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Defective desaturation and elongation of N-6 and N-3 fatty acids in hypertensive patients
Prostaglandins Leukotrienes and Medicine 15: 159-165, 1984
IKE DESkl!URATION AND EZIOBGATION OF N-6 AND N-3 FATTY ACIDSIWIiYPRRTEWSIVEPATlXNTS Peter Swer, WaltraudJae er, SiegfriedVoigt and Helmut Thiel CentralInstitutefor Card9ovascularResearch,Academyof Soienceeof the GDR, DDR-?I15Berlin-I&h,GDR. (reprint requeststo PS). ABSTRACT
Rypertsnsive patientshad higherlevelsof linoleicacid (U) in serum lipidsthan normalcontrols.Admini~~tration of largedoees of LA failedto raise the percent of its l&etabolitearachidonic acid (AA) in serum lipids. "1$ imilarly,intake of largeamountsof A-linolenic acid (d-&WA) fail& to inoreas the amountof eicosapentaenoic acid (TEA).The ZR?Ain serum lipidscouldreadilybe increased dire& a&inistrationof comparably low doses in a maclcere Hypertepisive subjects seem to desaturateand elongateLA and aL-IJ?A only very slowly. JXEUUXJCTION ,
failedto dearonstrats an incsease of 20:5, n-3) in plaser? lipids of a
ion of large aammts of limea f d-linolenic acid (d of codliver oil oonta of EPA, providing only about one s%xth of the resulted in a marked rise in EPA. The authors the capacity of ttr huma organism to desatur oc-U!?A mast be limited,On the otherhand,Yes
oil
ooy
0
e
found a significantincreaseof EZA in phoe holipidsof volunteers after a dfet supplemented with linsee B oil. The question arises as to whether this reduoedability to metabolieeor-U!A is also true for linoleicacid (LA,1882, n-6) which is assured to be converted to arachidcmic acid (AA,2Qr4,n-6) by the same enzymese@enoe. A maed ability to synthesizeeicosapolyenoic aeidrs from theti po~&tzra-bed C 18 precursorsin humansmight be importantsince LA is recom-
159
mended for dietary control of cardiovasculardisease risk factors, for instance,arterialhypertensionand hgpercholesterolemia (3,4,12).There is already good evidencethat humans with hyperlipidaemiahave reduced capacityfor convertingLA to amma-LNA (18:3,n-6), dihomogamma-LNA(20:3,n-6) and AA (II,127. RESULTS AND DISCUSSION
We have studied the effects of sunfloweroil (which contained 75% of LA) and linseed oil (which contained64% of ok-LNA),respectively,on several haemodynamicand biochemical parametersin 16 male 'uvenilepatients (of normal body weight, without drug treatmentj , who had mild essentialhypertension. The compositionof the oils can be seen from Table I. The oils were given to two subgroups (of 8 inpatientseach) at doses of 20 ml three times daily (after each meal) for fourteen days within a strict controlledhospital diet, which consistedof about 2200 caloriesper day the relation of carbohydratesto fat to protein being nearly 40 to 40 to 20. A remarkablyhigh percentageof LA was found in serum lipids of hypertensivepatients prior to the diets (Table 2). This was significantlyabove that in matched control subjectswith normal blood pressure,LA rose strikinglyafter sunfloweroil and to some extent after linseed oil, probablypartly because of the LA in the linseed oil and partly b8CauS8 ~c-IXA interferes with LA metabolismat the delta-6desaturase level. I?0 significantchanges of AA and EPA in serum triglycerides(TG) after either on LA- or on uC-LNA-richdiet could be obtained. This suggests a decreaseddelta-6-desaturase activity (7) which catalysesth8 desaturationof LA and cC-LNA.On the contrary, there was a fall of AA in cholesterolesters (CE), reaching significanceafter the id-WA-rich diet. This situationis differentfrom the significantincrease of LA and AA associatedwith deCr8aS8Sof EPA and doooa&h8xaenoic acid (DHA, 22:6, n-3) in serum lipids of spontaneouslybypertensiverats (SHR) after feeding a LA-rich diet (8). Therefore, no conclusionscan be drawn from rats to human be as pointed out already by Dyerberg et al. (I). The deltaiYs-' desaturasewhich forms AA has already been shown to be relatively inactive in humans (13). There is no very rich source of dietary AA, but EPA is found in large amounts in oily fish. Therefore,a mackerel diet consistingof two cans equivalentto 2.2 of EPA and 2.8 -g of DHtldaily for fourteen days was given to 8 patientswith mild rtension in a second study. As in normotensive a significantincreaseof EPA in serum lipids )f th8 hypertensivepatients could be observed (Table 2).
