title experimental study on fat metabolism ......fat metabolism from the view-point of ketone body...

Title EXPERIMENTAL STUDY ON FAT METABOLISM FROMTHE VIEW-POINT OF KETONE BODY FORMATION

Author(s) Hashino, Hiroyasu

Citation 日本外科宝函 (1955), 24(5): 488-511

Issue Date 1955-09-01

URL http://hdl.handle.net/2433/206210

Right

Type Departmental Bulletin Paper

Textversion publisher

Kyoto University

488 目本外科宝函第24巻第5号

EXPEIHMENTAL STUDIES ON FAT METABOLISM FROM

THE VIEW-POINT OF KETONE BODY FOR:¥IATION

by

HIROYASU HASHING

From the Se~ond Surgical Division, Kyoto University Medical School (Director : Prof. Dr. Y AS口MAsAAoY Am)

(Received for Publication : Au5ust 18, 1955)

We have succeeded in the production of a fat emulsion, which consists principally of neutral fat and can be administered intravenously.36> AsADA,5JNAKATA,r.nN1sttrna7°l

and SEN♂ηexamined histo- and biochemically the metabolic process of the fat

emulsion in our laboratory and demonstrated clearly that; the infused fat globules

were五rstphagocytized by the cells of the reticuloendothelial system in the lung,

liver and spleen. The fatty acids, contained in the infused fat emulsion, were oxi-

dized aft巴rneutral fat was changed into phospholipid in these cells.

St.udies on fatty acid oxidation retared in contrast to the advances in the field

of carbohydrate metabolism. More rapid progress has been made since Mu長ozand

LELOIR唱，57，明 appliedwashed liver particles in oxidation of short chain fatty acids.

Studies on long chain fatty acids, however, have been hard1y performed and their

metabolism is still not completely understood. The outline of fat metabolism, which is

generally recognized now, is considered as Fig. I : Fatty acid is converted completely

to 2-carbon fragments viz. acetyl coenzyme A (acetyl-CoA) by successive β－oxida-

tion. A part of acetyl-CoA enters into the tricarboxylic acid cycle (T.C.A. c｝℃le)

and pairs of th巴 partreact together to form acetoacetic acid (ketone body), which

diffuses into the blood stream and is carried to the extrahepatic tissues, especially

muscle and kidney etc.. After the ketone body converts again into acetyl-CoA

and is activated in these tissues, acetyl-CoA enters indirectly into the T.C.A. cycle, in which it is oxidized completely to carbon dioxide and water1・8・13 14 16 30 ・16・川 I，民間，60,102).

All enzyme systems catalizing the reactions of fatty acid oxidation are contained in

mitochondria.

If the changes of blood and urine ketone bodies levels following intravenous

infusion of the fat emulsion are investigated, we shall be able to judge whether

the fat emulsion is utilized effectively and smoothly, and to decide the methods,

by which the administration of the fat emulsion can be most effectively done for

purpose of parenteral nutrition.

MATERIALS AND METHODS

Experimental Animals －耳目lthymale albino rabbits, each weighting appro-

ximately 2 kg, were used. They had been fed by the standard diet for two weeks

and were fasted for 24 hours, being in the post-absorptive state, at the onset of the experiments. In case of necessity, adult dogs or cats were used.

Collection of Urine Specimens - The bladder was completely emptied by

H－〉4v白寸〉回OFHm呂町財O呂古田〈田名七OHZ寸O町内出寸OZ阿国Oロペ吋OHN豆〉ゴ

oz九日∞U

乱、パグ

S

Outline of metabolism of fat and carbohydrate

GLYCERO -PHOSPHATE

Fig・. 1.

490 日本外科宝函第24巻第5号

catheterization before beginning of the experiments. After intravenous administ-

ration of the fat emulsion, the rabbits were kept in cages with urine collecting

apparatus. After 24 hours the rabbits were catheterized again. The sum of the

accumulated urine in the apparatus and the catheterized urine was regarded as the

24 hour urine sp巴cimen.

Fat Emulsion ~－－ In the present investigation, 15 per cent sesam巴oilemulsion

(Emulsion A) was used as a rule. This fat emulsion contains 15 per cent sesame

oil, 7 per cent glucose and small quantities of stabilizers. Its principal fat compo-

nent is neutral fat. In cas巴 ofnecessity, 15 per cent sesame oil emulsion contain-

ing no glucose (Emulsion B) or 15 per cent cod liver oil emulsion (Emulsion C)

was used. The average daily ingestion of fat by japanese p巴opleis 0.5 g per kg

of body weight, as is widely known. The standard dose of the intravenous admi-

nistration of the fat emulsion was defined as 3.3 cc of 15 per cent fat emuls'.on,

which is equal to 0.5 g of fat, per kg of body weight.

Used Drugs一一一 Inthe present inve5t:gation, methionine as 1-methionine, ribo-

fla vin as ribofla vin-5’－phosphate, vitamin C as 1-ascorbic acid, nicotinic acid as

niacin amide, pantothenic acid as calcium pantothenate and vitamin B1 as thiamin

hydrochloride, were used in the formation of the solut"on.

Procedures of Measu1 c111c11t The determination of ketone bodies was made

by the method of GREENBERG and LESTER的 andthe total ketone bodies were ex-

pressed as acetone. Blood sugar levels were measured by the method of SoMOGYI.明

RESULTS

1. Pe1 fusion Experiment of the Isolated Liver

As above mention吋， AsADA,5lIzuKURA,'10J NAKATA67J and SEN68＇】 establishedh;sto-

and biochemically that the infused fat globules were phagocytized by the cells of

the reticuloendothelial system and entered into the hepat:c parenchymatous cells

after lipoidization of neutral fat by t'1e former cells. The present perfusion experi-

ment of the isolated liver, furthermore, ascertained b:ochemically how the fat emul-

sion, which entered into the hepatic parenchymatous cells in the form of phospho-

lipid, was metabolized. Its techniques and condit"ons followed those of SENδ．問 The

isolated livers were perfused through the portal 吋 infor two hours with OHASHI’s

closed system circulator. Defibrinated blood of the same individuals, whose livers

were isolated, ¥Vas diluted three times with modified RINGER’s solution, and 150 cc was used as the circulating fluid (Basic fluid).

Perfusion of Isolated Rαbbit Liver --- As shown in Table I, ketone bodies

levels in the circulating fluid in the perfusion w:th the basic fluid plus Emulsion

A, 1.2 cc increased in contrast to the controls with the basic fluid alone. Perfusions

were made with the addition of methionine, 14 mg and vitamin B 12, 2γ，both of which accelerated lipoiclization of the fat emulsion「町田Jto the basic flu:d plus

Emulsion 入， 1.2 cc. The results in Table II show引lthat ketone bodies levels

in the circulating flu'.d increased slightly in contrast to the perfusions with the basic fluid plus Emulsion A, 1.2 cc .

