Effect of uremia on incorporation of acetate into rat plasma and tissue lipids

Effect of Uremia on Incorporation and Tissue Robert

J. Morin,

Mayasandra

U

REMIA results in a hyperlipidemic state in man and animals’,2 and may be a major cause of the increased atherosclerosis and its complications observed in chronic renal disease patients.3’4 The hyperlipidemias and atherosclerosis have been reported in some studies to be worse in renal disease patients undergoing hemodialysis than in those not receiving this treatmenL4” Acetate is the most common alkalinizing agent used during hemodialysis, and these patients are subjected to large unphysiologic plasma acetate loads.6S7 Acetate is a well known lipid precursor, which might contribute to the elevated plasma lipids in these patients. The present investigation was aimed at determining whether experimental uremia alters either the catabolism of acetate to CO, or its conversion to plasma and tissue lipids, so as to gain further insight into the possible aggravating factors in uremic hyperlipidemia. AND

METHODS

Sixty male Sprague-Dawley rats weighing about 200 g were used in this study, and were divided into six groups containing IO rats each. The groups were: (1) sham operated-studied 0.5 hr after operation; (2) bilateral nephrecMetsbolism,

Vol.

29,

No.

4

(April),

1980

Into Rat Plasma

Lipids

V. Srikantaiah.

Experimental uremia was induced in rats by means of bilateral nephrectomy or bilateral ureteral ligation. Incorporation of acetate-l -‘k into expired ‘*CO2 and into plasma and tissue lipids was studied immediately after surgery and at 48 hr, when the rats were uremic. In rats studied immediately after surgery, bilateral nephrectomy. but not bilateral ureteral ligation. significantly decreased the conversion of acetate-l-‘? into expired ‘%O,. In uremic rats at 48 hr. acetate-l -‘% metabolism to “CO, was not significantly altered in either group. Plasma triglyceride concentrations and ‘%-acetate incorporation into triglycerides were increased in the 48-hr uremic groups, but plasma and liver triglyceride specific radioactivities were not significantly altered. Plasma free fatty acid concentrations and incorporation of acetate into free fatty acids were lower in the 48-hr uremic groups than in controls. Plasma cholesterol concentrations and specific radioactivities were increased in these uremic groups, as were liver free cholesterol specific activities. These results suggest that increased triglyceride and cholesterol synthesis from acetate may contribute to the hypertriglyceridemia and hypercholesterolemia observed in uremic rats.

MATERIALS

of Acetate and Warren

D. Davidson

tomy (renal artery ligation)-studied 0.5 hr after ligation: (3) bilateral ureteral ligation-studied 0.5 hr after ligation; (4) sham operated-studied 48 hr after operation; (5) bilateral nephrectomy-studied 48 hr after nephrectomy; and (6) bilateral ureteral ligation-studied 48 hr after ligation. The rats were maintained in the fasting state and then were given acetate-l-‘% (59.0 mCi/mmol. New England Nuclear. Boston, Mass.), 100 &i/kg and nonradioactive acetate, 10 mmole/kg intraperitoneally. “C0Z in expired air from each rat was monitored continuously for 4 hr using a vibrating reed electrometer-ionization chamber method.’ The rats were killed by exsanguination and blood and tissues were obtained for lipid analysis. Total lipids in rat plasma, liver, epididymal adipose tissue, aorta, spleen. testes, and kidney were extracted by homogenization twice in 10 times their volume of chloroform/ methanol, 2/ 1. using a Polytron homogenizer. The combined extracts were washed with acetate buffer (pH 4.0) to remove nonlipid components. Mean recovery of total lipids was 94%. Phospholipid concentrations were determined following digestion of aliquots of the washed lipid extracts at 180°C for 2.5 hr with perchloric acid. Calorimetric phosphate analysis was done by addition of hydrazine sulfate. stannous chloride. and sodium molybdate, and optical densities at 815 nm recorded automatically using a Technicon Autoanalyzcr.’ Plasma triglycerides were extracted into N-nonane and isopropanol (2:3.5, volume:volume). After transesterification with ethoxide, free glycerol was recovered in the aqueous phase and color developed with acetylacetone.‘” The absorbance was read at 410 nm in a Hitachi spectrophotometer. Total plasma cholesterol was determined enzymatically.” In this method, serum cholesterol esters were hydrolyzed to free cholesterol by cholesterol ester hydrolase. The free cholesterol was then oxidized by cholesterol oxidase to cholest4-en-3-one, with the simultaneous production of hydrogen peroxide; the latter oxidatively couples with 4-amino antipyrine and phenol in the presence of peroxidase to yield a chromogen with maximum absorption at 500 nm A single aqueous reagent obtained from Abbott Laboratories. Chicago, Illinois was utilized, and after a IO-min incubation, optical densities were recorded automatically using an Abbott Bichromatic analyzer. Plasma free cholesterol was determined by the same method except that addition of _ From the Departments of Pathology and Medicine, Harbor General Hospital, UCLA School o/ Medicine. Torrance, Calif. Received for publication May 7. 1979. Supported by Artificial Kidney Program (NIH) Contract NOI-AM-S-2209 and NIH Training Grant AM-05383. Address reprint requests to Dr. Robert J. Morin, Department of Pathology. Harbor General Hospital, UCLA School of Medicine, 1000 West Carson Street, Torrance. Calif. 90509. 0 I980 by Grune & Stratton, Inc. 0026-0495/80/2904~003$01.00/0

