- Email: [email protected]
Impaired fatty acid metabolism in the hereditary hypertriglyceridemic rats
Poster Presentations Monday 21 July
EFA & Eicosanoids 1997 - Edinburgh
217
P13
P14
EFFECT OF GAMMA-LINOLENIC ACID ON PLASMA AND MEMBRANE LIPIDS AND RENAL PROSTAGLANDINS IN OLD SUBJECTS. A. Homych,* F.Gimult,S.Omvec,* B.Fomtte,** D.E Horrobin, INSERM U-430 ,Broussais Hospital, * St.Perine Hospital, Paris, France and • * Scotia Re,arch Institu!e,Slirling,Scotland.
Docosahexaenoic Acid-Rich Fish Oil Does Not Affect Serum Lipid Concentrations of Normolipidemic Young Adults
Ageing is associated with decreased acti~ it) of A6-desaturase translorming linoleic acid to gamma-linolenic acid (GLA).This defect may contribute to disequilibrium in plasma and membrane lipids and eicosanoids.We were interested whether prolonged supply of exogenous GLAm old subjects may improve their cardiovascular, renal and metabolic status. Methods: Ten mobile old subjects, 9 women and 1 man of mean age of 83 years,hospitatised in a geriatric department and without metabolic or degenerative diseases,were discharged in ambulatoW treatment with a daily supplement of 320 mg GLA, given as Eix)gam capsules (Scotia Pharmaceuticals Ltd) 4x2/day; each capsule containing 500 mg of evening primrose oil supplying 40 mg GLA and I0 mg vitamin E. In all subjecls were measured the following parameters before (Do) and after 30 and 90 days (D90)of Efamol treatment: blood pressure (BP), plasma electrolytes,lipids, essential fatty acids (EFA) (C14-C22) and red cell membrane EFA, renal functions and urinary prostaglandins (PC,). Results: BP moderately decreased,especially diastolic from 86+12 (±SD)(Do) m 81-+-13 mmHg (D90) Plasma cholesterol (Chol) decreased from 6.07+1.30 to 5.81±1.06 mmol/l and HDL Chol increased from 1.81±0.50 to 1.90~_0.51 mmol/I.Apo A 1 increased more: DO 1.35+0.30, DgO 1.5t±0.30 g/l. Plasma and arinaU electrolytes,creatinineclearance, urinary 6-keto-PGFl ~,,, PGF2nt and TxB 2 were not significantly modified, while PGE2 excretion increased lmm 698+591 to 1104+1160 pg/mg creat. (+86%). There was a significant increase of plasma dihomogamma-linolenic acid from 3.60±0.72 to 4.12±1.02 % (p<0.002) after the treatment,but its increase in red cell membrane fipids was not significant: D0 1.27±0.81, D90 1.48+0.91%.The other FFA in plasma and in red cell membrane lipids were not significantly modified. Conclusion: Exogenous supply of GLA (Epogam) for 3 months significantly increased plasma dihomogamma-linotenic acid with a)beneficial reduction of cardiovascular risk factors: decrease of BP and plasma Chol with an increase of HDL Chol and AlX~AI, b) the stability of renal functions and c) large inercase of renal vasodilator PGE2.
Tomohito Hamazaki, Shigeki Sawazaki, Etsuko Asaoka, Miho Itomura, KazunagaYazawa,ToyomiKuwamori,and MasasNKobayashi The First Deptof Int Med,ToyamaMed and PharmUniv,Toyama-shi,Toyama 930-01,Japan Fish oils, purified e i c o s a p e n t a e n i c acid and docosahexaenoic acid (DHA) have been reported to improve blood lipid concentrations, especially those of triglycerides in humans. However, to our knowridge there have been no double-blind studies investigating the effects of DHA-rich fish oil on blood lipid concentrations. Therefore, we conducted a placebo-controlled double-blind study. Twenty-four healthy, normolipidemic young adults took either DHA-rich fish oil capsules containing 1.5-1.8 g of DHA or control oil capsules containing 97% soybean oil and 3% fish oil for 13 wk. Blood samples were taken at the start and end of the study, and serum lipids concentrations were compared. There were no significant changes over time in the DHA group in the following serum lipids: total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, lipoprolein(a), and apolipoproteins A1 and B. In contrast, apolipoprotein A1 concentrations slightly (10%) but significantly increased over time in the control group. Docosahexaenoic acid at a dose of less than 2 g/d did not change serum lipid concentrations of normolipidemic subjects. The effects of DHA in hyperlipidemic patients remain to be investigated in a double-blind study.