FAT METABOLISM FROM THE VIEW-POINT OF KETONE BODY FORMATION 491

Table I. Ket one Bodies Levels in the Circulating F'luid of the Perfused Rabbit Liver. (Emulsion A, l.2cc was added to the basic fluid.)

Rematl{s 1 ·~~· I w~＞ifght I －山一 II…Dii~~~闘訓 it liver 0 I 15 I 30 I 60 I 90 I 120 I I control

~ I 7寸lf~γア刊日：；11 高；；「Basic fluid

Basic fluid +

Emulsion A

(I.Zee)

Remarks

Basie fluid +

Methionine +

V. B12

Basie fluid + Emulsion A+ Methionine +

V. Bia

6

8

9

マfnuoo

pDFDCO

0.18 I 0.29 I 0.41 i 0.18 I r.oo I i.30 I u2

::: I ::: I ::: I ::: I ::: I ::: I :::

。63

o.94 I 1.33 ! 1.98 戸、υco n

a

ρL

，叶晶、山 0.14 0.29 2.63 1.51 2.77

Perfusion of isolated Cat Liver一一 Isolatedlivers from adult cats, ranging in

weight from 2.5 kg to 3.0 kg, were perfused as well as rabbits. Perfusions with the basic fluid plus Emulsion A, 2 cc or 3 cc showed the results in Table III that

increase in ketone bodies levels in the circulating fluid was more remarkable than

the controls with the basic fluid alone. Slight increase in ketone bodies levels was

observed even in the controls probably by reason of the fact that fatty acids, which

were contained physiologically in the liver and blood, were oxidized.

From these results and previous reports from our laboratory／・刊明 weare able to

postulate that the fat globules added to the circulating fluid were phagocytized by

KUPPER’s cells, in which they were chang巴d into phospholipid and thereafter a

part of the fatty acids contained in the infused fat emulsion entered into the T.C.A.

cycle via the stage of acetyl－じ01¥. Pairs of the surplus acetyl-CoA react together

to form acetoacetic acid which <Hfuses into the circulating fluid. Accordingly these

results in the present perfus'.on experiment indicate that the fat emulsion can be

第5号第24巻日本外科宝函492

Ketone Bod・ies Levels in the Circulating Fluid of tile Perfused Cat Liver.

(Emulsion A, 2cc or 3cc was added to the basic fluid.)

Table Ill.

1

2

3

5

7

一竺

' I Diff巴renceIncrease I from

I control

mg/dl I mg/dl 0.92

1.28

1.74

2.29

1.00

-, 1.44

120

mg/di 1.38

1.38

2.10

2.75

1.36

90 I mg/di 1.12

0.92

1.94

2.10

0.86

bdM

h－E

C

fluid

Remarks

Basic

。8.11

8.30

8.29

1.79

8.57

8.76

8.75

1.39

7.31

6.37

5.51

4.13

4.38

l.13

oonUTム

44aA

噌E4

Basic fluid +

A Emulsion

6.79 8.23

7.40

10.35

8.74

8.69

7.60

10.45

9.10

6.40

5.82

6.37

6.12

4.21

5.20

l.91

5.96

2.60

1.17 I 2.38 ]

0.20

0.10

0.36

90

102

117

106

n

a

e

T『ム

、店

12

13

It

I :¥lean j

( 2 cc)

Basic fluid +

A Emulsion

7.39 8.83 9.05 6.10 5.35

Fig・. 2. Influenc巴 ofvarious drugs on ketone body formation from the fat emulsion by perfused cat liver.

0.22 108 ( 3 cc)

oxidized by the hepatic parenchy-

matous cells. As compared with

the results in the cat and rabbit,

the former viz. carnivore is stronger

in the ability to dispose of fat than

the latter viz. herbivore.

The results in Table IV and Fig. 2 were obtained by perfusions

with the addition of methionine, 14

mg and vitamin B12, 2γto the

basic fluid plus Emulsion A, 3 cc.

Ketone bodies levels in the circulati-

ng fluid increased more significantly

than those in the methionine cont-

rols or in perfusions with the basic

fluid plus Emulsion A, 3 cc(Table

IV and Fig. 2). Since methinoine

is not a ketogenic amino acid,8・18"・1)

it is accepted, as mentioned by Senδ

町， thatmethionine and vitamin B12

accelerate lipoidization of neutral fat

by KUPPER’s cells and secondarily

/)

。i. r入↑ E¥!U［ぷHlN(2cc) 2. FAT E¥[lfJぷflJN 13cc) 3. FAT r:¥rUJぷlllNr3ccJ +¥IETJIIC!:¥IJ¥E 4. FAT Ei¥llfL::->Ir l;¥; I 3cc) +RIBOFLAVIN 5. FAT E¥IUIぷI<JN 13cc〕＋RIBOFLA VI!¥ +

ASCORBIC ACID

ID

s

『也、、Eq、Anv

、、hw＼ミa

ヘ句、〉＼＼九可

Mwq

句、U＼て、


Table N. Ketone Bodies Levels in the Circulating Fluid of the Perfused Cat Liver.

(Emulsion A, 3cc, m巴thionine,14mg and vitamin B12, 2y were added to the basic fluid.)

Remarks

Basic fluid +

Methionine +

V. B12

Basic fluid +

Emulsion A+

Methionine +

V. B1:1

No. I Weight of I of cat I liver a I

mg/di 0.20

0.20

0.54

0.31

Time of perfusion (min.)

~111~日dllti ~I 1.37 。“一

PDF01A

一日U

FD↑

F口

ワuRu

一pb

－

一

－

－

－

－

－

3

一1

6

5

一4

－I

l

l

－－

Difference Increase I from

control

mg厄日一元7d「3.68

2.53

円五l 0

11.30

15.80

15.71

i山 1 I 11.06

Table V. Ketone Bodies Levels in the Circulating Fluid of the PeグfusedCat Liver.

(Emulsion A, 3cc and riboflavin, 5mg were added to the basic fluid.)

Remarks

Basic fluid +

Riboflavin

Basic fluid +

Emulsion A+

Riboflavin

Weight of

liver

g 84

128

80

1.70

0.36

0.46

0.10

0.31

。目93

1.27

1.27

2.86

3.10

3.36

1.16 3.11

Difference fo.creas巴Ifrom

control

mg/di I mg/di 2.35

2.10

2.46

No. I Weight of I of cat I liver

Ascorbic acid 1 1

Mean I 108

Basic fluid + I 37 I 86

Emulsion A + I 38 I 95

Riboflavin + I 41 I 90 Ascorbic acid ｜一一一一一1一一一

' an I 90

Time of perfusion (min.)