160
TABm
1:
FATTY ACID CXWJ?OS~IM (W3X&%l# IEJp;BIR
'l6:O 18:0 18:7(n-9) 18:2(n-6) 18:3(n-3)
Sunfloweroil
Linseed oil
4.1 2.2 14.8
2.4 14.5
22.2
74.7
14.5
2.9
64.0
2.1
3.7
1.4
2O:l
Mackerel 16.5 3.9
9.5
(n-9) 20:2(n-6) 20:4(x+6) 20:5(n-3)
0.3 0.2
0.5 4.4 16.3
22:la
0.2
22:5(n-3) 22:6(n-3) 24:0 24:l
7.0 0*9 1.2
aThe docosenoicacids are not subdividedaccordingto the position of their double bond,
161
:E" TG CE
TG CE TG CE TG CE
1.1%*4 7.Os.8 1.1%.8 2.421.3
26.5%3++ 65.1+-3.7++ l.lf0.2 0.3k.l 1.5b.4 6.421.2 0.4+lo.5 0.4b.2 0.8%1 o&o.4 0.8b.5 0.5b.3
I%!&.2 53.6b.4 1.3%5 0.5k.3 1.5k.3 7.2t2.4
15.923.4 53.3b.l 1.220.5 0.3%.1 1.2ti.6 7.722.3 0.420.4 0.6%.4
12.6k2.1 51.423.4
1.0%.7 0.4b.4
20.4i2.5++ 58.725.9++ 11.9+-2.7+' 5.421.8++ I.&,6 5.1%2.1++
After 2 wk
Before
Beforex
(n=7)
After 2 wk
Linseed oil(n=8)
Xormals
Sunflower oil(n=8)
14.1+-5.9 48.3ti.O 1.4to.8 0*9%7 1.5to.4 7.M.l 0.3a.2 1.420.7
Before
12.9t3.5 36.8%6++ 1.$0.9 1.7+4.7 2.1ti.5 8.022.2 2.7+-1.5++ 10.3ti.l++
After 2 wk
Mackerel diet(n=8)
POLYUNSATUFWIXD FATTY ACIDS IN SEFUM LIPIIX OF PATIENTS WITH MILD ESSEXTIAL BXPF,RTXNSION BZFORE AJ$D AJ?!PER FXXDING ti~LO-$ER OIL, LINSEED OIL AND MACXERXL DIET. RESULTS ARX EXPRESSED AS A PEFKXNTAGE OF TOTAL FATTY ACIDS PRESENT.
TG
= triglycerides; CE = cholesterol esters x iMean standard deviation (S.D.) %ignificantl.y different (t-test) after diet; P
18:2 (n-6) 18:3 (n-3) 20:4 _ (n-6) g 20:5 (n-3) 22:6 (n-3)
TABL& 2:
163
This appeared more pronouncedin CE, whereas in serum TG an increaseof DHA was predominant.The incorporationof these long chain n-3 fatty acids into several serum lipids might be different indicatingspecificfunctionsfor each fatty acid.. Moreover, systolic blood pressurewas significantlylower only after mackerel diet although it also fell on the sunflower oil supplementation(Table 3). Diastolic blood pressure remained unchanged during the studies. Thus, in hypertensivepatients the ability to desaturate and elongate LA and*-LNA seems to be small confirmingthe results in a normal subject (1) and in individualswith hyperlipidaemia (11,12).The levels of AA and EPA in serum could not be influencedeven by very high intakes of LA and or-U?Athe latter being almost twenty times higher than the dose of EPA in the mackerel diet. Whether this finding also applies to other tissues remains to be clarified.Since the levels of LA in serum lipids were higher in hypertensivesthan in normals, there may be a differencebetween these two groups in their ability to desaturateLA. Nevertheless,the inverse relationship between LA in serum lipids and adipose tissue of patients with mild essentialhypertension(6) cannot be explainedand has to be elucidated. In summary,the idea that all humans can synthesizethe -polyunsaturatedn-6 or n-3 fatty lon er chain and more , should not be accepted. aci8s from LA or
1.
