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* Human Nutrition Research Group, Department of Food Science and Nutrition;
Department of Anatomy and Physiology and
** The Nutraceutical and Functional Food Institute, Laval University, Quebec, QC G1K 7P4 Canada
2To whom correspondence should be addressed. E-mail: helene.jacques{at}aln.ulaval.ca.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • fish protein • (n-3) fatty acids • triglycerides • lipoprotein lipase • hepatic lipase • rats
Fish consumption has been shown to be inversely associated with the risk of coronary heart disease (CHD) (1 –3 ). In many clinical trials, the cardiovascular benefits of fish consumption have been attributed to the hypotriglyceridemic and antithrombogenic effects of fish oil (n-3) PUFA (4 ,5 ). The (n-3) PUFA have been shown to lower plasma triglyceride concentrations by decreasing hepatic triglyceride (TG) and VLDL synthesis and secretion (5 –7 ), and possibly by accelerating VLDL and chylomicron degradation by LPL (5 ,8 ,9 ).
The protein component of fish also influences plasma lipid concentrations. Human studies conducted in our laboratory showed that fish protein, compared with other animal proteins, lowered plasma VLDL triglycerides (VLDL-TG) in premenopausal women (10 ), and did not affect total cholesterolemia and LDL-apoprotein B (low baseline concentrations) in postmenopausal women (11 ). It has also been suggested that lean fish may promote the formation of small, dense VLDL particles in men and premenopausal women compared with other sources of animal proteins (10 ,12 ). In rats, cod protein was shown to decrease plasma TG and cholesterol concentrations (13 ) and to increase LPL activity in adipose tissue (14 ) compared with casein. Cod protein was also found to induce beneficial effects on plasma lipid concentrations in rabbits compared with casein and soy protein because it decreased VLDL-TG (15 ), increased HDL cholesterol and elevated postheparin plasma LPL activity (16 ). Based on studies in rats and rabbits, it has also been proposed that cod protein may interact with dietary (n-6) (15 ) and (n-3) (14 ) PUFA to modulate plasma triglyceride and cholesterol concentrations.
Because fish protein and (n-3) PUFA are consumed simultaneously in fish and these two nutrients can affect plasma triglyceride concentrations, the present study used rats to examine the mechanisms by which the combined consumption of fish oil and fish protein may affect triglyceride metabolism. Plasma and hepatic lipid concentrations, triglyceride secretion rates and postheparin plasma LPL activity were determined in rats fed diets varying in both protein (cod protein vs. casein) and lipid (fish oil vs. beef tallow) content. The rat was chosen because it is practically the only species among animal models that displays the hypotriglyceridemic response to fish oil feeding seen in humans (17 ).
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Male Sprague-Dawley rats (Charles River, St-Constant, QC, Canada) initially weighing 
200 g were housed individually in stainless steel wire-bottomed mesh cages. The temperature (20 ± 2°C) and humidity (45–55%) of the animal room were constant and the rats were kept under a daily inverted light:dark cycle (light: 2100 to 0900 h). During an adaptation period of 2–6 d, rats were fed a nonpurified commercial diet (Purina, St. Louis, MO). There were 4 groups of rats (n = 14/group). For a 28-d period, purified diets and tap water were supplied once daily for rats to consume ad libitum. Food intake was recorded daily and body weight was monitored 3 times/wk. This protocol was approved by the Animal Care Committee of Laval University according to the guidelines of the Canadian Council on Animal Care.
Purified diets.
Diets were similar except for the protein (200 g/kg) and the lipid (140 g/kg) sources (Table 1). The four experimental diets were composed of the following protein-lipid mixtures: casein-menhaden oil, casein-beef tallow, cod protein-menhaden oil or cod protein-beef tallow. The cholesterol concentrations of menhaden oil and beef tallow were 5.23 and 1.09 mg/g, respectively. Therefore, menhaden oil provided only 0.5 g cholesterol/kg in menhaden oil diets, and beef tallow provided only 0.1 g cholesterol/kg in beef tallow diets. We considered these amounts to be negligible. Soybean oil was added to the diets to meet the essential fatty acid (EFA) requirements of rats, particularly 
-linolenic acid (18
). As suggested by Fritsche and Johnston (19
), -tocopherol, butylated hydroxyanisole and BHT were added to the diets to minimize the oxidation of (n-3) and (n-6) fatty acids in menhaden oil, and (n-6) PUFA in soybean oil and beef tallow. Cod protein was prepared in our laboratory by lyophilization of frozen cod fillets, which were delipidated with diethylether in an industrial Soxhlet-type apparatus (Canadawide Scientific, Montreal, QC, Canada). The level of protein in the diets was adjusted at the expense of cornstarch on an isonitrogenous basis.
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On d 23, rats were cannulated via the jugular vein under isoflurane anesthesia. Rats were allowed to recover for 3 d before being subjected to subsequent procedures. On d 26, after 12 h of food deprivation, rats were administered 200 IU heparin/kg body through the jugular catheter. A 0.25-mL blood sample was collected 10 min later and centrifuged (1500 x g, 4°C, 15 min) to obtain plasma, which was stored at -80°C for subsequent determination of LPL and hepatic triglyceride lipase (HTGL) activities. Postheparin plasma LPL and HTGL activities were determined by measuring in vitro hydrolysis by postheparin plasma samples of a labeled triolein emulsion in the presence of 0.1 or 1 mol/L NaCl (20 ).
Determination of triglyceride secretion rate.