L己i三1とと上~I

~＇ I ~II ~＇ I m'l~r 120

mg/di ・ 2.45

2.29

2.91

97 0.25 I 0.33 I 0.78 I 1. 73 I 2.33 I 2.55 I 2.30

0.68

0.68

0.64

・0.67

o I mg/di 0.64

0.64

0.45

1.31

1.17

1.41

2.41

2.17

2.44

3.79

3.59

5.94

5.40

6.78

6.72

1.30 6目30

。7.75

7.66

8.72

7.07

6.98

8.08

5.07 2.34 4.44 8.04 7.37

Table VI. Ketone Bodies Levels in the Circulating Fluid of the Perfused Cat Liver・

(Emulsion A, 3cc, ribof!arin, 5mg and ascorbic acid, 25mg were added to the basic fluid.)

Remarks

Basic fluid +

Riboflavin +

。目58

0.45

0.73

0.68

0.62

。


expedite fatty acid oxidation by the hepatic parenchymatous cells.

Perfusions with the addition of riboflavin, 5 mg to the basic fluid plus Emulsion

A, 3c心， orwith the addition of riboflavin, 5 mg and ascorbic acid, 25 mg to the

basic fluid plus Emulsiou A, 3 cc were made. As shown in Table V, VI and Fig.

2, increase in ketone bodies levels in the circulating fluid was slightly less than in

perfusions with the basic fluid plus Emulsion人， 3cc alone. These results indicate

that the liver weakly utilizes ketone bodies65，問 andthat its action is intensified to

some degree by the addition of these enzyme systems, which are concerned in fat

metabolism.

2. Intravenous Administration of the Fat Emulsio仰

（α） Single I仰fusion仇toRabbits

Intravenous Administration of Fat Emulsion Alone - Since Emulsion A

contains 7 per cent glucose, blood ketone bodies levels and their urinary excretion

following intravenous administration of 3.3 cc of 7 per cent glucose solution per kg

of body weight were measured as controls for the present single infusion experiment.

The results are recorded in Table VII and Fig. 3 ; blood ketone bodies levels fluc-

tuated slightly within a range of I r時／dland increased by 30 per cent over pre-

experimental l巴vels24 hours after infusion. Therefore it was demonstrated that

blood and urine ketone bodies were not influenced by the collection of blood speci-

mens in the present investigation.

When the standard dose of Emulsion A was administered intravenously into

rabbits, blood ketone bodies began to increase 6 hours after infusion and reached its

maximal level 12 hours after infusion. Thereafter the level decreased and were

Table Vll. Ketone Bodies Levels Following intravenous Infusion of 7 Per Cent Glucose Solution (3.3cc per kg〕w Emulsion A (3.3c・c.per kg).

R巴marksNo. of

rabbit

Control (7 per

8

1

2

5

7ム

つ

臼

nL

つ＆cent glucose

solution)

い干し一Emulion A

(3.3cc per kg.)

! Cha時 c（九）｜


Table珊. Ket one Bodies Levels Following Intravenous I作fusionof E例 ulsionA or E例 ulsionC.

Remarks No. of

rabbit

Emulsion A

nwdnuqdnnu

ηLqJη3η3

(1.7cc per kg.)

Mean 1 Ch叩（%）｜

(6.6cc per I Mean I

丙ふ玩l

Emulsion A

Emulsion C

RUQunu

ワ白

qoqJdazaaτ (3.3cc per kg.)

Mean

I Ch叩（%）｜

Blood I Urine

0 I 1hrs.13hrs.1伽hrs.I 9hrs. IロZhrs.j 18hrs. [ z4hrs.

mも（ff~I mも（ffJim1句lm1:iJlm1匁Im号：~~I m1：~il m1：~~I m1:g~1 「~£g1 I d ~ ：~ 0.921 1.621 2.111 1.071 1.681 1.531 1.751 1.561 1.30 I 1.69

~：~~I ~： ~~I ~：：~1 ~：：：1 ~：~~I ~：：~1 ~：：~1 ~：~！ I ~：：~ 0.121 0科 1.261 1.741 I叫 1.611 I吋 1.751 1.581

o I + 15J + 751 + 14zl ＋叫＋叫＋1261 ＋吋＋叫

~ ~ l! i~~ i~ i~ ~~~~ii 0.761 1.251 1判 2.141 2.411 2叩 I2.同 2.371 2.271 3.07

o I +641 ＋以＋問21+2付＋2031＋判＋叫＋判

0.62[ 1.261 1.561 2.付1.561 1.691 1.921 2.491 1九o I + 1州＋叫＋叫＋叫＋I可＋州＋3021 + 119:

3.40 3.10

3.94 2.84

3.32

slightly higher than the controls 24 hours after infusion. The urinary ketone bodies

excretion was far more than that in the controls(Table VII and Fig. 3). Following

the intravenous administrafon of a half or twice of the standard dose, blood and urine

ketone bodies levels fluctuated correspondingly without abnormal deviation (Table VIII). Instead of Emulsion A, an equivalent dose of Emulsion C was administered

intravenously. The results are shown in Table VIII. Blood ketone bodies levels

increased early after infusion, with marked fluctuations, and showed as high as

three times of the pre-experimental levels 24 hours after infusion. KENNEDY and

LEHNINGER4の foundthat short chain even cabon fatty acids formed chiefly acetoacetic

acid in the liver, while long chain even carbon fatty acids yielded chiefly carbon

dioxide under identical conditions. Short chain fatty acids are obligatory ketogenic,

1 and long cha!n fatty acids are facultative ketogenic.';i・7川 02J Since cod liver oil contains

large quantities of short chain fatty acids in contrast to sesame oil, the above results

would be obtained. It should be also considered that short chain fatty acids are

directly oxidized in the tissues while long chain fatty acids are able to stored in fat

depots. 14, 18,81,82)

普 Simulta抑制SI山側 ofVarious Drugs wi山 tヤFatEmulsion - Previous

reports from our laboratory5・r;7，問 andthe present pertusion experiment demonstrated


that methionine accelerated phagocytosis and lipoidization of the fat emulsion by

the reticuloendothelial cells and secondarily expedited fatty acid oxidation in the

hepatic parenchymatous cells. Furthermore, TsuKADA,96' 0sA,73i NISHINo'0l and TAKEDA

"'' reported that the intravenous administration of the fat emulsion was made nu-

trit:ously effective by the simultaneous administration of riboflavin. After phos-

phorylation in the intestinal mucosa, riboflavin synthetizes flavin adenine dinucleotide

(F.A.D.) chiefly in the kidney and liver10'l. Riboflavin is biochemically active

only in the form of F.A.D. or flavin mononucleotide (F.M.N.). In vivo the major

part of riboflavin is present in the form of F.A.D., while F.M.N. is found in small

quantities and fr巴eriboflavin is the least quantity.2"1'5J Therefore it is expedient that