P15
P16
Effect of lipid-lowering drugs on essential fatty acid metabolism in hyperlipidemic coronary patients
Impaired Fatty Acid Hypertriglyceridemic Rats.
Metabolism
in
the
Hereditary"
P. Salen, M. de Lorgeril, P. Boucher, A. Geyssant and JJ. Vallon, Facult6 de Mddecine J. Lisfranc, Saint-Etienne and H6pital Herriot, Lyon, France.
Bohov P., Seb0kov~i E., Klime~ L Institute of Experimental Endocrinology, Slovak Academy of Sciences, SK-83306 Bratislava, Slovak Republic
E s s e n t i a l fatty acids ( E F A ) are i m p l i c a t e d in l i p i d and l i p o p r o t e i n m e t a b o l i s m . W h e t h e r a l t e r a t i o n of b l o o d l i p i d s b y l i p i d - l o w e r i n g d r u g s ( L L D ) m a y in turn affect E F A m e t a b o l i s m a n d w h e t h e r different LLDs m a y affect differently E F A m e t a b o l i s m in h u m a n s are not k n o w n . In a 1 2 - w e e k r a n d o m i s e d d o u b l e - b l i n d s t u d y , w e e x a m i n e d (and c o m p a r e d ) the effect of fenofibrate (F), a p e r o x i s o m e proliferator, and s i m v a s t a t i n (S), an H M G C o A r e d u c t a s e inhibitor, on E F A p l a s m a levels in h y p e r l i p i d e m i c (F, n=30; S, n=31) coronary patients f o l l o w i n g a prudent, o m e g a - 3 FA-rich, cardioprotective diet. W h e r e a s the patients did not m o d i f y there dietary habits (in particular the intake of E F A ) d u r i n g the study, linoleic acid and alpha-linolenic acid w e r e s i g n i f i c a n t l y r e d u c e d : f r o m 27.3 + 3.6 % of total F A to 25.1 + 3.9 ( p < 0 . 0 0 1 ) a n d f r o m 0.71 + 0.29 to 0 . 5 9 + 0.27 (p=0.001), r e s p e c t i v e l y . There w e r e parallel s t a t i s t i c a l l y s i g n i f i c a n t i n c r e a s e s in 20:3 o m e g a - 9 ( f r o m 0.16 + 0 . 0 6 to 0.25 + 0.12, p < 0 . 0 0 1 ) and 18:3, 20:3 and 2 0 : 4 o m e g a - 6 ( p < 0 . 0 0 1 ) w h e r e a s omega-3 F A other than alpha-linolenic acid were not modified. The data s u g g e s t that : 1) s h o r t - t e r m t r e a t m e n t b y c o m m o n l y u s e d L L D s significantly affects E F A m e t a b o l i s m ; 2) L L D treatment results in i n c r e a s e d d e g r a d a t i o n of the 2 m a j o r E F A , l i n o l e n i c a c i d and a l p h a - l i n o l e n i c acid, a s s o c i a t e d w i t h an a u g m e n t e d s y n t h e s i s of a r a c h i d o n i c acid but not of e i c o s a p e n t a n o i c acid, the p r e c u r s o r s of e i c o s a n o i d s ; 3) the 2 m a j o r classes of L L D s (fibrate d e r i v a t i v e s and H M G C o A i n h i b i t o r s ) , k n o w n to i n t e r f e r e w i t h l i p o p r o t e i n m e t a b o l i s m t h r o u g h d i f f e r e n t m e c h a n i s m s , s e e m to a f f e c t E F A m e t a b o l i s m t h r o u g h s i m i l a r m e c h a n i s m s , i.e. a c t i v a t i o n o f d e l t a - 6 and delta-5 d e s a t u r a s e and e l o n g a s e s . F u r t h e r s t u d i e s and l o n g e r follow-up are needed to evaluate the long-term clinical effect of L L D i n d u c e d m o d i f i c a t i o n s o f E F A m e t a b o l i s m and to i n v e s t i g a t e the m e c h a n i s m ( s ) of these effects.