311

312

MORIN.

SRIKANTAIAH,

AND DAVIDSON

cholesterol ester hydrolase was omitted. Plasma free fatty acids were determined calorimetrically after reaction of cobalt soaps of the free fatty acids with LYnitroso$ naphthol.” For determinations of radioactivities, plasma and liver lipid classes were separated by thin-layer chromatography on silica gel G plates coated with fluorescein. The plates were developed with petroleum ether-diethyl ether-acetic acid (SO:ZO: I), the lipid zones detected under UV light, collected, eluted, and radioactivities in aliquots of these eluates determined by lipid scintillation counting. Mean recovery of lipids was 90.5%. Significance of apparent differences between groups was determined by the t test for unpaired groups. RESULTS

The blood urea nitrogen levels in each of the experimental groups were as follows: sham (OShr), 24.6 mg/dl i 6.7 (SD); bilateral nephrectomy (0.5-hr), 52.9 f 11.6; bilateral ureteral ligation (0.5hr), 38.3 + 9.3; sham (48 hr), 20.8 + 3.8; bilateral nephrectomy (48 hr), 216.5 + 37.6; bilateral ureteral ligation (48 hr), 259.2 + 44.8. The time courses of oxidation of the administered 14C-acetate to “C0, in each of the experimental groups are indicated in Figs. 1 and 2. Percentages of the administered acetate catabolized to CO, over the 4-hr experimental period are shown in Table 1. In rats studied immediately after surgery (mild uremic groups), bilat-

MINUTES Fig. 2. Recovery of “CO, in expired air following intraperitoneal injection of acetate-l-? into uremic rats 48 hr after bilateral ureteral ligation (O---O) or bilateral nephrectomy (O---O) compared to sham operated. nonuremic controls (O---O). Each curve is the mean expired “CO, in 10 rats. The areas under the three curves (total recovery of “COJ are not significantly different.

era1 nephrectomy, but not bilateral ureteral ligation, significantly reduced the recovery of r4C0, from injected acetate-l-14C, compared with sham-operated controls. In the severely uremic rats, neither bilateral nephrectomy nor bilateral ureteral ligation significantly altered recovery of 14C0, from injected acetate- 1-14C, compared with sham operated or mild uremic controls. Results of rat plasma lipid analysis are indicated in Table 2. Free and esterified cholesterol and triglyceride concentrations were significantly elevated in the 4%hr nephrectomized and

ureteral ligation groups, whereas free fatty acids were decreased below the sham-operated controls in both these groups (p < 0.01 for all). As Table 1. “C0,

Recovery After

Acetate-l-‘?

Administration

ii Group

”

I%)

SD I%)

P

0.5-hr 0

30

60

90

120

I60

240

MINUTES Fig. 1. Recoveryof ‘*COz in expired air following intraperitoneal injection of acetate-l -‘*C into nonuremic rats 0.5 hr after bilateral ureteral ligation (O---O), bilateral nephrectomy (O--O), or sham operation (O--O). Each curve represents the mean expired ‘%ZO, in 10 rats. The area under the curve (i.e., recovery) for rats with bilateral nephrectomy is significantly less than in the sham operated rats. *Indicates p > 0.05 (see Table 1).