F.A.D. or at least F.M.N. is infused simultaneously in the case of intravenous ad四

ministration of the fat emulsion, but at pr巴sent pure F.A.D. is expensive to

produce. Since riboflavin-5’－phosphate synthetized by FLEXSNER and F ARKAs24> is identi-

cal to F.M.N., riboflavin四 5’－phosphatesodium solut;on was used in the present investi-

gation. Recently NATH and CHAKRABARTI叫 reportedthat rabbits receiving continuous

injection of sodium ac巴toacetateand β－hydroxybutyrate for three months showed

a state of riboflavin and nicotinic acid defficiency. HrKASA and IsHIGAMI3a-a) observ-

ed that simultaneous infus:on of ascorbic acid with the fat emulsion was effective

in aiding metabolism of the infused fat emulsion as a result of intensification of

activity of lipase in serum and the liver. In fatty acid oxidation, as above men-

tioned, fatty acid is oxidized in the form of derivatives of coenzyme A by succesive

β－oxidation, and consequently is converted to acetyl-CoA,1・9・'7・58・ao，附 whichenters into

the T.C.A. cycle by condensation with oxaloac巴tic acid. It has been established

that in turn of T.C.A. cycle α－ketoglutaric acid converts to succinic acid via

succinyl四 CoAby combination with coenzyme A and by oxidative decarboxylation2"・4ラ，

'"' Pairs of the surplus acetyl-CoA, unable to enter into the T.C.A. cycle, react

together to form acetoacetic acid (ketone body), which diffuses into the blood stream

and is carried to the extrahepatic tissues. In these tissues ketone bodies convert

Fig. 3. Changes in blood ketone bodies levels following again into acetyl-CoA and indirectly intravenous infusion of the fat emulsion.

400

ト－

~ 300 ιJ

内

HunU

44

包凶

azw

~ 100 工仁J》

．』ー－－. CONTROL

←＿＿＿. FAT EMULSION

~FAT E門ULSION＋阿ETHIONINE+RIBOFLAVIN+ NIACIN A附IDE+ ASCORBIC ACID+ PANTOTHENIC ACID

enter into the T.C.A. cycle.32,s• r.3,01，＂＇〕

Therefore coenzyme A plays a very

important role in fat metabolism.

It is evident from the studies of Lr-

PMANN and his co-workers"2・7" that

pantothenic acid is a chemical com-ponent of coenzyme A.

According to the above mention-

ed reports, the author investigated

how the metabolic process of the

fat emulsion was improved by the

simultaneous infusion of the follow-

ing drugs. Methioninene, 5 mg,

497 FAT METABOLISM FROM THE VIE¥V-POI:¥T OF KETO?¥£ BODY FORMATION

Effect of Si附 ultaneousInfusion of Various Drugs with the Standard Dose of E例 ulsionA. (Each values show mean of four samples.)

Table JX.

！山…l~~~l !2h~l 18h~ I

皐型1°~1 斗；：：i ヰ：：｜二；；I +2~~~1 +1~~； 1 +

~：~~；~：~n A + ！~＿h~！~€／~！~ J! o.~61 ：·~；1 :;t当」；；I~－：~＼ :・：~＼：－~；＼：－：~＼ z.おノこ：ご：：ご：~d+ I忠諜1t~ ） 1 ~二：：~~三：~互I~~；ヒア瓦立：：L：」；《ii

語＝子I~話引1－~~！1 王｜司；：：~同［三；｜斗 2.222

I

誌~~＼i~~~~ : \c:t：~1t~ ） 1 o.7:1 ＋＼~~1 ：－~~！ ~－~：1 ：－ ~~1 ~－~：！：·：~i ＋＼~：！ +

踏？三λ：暑tll)I'':I ~：：； ':: :::1 ：：~ ~：：1 ・1;::1 .¥::1 ：~：i '°' ｜ ~~~；配d: I品t~） I os:I ：：~ :I:r止一＋：；；器~措苧宇le空鍔司三；l王~l~I~ ~：：［・1;::¥ ：~

的）i＿士山I:::[ ::l .!;::[ .l;:f +I中：i1.77 I 1 . 58·－~

1.87.

1.52

1.18

1.97

2.21

1.94

2.22

1.31

。No. of

rabbit

Emulsion A + I

Methionine

Remarks

riboflavin, 2 mg, ascorbic acid, 10 mg, niacin amide, 4 mg and pantothenic acid, 5

mg per kg of body weight were administered intravenously into rabbits in various

combinations. The results are presented en bloc in Table XI and Fig. 3. The metabolic

process of the infused fat emulsion improved merely by the simultaneous infusion of

methionine, riboflavin and ascorbic acid with the fat emulsion, in consequence, urinary ketone body excretion decreased markedly. The decrease in blood ketone bodies levels,

however, was insufficient. Further addition of niacin amide and pantothenic acid to

these three drugs was necessary. Thus blood and urine ketone bodies presented no

significant difference from the controls. It is accepted that fatty acids, contained

in the infused fat emulsion, enter into the T.C.A. cycle, in which fatty acids are

finally oxidized by means of action of these drugs with the most nutritious effect.

’

iztf

第5号

Repeated Infusions into Rabbits

Each of the following series of drugs wer巴 dailyadministered intravenously for

20 days into normal rabbits fed by the standard diet under identical conditions as

the single infusion experiments ; 7 per cent glucose solution, Emulsion A alone,

simultaneous combinations of the above mentioned various drugs with Emulsion A.

Similar results to those in the single infusion experiments were obtained (Table X,

XI, XII and XIII). As shown in Table XIV the rate of body weight gain in the

group, which was given simultaneous infusions of methionine, riboflavin and ascorbic

acid with the fat emulsion, was higher than that in the group of infusions of the

fat emulsion alone. In the group given the simultaneous infusions of methionine,

riboflavin, niacin amide, ascorbic acid and pantothenic acid with the fat emulsion

the rate of body weight gain was the highest. According to these results, the im-

第24巻日本外科宝函

(b)

498

Ketone Bodies Levels Following Daily Intravenous Infusions of 7 Per Cent Glucose

Solution (3.3cc per kg〕for20 Days.

Mean

mg/di

。目92士0.068

1.06

1.00

0.90

0.83

1.18

0.89

0.58

0.68

1.74

0.89士0.053

20

mg/di 1.16

0.45

0.45

16

mg/di 1.16

1.33

1.15

12

mg]{il 0.45

0.45

1.50

mg

2.22士0.110

mg 2.65

2.80

1.62

mg 2.24

3.54

2.05

mg 1.62

1.63

3.48

Table X.

t

－b

Lυ a

TA

P＋A

O

O

N

可。D【凶

mg 2.28

2.11

1.82

mg 1.40

2.28

1.74

nunLPO

唱

4

7

8

r・・・

r

1

2

0

102

103

105

己DZU』UH一同

U

ロロD

一一

Mean

1.05土0.054

5.26士0.444

mg/di

1.87士0.133

市

DD

－mH

む口市』己

499

m耳／di I mg/dl 0.82 !

0.58 !

1.42 j

FAT ¥IETABOLISM FROM THE VIEW-POINT OF KETONE BODY FOR¥L¥TION

Table XIJ. Ketone Bodies Levels Following Daily Simultaneous Infusions of Methionine (Smg per kg 1, Riboflavin (2例 g per kg) and Ascorbic Acid (10刑 gpeγ kg) with the Stan-dard Dose of E例 ulsionA for 20 Days.