Dyerberg J, Bang HO, Aagaard 0. d-Linolenic acid and eicosapentaenoicacid. Lancet I: 199, 1980. 2. Mest HJ, Beitz J, Heimroth I, Block HV, FiirsterW. The influenceof linseed oil diet on fatty acid nattern in phospholipidsand thromboxaneformation in platelets inman* Klin. Wochenschr.61: 187-191, 1983. 3. Comberg EN, Hegden S, Hames CG. Bypotensiveeffect of dietary prostaglandinprecursor in hmertensive man. Frostaglandins15: 193-197, 1978. 4. FleischmanAI, Watson PB, Stier A, Somol H, BierenbaumML. FXfect of increaseddietary linoleateupon blood pressure, platelet function and serum lipids in hypertensiveadult humans. Preventive%ed. 8: 163, 1979. D, Baumann R. 5. Singer P, Voigt S, GoedickeW, Pf'eiffer The fatty acid pattern of serum triglyceridesand FFA in patientswith essentialhypertensionof differentstages, athletes,and normal subjects. Cor et Vasa 22: 327-334, '@SO.
164
6. Singer P, Voigt S, GoedickeW. Inverse relationshipbetween linoleic acid in serum and adipose tissue of patients with essentialhzypertension.ProstaglandinsLeutrienes and Medicine 9: 603-613, 1982, 7. Horrobin DE'. Loss of delta-6-desaturaseactivity as a ke factor in aging. Medical wotheses 7: 1211-1220, 19z1. 8. Singer I?,Moritz V, Foerster D, Voigt S, Wirth M, Naumann E, ZimontkowskiS. Effect of linoleicacid-rich diet on blood pressure, lipids, catecholamines,and dopamine-B-hydroxylase in spontaneouslyhypertensive rats (SHR). Acta Biol. Med. Germ. 41: 215-225, 1982. 9. Singer P, Jaeger W, Wirth M, Voigt S, Naumann E, Hajdu I, GoedickeW. Lipid and blood pressure lowering effect of mackerel diet in man. Atherosclerosis46: 99-108, 1983. of hyper10. Connor WE, Connor SL. The dietary treatment, lipidemia. Rationale,technique and efficacy.Med Clin NA 66: 485-518, 1982. 11. Nichaman MZ, Olson RE, Sweeley CC. Metabolismof linoleic acid-I-14Cin normolipemicand hyperlipemichumans fed linoleatediets. Am J Clin Nutr 20: 1070-1083,1967. 12. Horrobin DF, Marku MS. How do polyunsaturateslower cholesterollevels? Lipids 18: 558-562, 1983. 13. Stone KJ, Willis AJ, Hart M. The metabolismof dihomogammalinolenicacid in man, Lipids 14: 174-180, 1979.
165
IKE DESkl!URATION AND EZIOBGATION OF N-6 AND N-3 FATTY ACIDSIWIiYPRRTEWSIVEPATlXNTS Peter Swer, WaltraudJae er, SiegfriedVoigt and Helmut Thiel CentralInstitutefor Card9ovascularResearch,Academyof Soienceeof the GDR, DDR-?I15Berlin-I&h,GDR. (reprint requeststo PS). ABSTRACT
Rypertsnsive patientshad higherlevelsof linoleicacid (U) in serum lipidsthan normalcontrols.Admini~~tration of largedoees of LA failedto raise the percent of its l&etabolitearachidonic acid (AA) in serum lipids. "1$ imilarly,intake of largeamountsof A-linolenic acid (d-&WA) fail& to inoreas the amountof eicosapentaenoic acid (TEA).The ZR?Ain serum lipidscouldreadilybe increased dire& a&inistrationof comparably low doses in a maclcere Hypertepisive subjects seem to desaturateand elongateLA and aL-IJ?A only very slowly. JXEUUXJCTION ,
failedto dearonstrats an incsease of 20:5, n-3) in plaser? lipids of a
ion of large aammts of limea f d-linolenic acid (d of codliver oil oonta of EPA, providing only about one s%xth of the resulted in a marked rise in EPA. The authors the capacity of ttr huma organism to desatur oc-U!?A mast be limited,On the otherhand,Yes
oil
ooy
0
e
found a significantincreaseof EZA in phoe holipidsof volunteers after a dfet supplemented with linsee B oil. The question arises as to whether this reduoedability to metabolieeor-U!A is also true for linoleicacid (LA,1882, n-6) which is assured to be converted to arachidcmic acid (AA,2Qr4,n-6) by the same enzymese@enoe. A maed ability to synthesizeeicosapolyenoic aeidrs from theti po~&tzra-bed C 18 precursorsin humansmight be importantsince LA is recom-
159