Sham

10

67.6

5.1

-

Bilateral nephrectomy

10

58.3

6.1

<0.0025*

Bilateral ureteral ligation

10

69.6 8.9

Sham

10

65.1

8.4

-

Bilateral nephrectomy

10

70.7

a.7

>o.o5t

Bilateral ureteral ligation

10

70.5

5.9

>o.o5t

>0.30’

48-hl

*Versus acute shams. tVersus chronic shams.

UREMIA

AND

LIPID

METABOLISM

313

Table 2. Plasma Lipid Concentrations

Group

in Control, Bilateral Nephrectomized.

Free

Esterified

Cholesterol

Cholesterol

and Bilateral Ureteral

TG

Ligated Rats

FFA

Phospholiplds

0.5hr

Sham

22.3

zk 1.1

49.3

2

1.9

25.8

+ 5.5

22.5

I

2.1

118.8

+ 6.1

Nephrectomy

20.7

r

1.5

51.6

f

2.6

24.4

+ 3.2

18.7

c

1.9

102.6

+ 7.0

Ureteral

27.9

+

1.7

52.2

+ 3.1

19.3

+ 2.0

22.3

+

1.3

90.0

5 6.7

Sham

25.6

k 0.8

57.9

+ 3.6

19.6

-i- 1.4

19.9

+

1.9

102.0

k 7.6

Nephrectomy

36.1

k 2.9’

75.1

t

5.5.

59.1

+ 7.2’

14.6

t

1.6*

137.6

+ 7.9

Ureteral

39.3

f

98.4

+ 7.2

50.1

r

15.0

t

2.0

109.0

i

ligation

48-hr

ligation

Abbreviations: Values

TG, triglycerides:

are mg/dl

*Indicates

48-hr

plasma

FFA,

3.0 free fatty

6.2

9.9

acids.

? SE.

nephrectomy

group

significantly

different

from

48-hr

sham,

seen in Table 3, acetate-14C incorporation into rat plasma total lipids was significantly increased in both the 48-hr nephrectomized and ureteral ligation groups compared with the 48-hr sham-operated group (p < 0.01). The percentage of total acetate-14C incorporated into free cholesterol, cholesterol esters, and triglycerides of the former two groups was increased, whereas the percentage incorporated into free fatty acids and phospholipids was decreased below that of Table 3. Incorporation

of Acetate-‘?

Total lbpid Group

p < 0.01

the 48-hr sham group (p < 0.01 for all). Similar results are seen when incorporation of acetate14C was calculated in terms of dpm incorporated into each of the individual plasma lipids/ml plasma. When calculated as specific radioactivity (Table 4, dpm/mg of each lipid class), only plasma free and esterified cholesterol showed an increased incorporation in the 48-hr nephrectomized and ureteral ligation groups compared with the 48-hr sham group (p < 0.01).

Into Plasma Total Lipids and Percent Distribution Free

Cholesterol

Cholesterol

Esters

1%)

(%I

(dpmlml)

in Lipid Classes

Free Fatty Tnglycerldes 1%)

Aads

Phospholipads

1%)

(%l

0.5-hr Sham

1084

k 59

9.2

k 0.6

20.8

k 0.9

27.8

+

1.4

3.3

i

0.2

40.3

1

Nephrectomy

1486

+

125

8.3

k 0.6

20.5

+

1.4

24.0

k 2.3

2.7

-r 0.2

44.2

+ 2.0

Ureteral

1025

f

64

9.9

*

24.8

t

1.4

20.2

+

1.4

2.9

i

0.4

42.6

i

2.5

ligation

0.5

1.6

2.2

48-hr Sham

i- 44

11.9

+ 0.9

23.5

f

13.3

k

1.1

2.9

+ 0.4

44.3

- 3.5

Nephrectomy

1943

739

+

153’

20.5

f

1.6*

37.4

+ 2.9s

22.5

+ 2.3’

1.0

f O.lf

20.5

-

1.8’

Ureteral

ligation

2225

-i

178’

21.3

+

1.7’

40.7

k 2.6*

24.4

k 3.1’

0.9

t

16.4

r

1.2’

that

nephrectomy

*Indicates

the 48-hr

and ureteral

Table 4.