No.…・I

qd4L’

m（仙

！

i1nc

例制

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M

L

e

n

nhugJ

－muA月

nυ

n

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品

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一

，，

w

u

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L

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f

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llili－

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一

一

一

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yTM

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－

1

t

一心6

4

9

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2

2

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f

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t

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s，iリ

一｜｜IT－－

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恥

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d

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99673507

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j

ド

S

一

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：

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＝

H

M

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－－回以一－

M

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A

k

d一

＝

（

〔

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；；

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cy

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z－－

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lt・H

b

p

マ】仰

g

ra－－e

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μ

A

5

a

t

D

L

d

y

Q

M丸

町

h

A

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・ぱ

M

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W

E

rk

削

，M叫

n

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何

MP町

LbdD

ωげれ山

m

・4eLula

－－S

）

’

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Rgm

B

u

h

f

wωwuA

加

h

p

n

evFOdO

Kμ例．口

市阻V

A

aiw Lu a

T

¥lean 12

mg/di 0.85

1.16

0.58

of

MU926

8才JJι6

叫

1

1

0

4

mg/di 1.45

1.42

1.30

0

mg7dl 0.20

1.13

1.16

107

108

111

可。。－伺 1.03土0.066

J.16

J.15

1.29

1.06

1.07

0.66

1.07

J.06

1.17

0.96

0.56

0.43

107

108

111

さ｜包；：： I E・；：； I O~I υ口｜

1.00土0.033

mg

2.43土0.101

mg 3.98

2.68

1.52

w

’Rvqd40・

叫叫勾

tRuqa

rnLnLnru

百Jg2.11

J.68

1.16

107

108

111

EOZU』uuh凶

ω口市aHhH

Mean

1.12土0.066

4

mgfdl 1.40

0.94

1.03

1.17

0.45

0.44

o I mg/di 1.16

1.16

1.30

0.43

0.70

I.06

No. of rabbit

唱。ロ－m

0.83士0.071

1.78土0.151

ロJgmg 1.49

2.00

1.49

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凋体企

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r14Tム

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v，。，uoOAU

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109

110

112

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hp

role in fat essential an portance of these vitamins, which were considered to play

metabolism 仰 vitro,was established also in vivo.

Examination on the Relationship between Carbohydrate and Fat Metabolism

Recently, according to studies on the T.C.A. cycle, it has been clarified that three major foodstuffs enter into this common metabolic pathway to be oxidized finally. It has been found that acetyl-CoA formed by fatty acid oxidation conden-ses with oxaloacetic acid to enter into the T.C.A. cycle.附 Therefore,when the fat

emulsion is administered intravenously, we must of course examine its relationship to carbohydrate metabolism, particularly, whether the intravenous administration of

the fat emulsion is likewise nutritiously effective or not in a state of disturbed car-

3.


Table XIV. Changes of Body Weight in the Repeated Infusions.

Remari's No. of rabbit Initial Final Increase (mean)

g g g per cent 100 1,700 2,000

Control 103 1,700 1,950 270 15.2

105 1,850 2,100

101 1,750 1,950

Emulsion A 102 1,750 2,150 260 15.1

104 1,800 2,000

Emulsion A + Methionine + 107 1,750 2,050

108 l,750 1,950 300 17.6 Riboflavin + Ascorbic acid 111 1,600 2,000

Emulsion A + ¥Iethionine + 109 1,700 2,100 Riboflavin + Niacin amide + 110 1,600 1,950 320 18.8 Ascorbic acid + Pantothenic acid 112 1,750 1,950

bohydrate metabolism. If not nutritiously effective, it is very important for the

further clinical application of the fat emulsion that we correct its defects. In this

case Emulsion B was generally used. In case of necessity, the addition of glucose

was made at various rate.

（α） Ketone Body Metabolism in Closed Circuit Anesthesia

It has already been observed that ether anesthesia causes not only hepatic da-

mag巴2・"'1land accumulation of carbohydrater.・7・21・・1s) or fat intermediates11・1"・""・77・"0 in bood,

but also disturbance of protein metabolism.問 Adult dogs each weighting approxi-

mately 10 kg were used. After basic narcosis with 2 per cent narcopon, 1 cc and

induction of anesthesia with 2.5 per cent pentothal sodium solution, 7 to 10 cc,

closed circuit anesthesia with ether was performed at third stage, second plane for

four hours. Blood ketone bodies levels, as shown in Table XV. increased remarkably not only during but after anesthesia. KUROKAWA刊 reported that blood levels of

pyruvic acid and lactic acid also increased in these cases. These facts indicate that

disturbances of carbohydrate and fat metabolism are caused by ether anesthesia. After

thiamin, 1 mg per kg of body weight, was subcutaneously injected into dogs, closed

circuit anesthesia was performed as described above. The results are shown in

Table XV ; blood ketone bodies levels markedly diminished as well as carbohydrate int巴rmediates.向 Whenriboflavin, 1 mg and ascorbic acid, 10 mg per kg of body

weight were subcutaneously injected into dogs before anesthesia, blood ketone bodies

levels decreased as in the case of thiamin injection (Table XV). On the contrary,

carbohydrate intermediates accumulated.18) Prior injection of these three vitamins,

as shown in Table XV, could prevent th巴 occurenceof not only of carbohydrate

but fat metabolism.

It is evident, however, from Table XVI that this result is applicable only in the

case of normal dogs but is not applicable in th巴 case of dogs, in which glycogen

FAT METABOLISM FROM THE VIEW-POINT OF KETONE BODY FOR¥IATION 501

Table XV. Blood Ketone Bodies Levels i冊 Anesthetized.¥'ormal Dogs. (Various drngs were injected previol1sl y.)

!No.吋 :ef：~t I 日記 I 0

Lt!1 ~I ~＇ bf bf~ ~1ean I 0.92 [ 1.14 I 2.78 2.37

! o I + 24 i +2位！二竺L

M削 1 o.88 I 1.33 I 1.41 I 1.86

~ ,E I :: I :] I : :: I :¥, I ~ Mean ¥ 0.89 ¥ 1.38 ¥ 1.30 ! 3'.

Change，抑戊nt一一L o I + ss I + 46 I + 2仁

一一 Mean j 附 1 1.10 I 1.00 I 1.01

Change，阿 c~nt I 0 I + 28 I + 16 I + 24

Remarks

Control

Thiamin

Riboflavin +

Ascorbic acid

Thiamin +

Riboflavin +

Ascorbic acid

d仏τFhυ

ワt

nvnUη’h

1

1

Table XVI. Blood Ketone Bodies Levels in Anesthetized Starved Dogs. (Various drngs were injected previol1sly.)