Hereditary hypertriglyceridemic (hHTG) rats represent an animal model of liver triglyceride hyperproduction. The aim of our study was to assess whether liver fatty acid (FA) metabolism is impaired in these animals. The relationship between the gene expression for lipogenic malic enzyme (ME) and FA composition of liver lipid fractions was also estimated. Adult, male hHTG Wistar rats and control (NTG) Wistar rats were ted ad libitum laboratory chow diet with 10 wt % partially hydrogenated beef tallow for 14 days. After decapitation liver was removed and fipids were extracted and separated by thin-layer chromatography. Phosphatidylcholine (PC), phosphatidylserine (PS), p h o s p h a t i d y l i n o s i t o l (PI), phosphatidylethanolamine(PE), cardiotipin(CL) and non-polarlipid fractions including triglycerides (TG) were used for fatty acid analysis with gas-liquid chromatography on SP 2340 fused silica capillary column. The ME mRNA levels in liver were determined by the Northen blot method. In hHTG rats, increased levels of 18:2n-6 and 20:5n-3 in all polar lipid fractions were found in comparison with controls. On the other hand, the percentage (wt %) of 20:4n-6 was decreased in PC (NTG: 27.03+0.85 vs hHTG: 18.79±0.16, p<0.01) and in PE (NTG: 27.03±0.08 vs hHTG: 24.86±0.19, p<0.05)ofhHTG rats. The decreased percentageof22:6n-3was also detected in majority of lipid fractions (e.g. PC-NTG: 7.47±0.60 vs PChHTG: 4.88e0.08, p<0.05; TG-NTG: 5.39±.06 vs TG-hHTG: 3.22±0.14, p<0.001).The most profound differences in FA compositionbetween NTG and hHTG rats were observed in PC, PS and TG fractions. Trans unsaturated FAwere increased in hHTG rats in these fractions as well. The product/precursor ratios of PUFA (lg:3n-6/18:2n-6, 22:6n-3/20:5n-3) were significantly lower in all lipid fi-actions of hHTG rats. Regression analysis revealed negative correlation between some long-chain polyunsaturated FA (PUFA) (especially 20:4n4 and 22:6n-3) in liver lipid fractions and liver ME mRNA (e.g. 20:4n-6 in PC: r =-0.96, p < 0.001; 22:6n-3 in PC: r = -0.88, p < 0.01; 20:4n-6 in TG: r=-0.99, p<0.001; 22:6n-3 in TG: r=-0.95, p<0.001). In summary, the bHTG rats exhibit hereditary impaired FA metabolism resulting in decreased levels of long-chain PUFA and altered regulation of some lipogenic processes at the gene level.
EFA & Eicosanoids 1997 - Edinburgh
217
P13
P14
EFFECT OF GAMMA-LINOLENIC ACID ON PLASMA AND MEMBRANE LIPIDS AND RENAL PROSTAGLANDINS IN OLD SUBJECTS. A. Homych,* F.Gimult,S.Omvec,* B.Fomtte,** D.E Horrobin, INSERM U-430 ,Broussais Hospital, * St.Perine Hospital, Paris, France and • * Scotia Re,arch Institu!e,Slirling,Scotland.
Docosahexaenoic Acid-Rich Fish Oil Does Not Affect Serum Lipid Concentrations of Normolipidemic Young Adults
Ageing is associated with decreased acti~ it) of A6-desaturase translorming linoleic acid to gamma-linolenic acid (GLA).This defect may contribute to disequilibrium in plasma and membrane lipids and eicosanoids.We were interested whether prolonged supply of exogenous GLAm old subjects may improve their cardiovascular, renal and metabolic status. Methods: Ten mobile old subjects, 9 women and 1 man of mean age of 83 years,hospitatised in a geriatric department and without metabolic or degenerative diseases,were discharged in ambulatoW treatment with a daily supplement of 320 mg GLA, given as Eix)gam capsules (Scotia Pharmaceuticals Ltd) 4x2/day; each capsule containing 500 mg of evening primrose oil supplying 40 mg GLA and I0 mg vitamin E. In all subjecls were measured the following parameters before (Do) and after 30 and 90 days (D90)of Efamol treatment: blood pressure (BP), plasma electrolytes,lipids, essential fatty acids (EFA) (C14-C22) and red cell membrane EFA, renal functions and urinary prostaglandins (PC,). Results: BP moderately decreased,especially diastolic from 86+12 (±SD)(Do) m 81-+-13 mmHg (D90) Plasma cholesterol (Chol) decreased from 6.07+1.30 to 5.81±1.06 mmol/l and HDL Chol increased from 1.81±0.50 to 1.90~_0.51 mmol/I.Apo A 1 increased more: DO 1.35+0.30, DgO 1.5t±0.30 g/l. Plasma and arinaU electrolytes,creatinineclearance, urinary 6-keto-PGFl ~,,, PGF2nt and TxB 2 were not significantly modified, while PGE2 excretion increased lmm 698+591 to 1104+1160 pg/mg creat. (+86%). There was a significant increase of plasma dihomogamma-linolenic acid from 3.60±0.72 to 4.12±1.02 % (p<0.002) after the treatment,but its increase in red cell membrane fipids was not significant: D0 1.27±0.81, D90 1.48+0.91%.The other FFA in plasma and in red cell membrane lipids were not significantly modified. Conclusion: Exogenous supply of GLA (Epogam) for 3 months significantly increased plasma dihomogamma-linotenic acid with a)beneficial reduction of cardiovascular risk factors: decrease of BP and plasma Chol with an increase of HDL Chol and AlX~AI, b) the stability of renal functions and c) large inercase of renal vasodilator PGE2.