mended for dietary control of cardiovasculardisease risk factors, for instance,arterialhypertensionand hgpercholesterolemia (3,4,12).There is already good evidencethat humans with hyperlipidaemiahave reduced capacityfor convertingLA to amma-LNA (18:3,n-6), dihomogamma-LNA(20:3,n-6) and AA (II,127. RESULTS AND DISCUSSION
We have studied the effects of sunfloweroil (which contained 75% of LA) and linseed oil (which contained64% of ok-LNA),respectively,on several haemodynamicand biochemical parametersin 16 male 'uvenilepatients (of normal body weight, without drug treatmentj , who had mild essentialhypertension. The compositionof the oils can be seen from Table I. The oils were given to two subgroups (of 8 inpatientseach) at doses of 20 ml three times daily (after each meal) for fourteen days within a strict controlledhospital diet, which consistedof about 2200 caloriesper day the relation of carbohydratesto fat to protein being nearly 40 to 40 to 20. A remarkablyhigh percentageof LA was found in serum lipids of hypertensivepatients prior to the diets (Table 2). This was significantlyabove that in matched control subjectswith normal blood pressure,LA rose strikinglyafter sunfloweroil and to some extent after linseed oil, probablypartly because of the LA in the linseed oil and partly b8CauS8 ~c-IXA interferes with LA metabolismat the delta-6desaturase level. I?0 significantchanges of AA and EPA in serum triglycerides(TG) after either on LA- or on uC-LNA-richdiet could be obtained. This suggests a decreaseddelta-6-desaturase activity (7) which catalysesth8 desaturationof LA and cC-LNA.On the contrary, there was a fall of AA in cholesterolesters (CE), reaching significanceafter the id-WA-rich diet. This situationis differentfrom the significantincrease of LA and AA associatedwith deCr8aS8Sof EPA and doooa&h8xaenoic acid (DHA, 22:6, n-3) in serum lipids of spontaneouslybypertensiverats (SHR) after feeding a LA-rich diet (8). Therefore, no conclusionscan be drawn from rats to human be as pointed out already by Dyerberg et al. (I). The deltaiYs-' desaturasewhich forms AA has already been shown to be relatively inactive in humans (13). There is no very rich source of dietary AA, but EPA is found in large amounts in oily fish. Therefore,a mackerel diet consistingof two cans equivalentto 2.2 of EPA and 2.8 -g of DHtldaily for fourteen days was given to 8 patientswith mild rtension in a second study. As in normotensive a significantincreaseof EPA in serum lipids )f th8 hypertensivepatients could be observed (Table 2).
160
TABm
1:
FATTY ACID CXWJ?OS~IM (W3X&%l# IEJp;BIR
'l6:O 18:0 18:7(n-9) 18:2(n-6) 18:3(n-3)
Sunfloweroil
Linseed oil
4.1 2.2 14.8
2.4 14.5
22.2
74.7
14.5
2.9
64.0
2.1
3.7
1.4
2O:l
Mackerel 16.5 3.9
9.5
(n-9) 20:2(n-6) 20:4(x+6) 20:5(n-3)
0.3 0.2
0.5 4.4 16.3
22:la
0.2
22:5(n-3) 22:6(n-3) 24:0 24:l
7.0 0*9 1.2
aThe docosenoicacids are not subdividedaccordingto the position of their double bond,
161
:E" TG CE
TG CE TG CE TG CE
1.1%*4 7.Os.8 1.1%.8 2.421.3
26.5%3++ 65.1+-3.7++ l.lf0.2 0.3k.l 1.5b.4 6.421.2 0.4+lo.5 0.4b.2 0.8%1 o&o.4 0.8b.5 0.5b.3
I%!&.2 53.6b.4 1.3%5 0.5k.3 1.5k.3 7.2t2.4
15.923.4 53.3b.l 1.220.5 0.3%.1 1.2ti.6 7.722.3 0.420.4 0.6%.4
12.6k2.1 51.423.4
1.0%.7 0.4b.4
20.4i2.5++ 58.725.9++ 11.9+-2.7+' 5.421.8++ I.&,6 5.1%2.1++
After 2 wk
Before
Beforex
(n=7)
After 2 wk
Linseed oil(n=8)
Xormals
Sunflower oil(n=8)
14.1+-5.9 48.3ti.O 1.4to.8 0*9%7 1.5to.4 7.M.l 0.3a.2 1.420.7
Before
12.9t3.5 36.8%6++ 1.$0.9 1.7+4.7 2.1ti.5 8.022.2 2.7+-1.5++ 10.3ti.l++
After 2 wk
Mackerel diet(n=8)
POLYUNSATUFWIXD FATTY ACIDS IN SEFUM LIPIIX OF PATIENTS WITH MILD ESSEXTIAL BXPF,RTXNSION BZFORE AJ$D AJ?!PER FXXDING ti~LO-$ER OIL, LINSEED OIL AND MACXERXL DIET. RESULTS ARX EXPRESSED AS A PEFKXNTAGE OF TOTAL FATTY ACIDS PRESENT.