! J Body Remarks ,No. of dogl

局I eight

I I kg I 16 I 8.5

Thiamin + I 17 I 10.0

Riboflavin + I 18 I 9.3 Ascorbic acid I Mean

Thiamin +Riboflavin

+ Ascorbic acid +

20% glucose solution

Used ether じ」三三｜二hrs~Jとr二

I ~：~~ I ~：~~ I ~：~： I ~： 1~

piur

、upnur町u

cnLnLnL

19

20

問下！…1一

30

30

¥Iean

Change, per cent


depots appeared to be exhausted after fasting for 5 days. When subcutaneous in-

jection of these three vitamins and 20 per cent glucose solution was made 30 minutes

before anesthesia, as shown in Table XVI, blood ketone bodies levels did not increase

without accumulation of carbohydrate intermediates州 even in the case of starved

anesthetized dogs. These results indicate that disturbance of fat metabolism in

closed circuit anesthesia is a secondary change due to defective carbohydrate meta『

bolism. Therefore the injection of thiamin into normal dogs or that of both thia-

min and glucose into starved dogs, in which glycogen depots were diminished, was

made. Carbohydrate metabolism was improved and the formation of oxaloacetic

acid, which was necessary for entrance of acetyl-CoA into the T.C.A. cycle, was

accelerated. This then represents a radical method for the improvement of distur聞

bances of both carbohydrate and fat metabolism in closed circuit anesthesia. If

possible, simultaneous injection of riboflavin and ascorbic acid is preferable. These

results demonstrate in vivo that carbohydrate and fat metabolism are closely relate

to each other.

(b) Is Simultaneous Infusion of Glucose Necessary or not for the Intravenous

Administrαtion of the Fat Emulsion into Normal and Stαrved Rabbits ?

In八Tormal Rabbits一一一 Viewedfrom the point of the decrease of blood ketone

bodies levels and their urinary excretion, the simultaneous infusion of the above

mentioned drugs with Emulsion え wasmore than that with Emulsion B, while

in the case of the infusion of the fat emulsion alone there was no significant diffe戸

rence between these two fat emulsions (Table XVII). Accordingly, application of

the emulsion containing 7 per cent glucose (Emulsion A) is necessary for the in-

n－ 5・m一10

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一

一

一

一

一

M

U

D

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一

dl必

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即

日

一

回

一

0

一目白山

ω必一

η一O

FIs－

－

o一／

an仏。仏一

ι一

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J

M

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一

一

m

一

一

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8

9

7

8

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0

1

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一

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一

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一

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3

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一叩ρ

U

M一一N0・山↑

1

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1

1

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G

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出

。

一

一

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一

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K

L

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W

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e

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T

Remarks

Emulsion B

Emulsion B +Me-thionine + Ribofl-avin +Niacin am-ide +Ascorbic ac-id + Pantothenic acid

3.53 3.19

1.95 1.95

2.58 2.05

1.79 1.97

4.57 2.28

2.72 2.06

FAT METABOLISM FROM THE VIEW-POINT OF KETONE BODY FOR'.lfATION 503

travenous administration into normal rabbits.

In Starved Rabbits一一一 Intotal starvation glycogen depots are first exhausted

and animals derive energy from both fat anq protein. In this state the liver oxidizes

successfully fatty acids mobilized from fat depots.74) Moreover, carbohydrates, espe-

cially oxaloacetic acid, which is necessary for direct or indirect entrance of large

amounts of formed acetyl-CoA into the T.C.A. cycle, has been already lacking.

Accordingly blood ketone bodies levels and their urinary excretion increase. When

fat depots are exhausted, the format;on of ketone bodies decreases and destruct=on

of tissue protein occurs rapidly and intensely.74) Of course, patients with malnutrition

are the object of our clinical application of parenteral nutrition with the fat emul-

sion. In these cases we can not determine the dose of the fat emulsion on the

base of the results only in normal cases. This problem was ascertained experi-

mentallv.

Since the hepatic glycogen content reaches the minimal level in 5.5 th day of

starvation ，~5，粉 fasted rabbits for 5 days were used in the present starvat：・on expeτi-

ment. RINGER'S solution, 3.3 c心 perkg of body weight, was administered intrave-

nously into starved rabbits as the controls. It was observed that one group showed

high blood ketone bodies levels and another showed relatively low (Table XVIII).

It was thought that the former group had preserved fat depots, while the latter

almost had more nearly exhausted them. Each of the following combinations were

intravenously administered into starved rabbits. Emulsion A alone, Emulsion B alone,

and the simultaneous combinations of above mentioned various drugs with each of

these two fat emulsions. Marked decrease in ketone bodies levels was not observed

(Table XVIII, XIX). Not only methionine, 5 mg, riboflavin, 2 mg, niacin amide, 4 mg,

Table X咽. Effect of Addition of Glucose to the Fat E例 ulsionon Blood Ket one Bodies Levels.

(Ringer’s solution or the fat emulsion was intravenously administered into starved rabbits.)

Ringer’s solution

135

136

141

一d02FU

G

－U5

3

5

間

1

1

0

mg河「1.66

1.07

Time after infusion (hrs.〕

3 / 6 I 9 I 12 i mg/dl I mg/di I mg/dl I mg/dl ' 1.63 I 2.09 I 1.96 I 1.03

1.76 I 1.71 I 1.72 I 1.52

1.19 I 1.14 I I.08 I 1.42

1s I

mg/di 1.68

1.14

1.18

24

mg/dl 1.93

0.95

0.99

Remarks No. of

rabbit

Emulsion B

同一

fjfMEL－恥

Emulsion A


Table X医. Effect of Addition of Glucose and VaパousDrugs to the Fat Emulsion ・on Blood

Ket one Bodies Levels.

(Vari附 d叩 W町 intravenou均 administe:ed~n;t伽ieo口市 with ) the standard dose of Emulsion A or Emulsion B into starved rabbits.,

Time after infusion (hrs.) Remarks

No. of

rabbit 3 I 6 I 9 I 12 I 1s 」I~＿

~＇ I ~＇ I Tir ~， 1－~1 ~， EmulsionB +Methionine+

Riboflavin+ Niacin amide

+Ascorbic acid + Pantoth-

enic acid

145

146

152

Mean

153

155

156

~＇｛f I Tif 1.63

1.60

1.45

1.82

1.54

1.45

1.12

1.18

1.53

1.08

1.35

1.59

1.71

2.08

1.78

1.18

1.70 I 1.27

1.05 i 2.09

2.93 i i.90 1.60 I 2.11

1.94

1.68

1.68

1.68

1.93

1.62

1.05

2.18

EmnlsionA + Methionin巴＋

Riboflavin+ Niacin amide

+Ascorbic acid+ Pantoth-

enic acid i.62 I i.25 I 1.34 戸ムド~I 2.03 I 1.68口Z

EmulsionA +Methionine+ I 160

Riboflavin+ Niacin amide!. 162

+Ascorbic acid +Pan to th-1 1 1 I 165 I 1.72 I 0.68 enic acid + 20% glucose I --i-一一一一-isolution I Mean I 1.44 I 0.65

1.11

1.05

0.46

0.87

1.43

1.19

1.63

1.42

1.71

1.08

1.18

1.32

Table XX. Blood Sugar Levels in Staγved Rabbits. (All values are in milligram per cent. I

1.71

1.86

1.68

1.75

Remarks I ~~bb~： I 0 11 hrs. J 3 hrs. [ 6 hrs. I 9 hrs. ¥ ~2－~~s-118 hrs. f 24 hrs.