Tomohito Hamazaki, Shigeki Sawazaki, Etsuko Asaoka, Miho Itomura, KazunagaYazawa,ToyomiKuwamori,and MasasNKobayashi The First Deptof Int Med,ToyamaMed and PharmUniv,Toyama-shi,Toyama 930-01,Japan Fish oils, purified e i c o s a p e n t a e n i c acid and docosahexaenoic acid (DHA) have been reported to improve blood lipid concentrations, especially those of triglycerides in humans. However, to our knowridge there have been no double-blind studies investigating the effects of DHA-rich fish oil on blood lipid concentrations. Therefore, we conducted a placebo-controlled double-blind study. Twenty-four healthy, normolipidemic young adults took either DHA-rich fish oil capsules containing 1.5-1.8 g of DHA or control oil capsules containing 97% soybean oil and 3% fish oil for 13 wk. Blood samples were taken at the start and end of the study, and serum lipids concentrations were compared. There were no significant changes over time in the DHA group in the following serum lipids: total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, lipoprolein(a), and apolipoproteins A1 and B. In contrast, apolipoprotein A1 concentrations slightly (10%) but significantly increased over time in the control group. Docosahexaenoic acid at a dose of less than 2 g/d did not change serum lipid concentrations of normolipidemic subjects. The effects of DHA in hyperlipidemic patients remain to be investigated in a double-blind study.
P15
P16
Effect of lipid-lowering drugs on essential fatty acid metabolism in hyperlipidemic coronary patients
Impaired Fatty Acid Hypertriglyceridemic Rats.
Metabolism
in
the
Hereditary"
P. Salen, M. de Lorgeril, P. Boucher, A. Geyssant and JJ. Vallon, Facult6 de Mddecine J. Lisfranc, Saint-Etienne and H6pital Herriot, Lyon, France.
Bohov P., Seb0kov~i E., Klime~ L Institute of Experimental Endocrinology, Slovak Academy of Sciences, SK-83306 Bratislava, Slovak Republic
E s s e n t i a l fatty acids ( E F A ) are i m p l i c a t e d in l i p i d and l i p o p r o t e i n m e t a b o l i s m . W h e t h e r a l t e r a t i o n of b l o o d l i p i d s b y l i p i d - l o w e r i n g d r u g s ( L L D ) m a y in turn affect E F A m e t a b o l i s m a n d w h e t h e r different LLDs m a y affect differently E F A m e t a b o l i s m in h u m a n s are not k n o w n . In a 1 2 - w e e k r a n d o m i s e d d o u b l e - b l i n d s t u d y , w e e x a m i n e d (and c o m p a r e d ) the effect of fenofibrate (F), a p e r o x i s o m e proliferator, and s i m v a s t a t i n (S), an H M G C o A r e d u c t a s e inhibitor, on E F A p l a s m a levels in h y p e r l i p i d e m i c (F, n=30; S, n=31) coronary patients f o l l o w i n g a prudent, o m e g a - 3 FA-rich, cardioprotective diet. W h e r e a s the patients did not m o d i f y there dietary habits (in particular the intake of E F A ) d u r i n g the study, linoleic acid and alpha-linolenic acid w e r e s i g n i f i c a n t l y r e d u c e d : f r o m 27.3 + 3.6 % of total F A to 25.1 + 3.9 ( p < 0 . 0 0 1 ) a n d f r o m 0.71 + 0.29 to 0 . 5 9 + 0.27 (p=0.001), r e s p e c t i v e l y . There w e r e parallel s t a t i s t i c a l l y s i g n i f i c a n t i n c r e a s e s in 20:3 o m e g a - 9 ( f r o m 0.16 + 0 . 0 6 to 0.25 + 0.12, p < 0 . 0 0 1 ) and 18:3, 20:3 and 2 0 : 4 o m e g a - 6 ( p < 0 . 