Gr0Ul

ligation

groups

Specific Radioactivities

FrlX

Esterified

Cholesterol

Cholesterol

were

significantly

different

from

0.1

the 48-hr

l

sham

group.

p

I 0.01

of Individual Plasma Lipids

TG

FFA

Phosoholnds

0.5-hr Sham

494

+ 38

338

k 29

1145

-r 229

128

k

15

306

r

18

Nephrectomy

635

2 69

355

+ 38

1535

k 230

204

i

22

550

t

49

Ureteral

398

k 30

283

+ 17

1181

+

110

121

*

10

462

t

37

+ 22

ligation

48-hr Sham

38

189

+ 25

748

f

39

117

f

14

321

Nephrectomy

1184

341

-r 133*

659

+ 106’

752

t

90

121

*

14

325

i

Ureteral

1291

k

543+51*

913

*

109

110

+ 25

325

k 29

ligation

Abbreviations: Values

TG,

are dpm/mg

*Indicates

that

triglycerides: lipid

the 48-hr

FFA,

f

167* free fatty

22

acids.

+ SE. nephrectomy

and ureteral

ligation

groups

were

significantly

different

from

the 48-hr

sham

group.

p J_ 0.01.

314

MORIN,

Table 5. Liver Lipid Concentrations Free Cholesterol

GrOWI

in Control, Nephrectomized, Esterified Cholesterol

SRIKANTAIAH,

and Ureter-Ligated

TG

AND

DAVIDSON

Rats

Phospholipids

FFA

0.5hr Sham

0.8 k 0.05

1.8 r 0.12

7.8 r 0.8

1.02 + 0.42

31.0?

Nephrectomy

1.1 + 0.04

2.1 + 0.12

5.4 + 0.3

1.18 r 0.29

31.1

k 0.6

Ureteral ligation

1.1 + 0.08

1.9 ? 0.09

4.8 k 0.5

0.97

31.8

k 1.2

48-hr Sham

‘_ 0.09

0.8

0.9 + 0.03

2.0 + 0.18

4.5 f 0.5

0.47

c 0.05

30.0

i 0.7

Nephrectomy

0.8 f 0.04

1.8 f 0.10

10.5 + 1.5’

0.46

k 0.04

31.4

+ 0.6

Ureteral ligation

0.8 + 0.06

1.7 f 0.09

6.7 t 0.8

0.34

r 0.04

28.3

+ 0.8

Abbreviations: TG, triglycerides; FFA. free fatty acids. Values are mg/g wet wt liver f SE. *indicates that liver triglyceride concentration was significantly higher in the 48-hr nephrectomy group than in the 48-hr sham group, p < 0.01.

Liver lipid concentrations in these rat groups are given in Table 5. The only significant difference observed was an increase in triglyceride concentration in the 48-hr nephrectomized group compared with the 48-hr sham group (p < 0.01). Incorporation of acetate-i4C into liver total lipids (Table 6) was increased in the 48-hr nephrectomized and ureteral ligation groups compared with the 48-hr sham group (p < 0.01). The percentage of total acetate-14C activity incorporated into free cholesterol and triglycerides of the former two groups was increased, and the phospholipid fraction showed a decreased percentage of incorporation (p < 0.01 for both). Similar results were seen when incorporation was calculated as dpm in each lipid class/g liver, with the exception that incorporation into the phospholipids of the 48-hr nephrectomized group was not significantly different from the 48-hr sham group. As seen in Table 7, when calculated as dpm/mg lipid, only free cholesterol specific activity was higher in the 48-hr nephrecTable 6. Incorporation

Group 0.5hr Sham

DISCUSSION

The present results indicate that severe uremia in rats does not significantly alter the catabolism of acetate to C02, and that the observed differences in incorporation of acetate into plasma and tissue lipids are probably not attributable to differences in availability of substrate between the severe uremic and the control groups. Acetate pool size could not be measured, however, and our conclusions are based upon the assumption that these pool sizes remained the same in the groups compared. Plasma triglyceride levels were increased in

Into Liver Total Lipids and Percent Distribution in Lipid Classes

of Acetate-%

Total Lipid (dpm/g)

tomized and ureteral ligation groups, compared to the 48-hr sham group. Incorporation of acetate-14C into the total lipids of spleen, testes, aorta, kidney, and epididymal adipose tissues are shown in Table 8. There were no significant differences in incorporation into any of these tissues between the various groups.