135 60 60 53 60 55 60 50 55

Ringer’s solution 136 58 98 56 58 68 55 54 56

141 60 70 65 70 58 60 60 50

137 59 167 52 77 60 72

Emulsion B 138 105 94 56 49 50 50 61

139 70 72 65 70 65 45 60 50

140 70 72 90 70 70 85 45 70

Emulsion A 143 99 69 80 113 90 90 50 128

144 88 105 105 82 88 116 60 80

EmulsionB +Methionine+ 145 46 46 50 82 92 53 60 60 Riboflavin+ Niacin amide 146 78 95 78 72 54 68 65 55 +Ascorbic acid+ Pantoth-enic acid 152 54 57 68 48 50 50 52 50

EmulsionA +Methionine+ 153 76 114 80 57 54 68 70 57 Riboflavin+ Niacin amide

155 57 90 50 50 48 50 60 46 +Ascorbic acid+ Pantoth-enic acid 156 63 80 50 53 53 57 60 63

EmulsionA +Methionine+ 160 63 206 74 63 46 52 60 63 Riboflavin+ Niacin amide

+Ascorbic acid+ Pantoth- 162 70 175 80 80 57 60 52 55 enic acid + 2.0% glucose

165 60 170 80 80 87 solution


15corbic acid, 10 mg and pantothenic acid, 5 mg but also 20 per cent glucose solution,

3.3 cc and thiamin, 2 mg per kg of body weight were intravenously administered

;imultaneously with the standard dose of Emulsion A. Blood ketone bodies levels

.ncreased slightly after a remarkable decrease, but there was no difference from the

:ontrols. These results are summarized in Table XIX. In Table XX the blood sugar

levels in the present starvation experiment are recorded.

When the standard dose of 15 per cent sesame oil emulsion is intravenously ad”

ministered into normal rabbits, the addition of 7 per cent glucose is sufficient, and

in starved rabbits the addition of larger quantities of both glucose and thiamin is ne-

:essary. Obvious results as in the case of closed circuit anesthesia were not obtained

in the present starvation experiment. This is possibly because of the uncertainty of

the experimental conditions, and also suggests that oxaloacetic acid, which is nece-

悶 ryfor entrance of acetyl-CoA into the T.C.A. cycle, are also formed from some

amino acids. Since protein metabolism is disturbed to some degree in ether anesthe-

;ia,30' it is surmised that in ether anesthesia deficiency of oxaloacetic acid is present to

a higher degree than in starvation.

DISCUSSION

While all short chain fatty acids convert to ketone bodies in the liver,4"・74> long

chain fatty acids are metabolized through the following three path ways.

(1) transported to fat depots30，剖】

(2) oxidized by the extrahepatic tissues伐町

(3) after conversion to acetyl-CoA in the liver, a part of acetyl-CoA is imme-

diately oxidized in the liver and pairs of major part of acetyl-CoA react together

to form acetoacetic acid, which diffuses into the blood stream. Both acetyl-CoA

and ketone bodies are carried to the extrahepatic tissues, where they are finally

oxidized.刊，M>Accordingly the process of fatty acid oxidation divides into direct oxi-

dation, in which fatty acids are directly oxidized in the tissues,28"'' and indirect oxi-

dation, in which they are oxidized finally in the extrahepatic tissues after conversion

to ketone bodies.10・1訊仏国，的 CHAlKOFFand his co-workers均 foundthat aft巴rintravenous

injection of C 1仁labeledtripalmitin emulsion into hepatectomized dogs, the conversion

of C1402 was less than 40 per cent of that in normal dogs. This fact illustrates

that less than 40 per cent of the infused radioactive palmitic acid is oxidized direct-

ly by the extrahepatic tissues and more than 60 per cent of that is first disposed

in the liver. The liver has been considered as the chief site for the formation of ketone bodies

according to various experiments applied liver slices!3・＂山』...~ . 4 3.民，，， .附J問 living animals

10 and perfusion techniques of the liver.叩，onAll these experiments, however, were

performed using free fatty acids, especially their esters of short chain fatty acids.

In the pn:sent perfusion experiment with sesame oil emulsion containing triglycerides

o~ long chain fatty acids, it was also found that ketone bodies were formed chiefly

in the liver. On the basis of the results of the perfusion experiment and intrave-

nous administration of the fat emulsion and those of previous reports from our labo-

506 日本外科宝画第24巻第5号

ratory, the metabolic pathway of the fat emulsion has been clarified. Considerable

lipemia is observed t巴mporarilyfollowing intravenous administration of the fat emul-

sion. As the infused fat globules are phagocytized by the reticuloendthelial cells,

the blood fat content decreases gradually.3"l As lipoidization of neutral fat progresses

in these cells, increase in the hepatic phospholipid content is observed biochemically 37). This fact, similar to histochemical findings,5，紛 illustratedclearly that the major

part of the infused fat, which is disposed of by the reticuloendothelial cells, enters

into the hepatic parenchymatous cells in the form of phospholipid Thus fatty acids,

which are contained in the fat emulsion, are oxidized in the hepatic parenchy-

matous cells. Consequently oxygen consumption in the liver increases remarkably.70l

It is accepted that the part of the fatty acids are oxidized finally to water and

carbon dioxide in the liver, but the major part of them are converted to the stage of

ketone bodies which diffuse into the blood stream with an increase in ketone bodies

levels. When ketone bodies are carried to the extrahepatic tissues to enter into

the final metabolic pathway, an increase in oxygen consumption in these tissues is

observed.10i These results agree with CttAIKOFF et al.29，明 andGEYER et al."1・28>

Since various enzyme systems are concerned in this metabolic process, we must

consider the enzym巴 systemsin order to utilize completely the infos巴dfat emulsion.

