratory (5) we have noted that female rats have lower stores of glycogen in the liver than males for periods of fasting up to 4 days. The sex difference in glycogen level of fasted rats has been confirmed by Blatherwick and coworkers (13). Although no differences were noted in unjasted animals on the stock diet in the earlier work, the present experiments leave no doubt that such a diver- gence does occur, not only after fat diets but after an essentially similar stock diet. We are unable to explain the failure to note the sex difference in unfasted animals in our earlier report; how- ever, the animals used in our previous work were obtained from commercial sources and they were not so uniform or in as good nutritional condition as those used in the present tests in which all came from our own colony.

The liver water is inversely proportional to the fat content. While it averages about 70 per cent in the animals on the stock diet (with a fat content of 3.76 per cent), a mean value as low as 47.3 per cent was noted in the cholesterol tests (37.92 per cent of fat). After intervals of fasting of 3 or 5 days, the rise of percent- age in liver water is invariably higher in the females than the males. This fact offers further support to the more rapid decrease in liver fat in the former case. The percentage of the total body weight attributable to the liver is usually higher in the fat-fed animals. In the tests on Cholesterol I in which the maximum liver fat was noted, the average value is 6.68 per cent compared with a normal percentage of 4.11.

The lipotrophic action of casein is illustrated in the tests on Cholesterol-Lard II. This diet contained 20 per cent of casein instead of the usual 5 per cent. The level of the liver fat was

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Deuel, Hallman, and Murray

reduced to approximately 50 per cent of that noted after a similar fat was fed with the low protein level. A slight ketonuria de- veloped during fasting after this diet, although it was the lowest level of any except the control group.

The loss in weight noted in all groups of tests (except Choles- terol-Lard II) during the 14 day period when the diets were in- gested is probably traceable to an insufficient protein intake. Although the food intake of those rats on the cholesterol diet which contained 20 per cent of casein (Cholesterol-Lard II) is no greater than that of the rats on the other diet, the former gained 5 to 17 gm. on an average compared with an average loss of 6 to 33 gm. in the other tests. The protein lack is also evident in the average value of urinary nitrogen. In the present tests the values are usually 3.00 gm. per sq.m. or less, while with the control rats previously on the stock diet the averages per day for the 5 day fast were 4.19, 4.41, 3.51, 3.28, and 2.86 gm. respectively. Simi- larly, the urinary nitrogen for Cholesterol-Lard II was 4.58, 3.64, and 3.24 gm. for the 3 day period. It should be noted that the high ketonuria may be related to the low endogenous protein metabolism (as reported by Shapiro (14)) as well as to the high liver fat.

The rats ate about 4 gm. of food per day per 100 gm. rat. In spite of the fact that this is only about one-half the level in Chan- non’s tests, the levels of liver fat which we obtained are consider- ably higher.

SUMMARY

A fasting ketonuria followed the administration to rats of diets high in butter fat, coconut oil, cod liver oil, and cholesterol-lard although no appreciable excretion of acetone bodies occurred during a 5 day period following a low fat diet. There was no direct relationship between the height of liver fat and the magni- tude of the ketonuria. In the experiments on cod liver oil in which the liver fat was lowest, the ketonuria reached the maxi- mum level.

Female rats consistently have a higher level of ketonuria than the males. It does not seem probable that this is associated to any degree with the quantity of liver fat available at the start of the fast, since a similar difference was noted in the cod liver oil

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Studies on Ketosis. XI

tests in which the liver fat was higher in the male rats. It seems quite likely that it is to be traced to a qualitative difference of the liver fat. The fat in the female apparently is much more labile than that in the male, as noted by the consistently faster rate at which it leaves the liver after various intervals of fasting. The rate of drop in liver fat is slower after the high cholesterol diet than in the case of the other fats.

Significant sex differences in the level of liver glycogen in un- fasted rats were consistently noted in the tests on the various fat diets as well as in the control tests with the low fat diet.

BIBLIOGRAPHY

1. Unpublished observations. 2. Butts, J. S., and Deuel, H. J., Jr., J. Biol. Chem., 100,415 (1933). 3. Deuel, H. J., Jr., Hallman, L. F., Butts, J. S., and Murray, S., J. Biol.

Chem., 116, 621 (1936). 4. Mirsky, I. A., Am. J. Physiol., 116, 424 (1936). 5. Deuel, H. J., Jr., Gulick, M., Grunewald, C. F., and Cutler, C. H., J.

Biol. Chem., 104, 519 (1934). 6. Best, C. H., and Channon, H. J., Biochem. J., 29,265l (1935). 7. Good, C. A., Kramer, H., and Somogyi, M., J. Biol. Chem., 100, 485

(1933). 8. Osborne, T. B., and Mendel, L. B., J. Biol. Chem., 37,572 (1918). 9. Deuel, H. J., Jr., Butts, J. S., and Hallman, L., Proc. Sot. Ezp. Biol.

and Med., 32,897 (1935). 10. Deuel, H. J., Jr., and Gulick, M., J. Biol. Chem., 96, 25 (1932). 11. Campbell, J., Am. J. Physiol., 116, 24 (1936). 12. Channon, H. J., and Wilkinson, H., Biochem. J., 30,1033 (1936). 13. Blatherwick, N. R., Bradshaw, P. J., Cullimore, 0. W., Ewing, M. E.,

Larson, H. W., and Sawyer, S. D., J. Biol. Chem., 113,405 (1936). 14. Shapiro, I., J. BioZ. Chem., 108, 373 (1935).

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MurrayHarry J. Deuel, Jr., Lois F. Hallman and Sheila

FASTING KETONURIA IN THE RATRELATION OF FATTY LIVERS TO

STUDIES ON KETOSIS: XI. THE

1937, 119:257-268.J. Biol. Chem. 

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