Free Cholesterol (%I

Cholesterol Esters 1%)

Triglycerides (%I

Free Fatty Acods 1%)

Phospholipids (%)

14,075

k 1182

13.4 + 1.0

2.7 r 0.2

15.8 t 1.1

6.2 k 0.9

63.1

+ 2.3

Nephrectomy

17,871

+ 1807

19.0 Yk 1.0

3.5 k 0.3

10.3 * 1.3

6.6 + 0.7

58.9

+ 3.3

Ureteral ligation

14,628

r 544

17.5 t 1.8

3.8 zk 0.2

10.0 + 1.2

7.0 + 1.1

61.3

+ 4.1

48-hr Sham

10,924

+ 470

21.9

t 2.6

3.2 + 0.3

2.0 + 0.4

66.2

? 2.6

Nephrectomy

15,880

k 1368.

36.2

+ 2.9*

2.2 + 0.2

18.3 +_ 1.9*

1.5 * 0.3

42.8

+ 2.8*

Ureteral ligation

13,662

k 775*

47.2

k 2.5’

2.0 f 0.1

13.3 k 1.5*

1.5 * 0.2

36.0

+ 2.1.

*Indicates incorporation into the 48-hr groups, p < 0.0 1.

8.0 f

1.2

nephrectomy and ureteral ligation groups was significantly different from the 48-hr sham

315

UREMIA AND LIPID METABOLISM

Table 7. Specific Radioactivities

Group

Free

Esterified

Cholesterol

Cholesterol

of Individual Liver Lipids

TG

FFA

Phosphollpids

0.5-hr Sham

3310

t 440

196 k 20

1192

+ 179

1175 f 355

1137

?45

Nephrectomy

3272

+ 346

14Bt

1340

+ 191

2205

2 485

1520

+ 106

Ureteral ligation

2272

? 454

161 i 9

1855 k 280

1290

k 90

Sham

2722

? 408

108 k 12

955 k 155

1022

t 30

Nephrectomy

5875

+ 551’

116 + 6

1029 + 134

1085

t 240

964 t 57

Ureteral legation

8687

+ 1032*

95 i 7

1060 + 170

1380 2 235

754 f 45

11

1292 t 181

48-hr 867 + 121

Abbreviabons: TG, triglycerides; FFA, free fatty acids. Values are dpm/mg lipid + SE. *indicates free cholesterol specific activity in the 48-hr nephrectomy and ureteral ligation groups significantly dtfferent from the 48-hr sham.pi0.01.

the 48-hr uremic groups, as has been previously observed in acutely uremic dogsI and in chronically uremic ratsI and humans.’ Unlike uremic humans, but similar to rats uremic for a IO-wk period,” plasma cholesterol concentrations were also increased in the present 48-hr uremic rats. Previous studies of the mechanism of the hypertriglyceridemia in uremic rats have indicated that there is no increase in hepatic triglyceride secretion rate,14.” acetyl CoA carboxylase activity,15 or heparin elutable tissue lipoprotein lipase activity,15 but that a substance present in the plasma of uremic rats may inhibit adipose tissue lipoprotein lipase activity,” and thereby result in a reduced triglyceride clearance rate. A similar inhibitor of lipoprotein lipase activity has been noted in uremic human plasma.16 In the present experiments, plasma triglyceride concentrations and total incorporation of acetate into plasma triglycerides were increased, but specific activities of plasma triglycerides were not increased in the severe uremic groups. In addition, plasma free fatty acids and the proportion of 14C-acetate found in the plasma free fatty acid fraction were lower in the 48-hr uremic groups than in the Table 8.

Incorporation

controls. These results, therefore, suggest that both increased synthesis and a decreased rate of removal may contribute to the hypertriglyceridemia in this 48-hr uremic rat model. Plasma cholesterol concentrations and specific radioactivities were both increased, suggesting a net increased cholesterol synthesis. In vitro studies have shown a twofold increase in sterol synthesis in uremic rat livers, compared to normal.17 Our previous studies in dogs undergoing hemodialysis also suggested a potentiation of cholesterol synthesis from acetate by uremia.” It has been reported that 50%-60% of the metabolism of mevalonate by pathways not leading to cholesterol occurs in the kidneys.“.” Nephrectomy results in decreased CO? production from mevalonate and increased synthesis of liver and plasma cholesterol from mevalonate.‘” It seems possible that the present group with surgical or functional nephrectomies had a decreased capacity to metabolize circulating mevalonate by the shunt pathway, resulting in greater utilization by the liver for cholesterol synthesis, as evidenced by the increased specific activities of liver free cholesterol in these groups. It is likely

of Acetate-‘?