0 0 1 ) w h e r e a s omega-3 F A other than alpha-linolenic acid were not modified. The data s u g g e s t that : 1) s h o r t - t e r m t r e a t m e n t b y c o m m o n l y u s e d L L D s significantly affects E F A m e t a b o l i s m ; 2) L L D treatment results in i n c r e a s e d d e g r a d a t i o n of the 2 m a j o r E F A , l i n o l e n i c a c i d and a l p h a - l i n o l e n i c acid, a s s o c i a t e d w i t h an a u g m e n t e d s y n t h e s i s of a r a c h i d o n i c acid but not of e i c o s a p e n t a n o i c acid, the p r e c u r s o r s of e i c o s a n o i d s ; 3) the 2 m a j o r classes of L L D s (fibrate d e r i v a t i v e s and H M G C o A i n h i b i t o r s ) , k n o w n to i n t e r f e r e w i t h l i p o p r o t e i n m e t a b o l i s m t h r o u g h d i f f e r e n t m e c h a n i s m s , s e e m to a f f e c t E F A m e t a b o l i s m t h r o u g h s i m i l a r m e c h a n i s m s , i.e. a c t i v a t i o n o f d e l t a - 6 and delta-5 d e s a t u r a s e and e l o n g a s e s . F u r t h e r s t u d i e s and l o n g e r follow-up are needed to evaluate the long-term clinical effect of L L D i n d u c e d m o d i f i c a t i o n s o f E F A m e t a b o l i s m and to i n v e s t i g a t e the m e c h a n i s m ( s ) of these effects.
Hereditary hypertriglyceridemic (hHTG) rats represent an animal model of liver triglyceride hyperproduction. The aim of our study was to assess whether liver fatty acid (FA) metabolism is impaired in these animals. The relationship between the gene expression for lipogenic malic enzyme (ME) and FA composition of liver lipid fractions was also estimated. Adult, male hHTG Wistar rats and control (NTG) Wistar rats were ted ad libitum laboratory chow diet with 10 wt % partially hydrogenated beef tallow for 14 days. After decapitation liver was removed and fipids were extracted and separated by thin-layer chromatography. Phosphatidylcholine (PC), phosphatidylserine (PS), p h o s p h a t i d y l i n o s i t o l (PI), phosphatidylethanolamine(PE), cardiotipin(CL) and non-polarlipid fractions including triglycerides (TG) were used for fatty acid analysis with gas-liquid chromatography on SP 2340 fused silica capillary column. The ME mRNA levels in liver were determined by the Northen blot method. In hHTG rats, increased levels of 18:2n-6 and 20:5n-3 in all polar lipid fractions were found in comparison with controls. On the other hand, the percentage (wt %) of 20:4n-6 was decreased in PC (NTG: 27.03+0.85 vs hHTG: 18.79±0.16, p<0.01) and in PE (NTG: 27.03±0.08 vs hHTG: 24.86±0.19, p<0.05)ofhHTG rats. The decreased percentageof22:6n-3was also detected in majority of lipid fractions (e.g. PC-NTG: 7.47±0.60 vs PChHTG: 4.88e0.08, p<0.05; TG-NTG: 5.39±.06 vs TG-hHTG: 3.22±0.14, p<0.001).The most profound differences in FA compositionbetween NTG and hHTG rats were observed in PC, PS and TG fractions. Trans unsaturated FAwere increased in hHTG rats in these fractions as well. The product/precursor ratios of PUFA (lg:3n-6/18:2n-6, 22:6n-3/20:5n-3) were significantly lower in all lipid fi-actions of hHTG rats. Regression analysis revealed negative correlation between some long-chain polyunsaturated FA (PUFA) (especially 20:4n4 and 22:6n-3) in liver lipid fractions and liver ME mRNA (e.g. 20:4n-6 in PC: r =-0.96, p < 0.001; 22:6n-3 in PC: r = -0.88, p < 0.01; 20:4n-6 in TG: r=-0.99, p<0.001; 22:6n-3 in TG: r=-0.95, p<0.001). In summary, the bHTG rats exhibit hereditary impaired FA metabolism resulting in decreased levels of long-chain PUFA and altered regulation of some lipogenic processes at the gene level.