TG
= triglycerides; CE = cholesterol esters x iMean standard deviation (S.D.) %ignificantl.y different (t-test) after diet; P
18:2 (n-6) 18:3 (n-3) 20:4 _ (n-6) g 20:5 (n-3) 22:6 (n-3)
TABL& 2:
163
This appeared more pronouncedin CE, whereas in serum TG an increaseof DHA was predominant.The incorporationof these long chain n-3 fatty acids into several serum lipids might be different indicatingspecificfunctionsfor each fatty acid.. Moreover, systolic blood pressurewas significantlylower only after mackerel diet although it also fell on the sunflower oil supplementation(Table 3). Diastolic blood pressure remained unchanged during the studies. Thus, in hypertensivepatients the ability to desaturate and elongate LA and*-LNA seems to be small confirmingthe results in a normal subject (1) and in individualswith hyperlipidaemia (11,12).The levels of AA and EPA in serum could not be influencedeven by very high intakes of LA and or-U?Athe latter being almost twenty times higher than the dose of EPA in the mackerel diet. Whether this finding also applies to other tissues remains to be clarified.Since the levels of LA in serum lipids were higher in hypertensivesthan in normals, there may be a differencebetween these two groups in their ability to desaturateLA. Nevertheless,the inverse relationship between LA in serum lipids and adipose tissue of patients with mild essentialhypertension(6) cannot be explainedand has to be elucidated. In summary,the idea that all humans can synthesizethe -polyunsaturatedn-6 or n-3 fatty lon er chain and more , should not be accepted. aci8s from LA or
1.
Dyerberg J, Bang HO, Aagaard 0. d-Linolenic acid and eicosapentaenoicacid. Lancet I: 199, 1980. 2. Mest HJ, Beitz J, Heimroth I, Block HV, FiirsterW. The influenceof linseed oil diet on fatty acid nattern in phospholipidsand thromboxaneformation in platelets inman* Klin. Wochenschr.61: 187-191, 1983. 3. Comberg EN, Hegden S, Hames CG. Bypotensiveeffect of dietary prostaglandinprecursor in hmertensive man. Frostaglandins15: 193-197, 1978. 4. FleischmanAI, Watson PB, Stier A, Somol H, BierenbaumML. FXfect of increaseddietary linoleateupon blood pressure, platelet function and serum lipids in hypertensiveadult humans. Preventive%ed. 8: 163, 1979. D, Baumann R. 5. Singer P, Voigt S, GoedickeW, Pf'eiffer The fatty acid pattern of serum triglyceridesand FFA in patientswith essentialhypertensionof differentstages, athletes,and normal subjects. Cor et Vasa 22: 327-334, '@SO.
164
6. Singer P, Voigt S, GoedickeW. Inverse relationshipbetween linoleic acid in serum and adipose tissue of patients with essentialhzypertension.ProstaglandinsLeutrienes and Medicine 9: 603-613, 1982, 7. Horrobin DE'. Loss of delta-6-desaturaseactivity as a ke factor in aging. Medical wotheses 7: 1211-1220, 19z1. 8. Singer I?,Moritz V, Foerster D, Voigt S, Wirth M, Naumann E, ZimontkowskiS. Effect of linoleicacid-rich diet on blood pressure, lipids, catecholamines,and dopamine-B-hydroxylase in spontaneouslyhypertensive rats (SHR). Acta Biol. Med. Germ. 41: 215-225, 1982. 9. Singer P, Jaeger W, Wirth M, Voigt S, Naumann E, Hajdu I, GoedickeW. Lipid and blood pressure lowering effect of mackerel diet in man. Atherosclerosis46: 99-108, 1983. of hyper10. Connor WE, Connor SL. The dietary treatment, lipidemia. Rationale,technique and efficacy.Med Clin NA 66: 485-518, 1982. 11. Nichaman MZ, Olson RE, Sweeley CC. Metabolismof linoleic acid-I-14Cin normolipemicand hyperlipemichumans fed linoleatediets. Am J Clin Nutr 20: 1070-1083,1967. 12. Horrobin DF, Marku MS. How do polyunsaturateslower cholesterollevels? Lipids 18: 558-562, 1983. 13. Stone KJ, Willis AJ, Hart M. The metabolismof dihomogammalinolenicacid in man, Lipids 14: 174-180, 1979.
165