Into Tissue Total Lipids Epldldymal

Group

Spleen

Testes

Aorta

Kidney

Adxpose

0.5-hr Sham

5122

k 293

1403 + 127

3352

+ 125

Nephrectomy

4135

+ 440

1546 f 72

3399

r 991

Ureteral ligation

4813

2 228

1389 2 35

3882

t 2666

9752

7484

6543

f 253

3029

r 347

4115

k 396

k 980

3636

+ 464

? 1264

4533

t 471

3288

+ 292

2983

+ 180

48.hr Sham

4549

+ 228

1253 k 108

3497

+ 653

Nephrectomy

4414

k 320

1735

3781

k 764

Ureteral ligation

5544

t 309

1412 _t 76

2796

+ 762

Values are dpm/g tissue + SE.

+ 102

9897

2 1021

MORIN,

316

therefore that hypercholesterolemia in experimental rat uremia develops by mechanisms dissimilar to the hypertriglyceridemia. Acetate conversion to lipids is altered by uremia, but the mechanisms may not be similar to those in human renal disease patients, since hypercholesterolemia is not usually observed in the latThis may be related to the much longer ter. 2’m23

SRIKANTAIAH.

AND

DAVIDSON

time periods that the investigated human patients were uremic compared to the rat model in the present study. ACKNOWLEDGMENT The authors acknowledge the expert technical assistance Bassist, S. Franklin, J. Ripley, P. Shuss, C. Kimm, D. Wright, and M. Merritt.

of L.

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Clin Chem 20:470-

MJ: Calorimetric ultramicro of free fatty acids. J Lipid

method for the Res 6:431-433,

13. Markeixicz K, Walasek L, Trznadel K, et al: Changes in serum lipid concentrations in acute experimental uremia. Acta Med Pol 15:89-95. 1974 14. Gregg R, Mondon CE, Reaven EP, et al: Effect of acute uremia on triglyceride kinetics in the rat. Metabolism 25:1557-1565, 1976 15. Bagdade JD, Yee E, Wilson DE, et al: Hyperlipidemia in renal failure: Studies of plasma lipoproteins, hepatic triglyceride production, and tissue lipoprotein lipase in a chronically uremic rat model. J Lab Clin Med 91:176186, 1978 16. Murase T, Cattran DC, Rubenstein B, et al: Inhibition of lipoprotein lipase by uremic plasma, a possible cause of hypertriglyceridemia. Metabolism 24: 1279-l 286, 1975 17. Lowenstein LM, Lowenstein JM, Brunengraber H. et al: Lipid abnormalities and atherogenesis in chronic renal failure. Proceedings Ninth Annual Contractor’s Conference, Artificial Kidney Program, NIAMDD, 1976, p 16 18. Morin RJ, Guo LSS, Rorke SJ, et al: Lipid metabolism in non-uremic and uremic dogs during and after hemodialysis with acetate. J Dialysis 2:113-l 29, 1978 19. Edmond J, Fogelman AM, Popjak G: Mevalonate metabolism: Role of kidneys. Science 193:154-156, 1976 20. Wiley MH, Howton MM, Siperstein MD: The quantitative role of the kidneys in the in vivo metabolism of mevalonate. J Biol Chem 252:548-554. 1977 21. Bagdade JD, Porte D Jr, Bierman EL: Hypertriglyceridemia: A metabolic consequence of chronic renal failure. N Engl J Med 269:181-185, 1968 22. Kleinknecht D, Laudat MH, Strauch G, et al: Lipoprotein and carbohydrate disorders in nephrotic syndrome and uremia. Rev Eur Etudes Clin Biol 17:27-3 1, 1972 23. Brons M, Christensen NC. Horder M: Hyperlipoprotein in patients with chronic renal failure. Acta Med Stand 192:119-125,1972