Methionine synthetizes

choline, which has remark-able lipotropic action,85・"7l by

means of transmethylation. Recently ARTOM3'4i and EN-

TENMAN1明 haveemphasized

that choline accelerates

fatty acid oxidation in

the liver. It has been

clarified by the results of

the present perfusion ex-

periment and of SEN082J

that methionine accelerates

markedly oxidation of neu-

tral fat at least to the

stage of ketone bodies in

Fig. 4. Fatty acid cycle (After Lynen59, 60〕

ーさH

-2H

< DPN ~ DPN2H)

the liver. Recently, according to biochemical studies in vitro on fatty acid oxidation by GREEN, LIPMANN, OcttoA and LYNEN etc., it has been recognized that both pyri-

dine nucleotides and flavoproteins play an essential role as hydrogen carrier in this

metabolic process (Fig. 1 and 4). Furthermore, it has been established from their

仰 vitrostudies that all hydrogen atoms, which are liberated by turn of the T.C.A.

cycle, are carried by pyridine nucleotides, flavoproteins and cytochrome systems to

combine with oxygen, and thus fatty acid is oxidized completely to water and car-

bon dioxide ... ＂・＂い川 Sincepyridine nucleotide and flavoprotein each contain nicotinic


acid22·~~.9Sl and flavin,1°5l both nicotinic acid and flavin are essential components of hydrogen carring system in fatty acid oxidation. More recently flavin has been iso-lated from some fatty acid oxidizing enzymeS.64'83) We must of course consider the importance of these enzyme system in the case of parenteral nutrition with fat emulsion, while many investigators have regarded only the caloric intake and have left this problem out of consideration. Prolonged injection of sodium acetoacetate into rabbits causes a decrease in not only riboflavin69> but also ascorbic acid in serum 附. It has also been demonstrated that ascorbic acid activates both aconitase初 andsuccinic dehydrogenase'11J and is able to convert acetoacetic acid probably to acetic acid and glycolic acid.附 Therefore,by means of the simultaneous infusion of me-thionine, riboflavin, niacin amide, ascorbic acid and pantothenic acid with the fat emulsion, the infused fat was oxidized smoothly and completely. Under these con-ditions the fat emulsion was nutritiously effective and resulted in an increase in body weight even in normal rabbits, in which the utilization of the infused fat was difficult. These facts demonstrate also the importance of these vitamins in catalyz-ing fat metabolism in vivo, which has alreadly been established 仰 vitro・

It has been disputed that carbohydrate is ketolytic or antikegenic. According to DEUEL’s experiment1"l applied liver slices and WEINHous’s findings山 lthat carbohy-drate increases the rate of oxidation of short chain fatty acids. It has been esta-blished recently that carbohydrate does not inhib!t ketone body formation by compe-tition but has a ketolytic action. Acetyl-CoA, which is formed by β－oxidation of fatty acids, and to which ketone bodies are reconverted, combines with oxaloacetic acid to form citric acid under catalyzation of the condensing enzyme and enters into the T.C.A. cycle and is oxidized to water and carbon dioxide. Oxaloacetic acid is formed by means of W ooo-W ERKMAN’s reaction附 chieflyfrom pyruvic acid, which is derived from carbohydrate, and partially from some amino acids. When glycogen depots are exhausted in starvation, the minimal necessary dose of oxaloacetic acid could be supplied merely by some amino acids. Consequently, fat depots are mobilized and fatty acids are oxidized excessively in the liver. Thus excessive formation of acetyl-CoA and depletion of oxaloacetic acid occur simultaneously, and remarkable ketosis appears. As shown in these results of the present investigation, when the fat emulsion is administered clinically into patients with malnutrition, the addition of 7 per cent glucose is insufficient and the addition of larger quantities of glucose and above mentioned various drugs are necessary. Thus 、theresults 、inclosed circuit anesthesia also clarified the relationship between carbohydrate and fat metabolism.

w・ SUMMARY

1. Perfusion of isolated liver was made by application of sesame oil emulsion 、containingtriglycerides of long chain fatty acids, and it was demonstrated that fatty acids contained in the fat emulsion were oxidized at least to the stage of ketone body in the liver. Methionine accelerated and enhanced this oxidation process of

fat metabolism. 2. Cod liver oil emulsion was more ketogenic than sesame oil emulsion.

508 日本外科宝画第24巻第5号

3. It is preferable that the fat emuls;on is administered simultaneously with

methionine, riboflavin, niacin amide, ascorbic acid and pantothenic acid. The im-

portance of these drugs in fat metabolism was clearly domonstrated.

4. In the case of intravenous administration of the fat emulsion into normal

rabbits, the fat emuls;on must be added to 7 per cent glucose.

5. In the case of intravenous administrat;on of the fat emulsion into starved

rabbits, a larger quant:ti巴sof glucose and the above mentioned drugs must be infused

simultaneously with the fat emulsion. Accordingly these facts must be carefully

considered especially in the case of clinical application of the fat emulsion into

patients with malnutrition.

6. Fat metabolism from the view-point of ketone body formation was discussed

by application of the fat emulsion.

7. Precautions for disturbances of fat metabolism in closed circuit anesthesia

were discussed.

The author wishes to thank Dr. YoRINORI HrKASA for his many valuable suggestions

and criticisms throughout the present investigation.

The present investigation was supported in part by a Research Grant from the Depart-

ment of・ Education Science Research Foundation.

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和文抄録

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ケトン体を中心ごした脂質代謝に関する実験的研究

大学院学生端野博康

京都大学医学部外科学教室第2講座（指導：青柳安誠教授）

教室創製の脂肪手L剤を試獣（家兎，猫，犬）の静除内ン，ピタミンC，ニコチン酸，パントテン酸等の脂肪

へ注入し，あるいは叉木脂肪乳斉IJによる別出肝臓滋流酸酸化酵素系の存在が必要である事実を印 vivoに

実験を行い，生体内に於ける脂質代謝過程をケトン体於てもよく端的に立証し得た．従って本腹筋乳剤の注

の産生状態から観察しr 次の所見を認識することが出入に当つてはご此等ビタミン類の併用が考慮されるべ

来た．きである．

(1）長鎖脂肪酸のトリグリセライトーからなる胡麻油 (4）健常試獣の静除内へ脂質を手Lイι惑の型で注入

手L剤を以ての易IJ出肝臓溢流笑験の結果，長鎖脂肪酸もし，その栄養学的効果を期待するためには常に 7%程

亦肝臓に於てケトン体の段階迄酸化され得て， mもメ度の糖添加が必要である．

チオユンはこの駿化過祥ーを著しく促進せしめる． (5) 飢餓試獣を対象とした際には 7%程度の糖添加

12）併し生体育争除内住人時の所見からすれば長鎖脂では不充分で，更に多量の糖添加を必要とし，更に可能

肪酸が facultativeketogenic であるのに＆して，短

鎖脂肪理主は obligatoryketogenicである．而してはiの

所見と併せ考えると，長鎖脂肪酸は肝臓のみならず他

の臓器に於ても酸化され得る事実を推察出米る．

13）脂質代謝が円滑に行われるためにはリボフラピ

なればピタミンB1の併用をも行うことが有利である．

(6）本脂肪乳剤jの静肱内注入会劉出）J+臓滋流実験，

更に叉エーテル使用による全身麻酔君主等を駆使して，

ケトン体を中心とした脂質代謝機構を生体に於てある

程度迄究開し得た．

title experimental study on fat metabolism ......fat metabolism from the view-point of ketone body...

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