On d 28, the TG secretion rate was measured according to the method of Otway and Robinson (21 ). After 12 h of food deprivation, rats were injected through the jugular catheter with 300 mg/kg body of Triton WR-1339, a detergent that prevents intravascular TG catabolism. Blood samples (0.15 mL) were taken before (0 min) and 20, 40 and 60 min after Triton injection and centrifuged (60 x g, 4°C, 10 min) to obtain plasma, which was stored at -80°C for subsequent determination of TG concentrations. Rats were then killed by CO2 overexposure after O2/CO2 anesthesia. Rates of VLDL-TG secretion were determined from regression analysis of TG accumulation in plasma vs. time, and adjusted for plasma volume estimated from body weight (22 ).
Plasma, lipoprotein and hepatic lipid analyses.
Total plasma TG concentrations were determined in plasma samples by an enzymatic method using the Triglycerides/GB kit purchased from Roche Diagnostics (Laval, QC, Canada). Total plasma cholesterol concentrations were measured by an enzymatic method (CHOD-PAP kit of Boehringer Mannheim provided by Roche Diagnostics) only in blood samples collected before Triton injection. The liver of rats was removed after killing and stored at -80°C. Liver lipids were extracted by chloroform:methanol (2:1, v/v) according to Folch et al. (23 ), and cholesterol and TG were determined enzymatically as described above.
Statistical analyses.
The results are expressed as mean ± SEM. To determine the main protein and lipid effects as well as interactions between dietary proteins and lipids, data were subjected to two-way ANOVA using the general linear model (GLM) procedure of the Statistical Analysis System (SAS Institute, Cary, NC). Tukey’s Studentized Range (Honestly Significant Difference) test was performed a posteriori to identify differences among dietary groups. Differences were considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Food consumption (18.8 ± 0.5 to 20.5 ± 0.5 g/d) and body weight gain (4.6 ± 0.2 to 5.6 ± 0.3 g/d) did not differ among the groups. Feed efficiencies, defined as the ratio of weight gain to food intake (0.24 to 0.27 g/g) also did not differ.
Plasma and hepatic triglyceride concentrations and triglyceride secretion rates.
Triglyceridemia at 0 min (before injection of Triton WR-1339) was lower in menhaden oil–fed than in beef tallow–fed rats (P = 0.02) (Table 2). The protein source did not independently affect triglyceridemia. However, the combination of cod protein and menhaden oil resulted in 50% lower plasma TG compared with the casein-beef tallow mixture, whereas the combination of casein and menhaden oil did not lower triglyceridemia relative to casein-beef tallow. The protein and lipid sources had independent effects on hepatic TG concentrations and liver TG secretion rates. Cod protein feeding lowered hepatic TG concentration (P = 0.05) and TG secretion rates (P = 0.04) compared with casein feeding. Triglyceride concentrations in the liver (P = 0.02) and TG secretion rates (P = 0.003) were also decreased by menhaden oil consumption compared with beef tallow consumption. The cod protein-menhaden oil mixture reduced hepatic TG concentrations and TG secretion rates compared with the beef tallow–based diets, whereas these variables were not decreased when menhaden oil was added to casein. Hepatic TG concentrations were positively correlated with TG secretion rates and plasma TG (r = 0.46, P = 0.002, n = 45), and remained so when data were adjusted for weight gain, LPL and HTGL activities.
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The lipid (P = 0.005) and protein (P = 0.03) sources affected plasma cholesterol concentrations, which were lower in menhaden oil-fed than in beef tallow-fed rats and in cod protein-fed than in casein-fed rats (Table 3). There was no protein x lipid interaction. The protein source, but not the lipid source, affected (P = 0.006) hepatic cholesterol concentrations, and cod protein consumption was associated with lower hepatic cholesterol concentrations than casein consumption.
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LPL activity did not differ among the groups (Table 2). In contrast, the lipid source affected HTGL activity (P = 0.035), which was lower in menhaden oil–fed than in beef tallow–fed rats.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The hypotriglyceridemic effect of fish oil in humans (24 ) and rats (17 ) is well established, and was reproduced in this study in menhaden oil–fed compared with beef tallow–fed rats. The plasma TG-lowering effect of menhaden oil was associated with a reduction in TG secretion rates and hepatic TG concentrations compared with beef tallow. This is in agreement with previous studies conducted in rats showing that fish oil reduces hepatic TG synthesis and secretion rates compared with saturated fatty acids (25 –27 ) or (n-6) PUFA (28 ).
The present study shows for the first time that cod protein lowers the rate of TG secretion into the blood. This effect could result from a reduction in hepatic TG synthesis, as suggested by the lower hepatic TG concentrations in cod protein–fed rats compared with their casein-fed counterparts, and by the correlation between hepatic TG levels and TG secretion rates. It is possible that that the lowering effect of cod protein on TG secretion may be related in part to its amino acid composition. Indeed, like soy protein, which has a hypotriglyceridemic effect compared with casein (29 ), cod protein contains more arginine and has a lower lysine/arginine ratio than casein (30 ).
Our previous dietary protein-lipid interaction study (14 ) showed a decrease in hepatic TG concentrations after cod protein feeding in the presence of coconut oil as the lipid source. However, this effect was not reproduced in menhaden oil–fed rats (14 ). In the present study, cod protein lowered hepatic TG concentrations in the presence of either saturated fatty acids from beef tallow or (n-3) PUFA from menhaden oil. The lipid concentration of the experimental diets (110 and 140 g/kg in the previous and the present study, respectively) and the lipid source to which menhaden oil was compared (coconut oil or beef tallow) could be responsible in part for the differences between the two studies. Indeed, as previously observed in rabbits, the type and amount of dietary fat may modulate the effects of cod protein on lipid metabolism (15 ).
Although cod protein significantly lowered TG secretion rates, protein did not affect plasma TG concentrations in food-deprived rats. This lack of an effect may be related to the relatively stringent physiologic conditions under which the study was performed. First, the measurements were made after 12 h of food deprivation. A previous study has shown that the hypotriglyceridemic effect of cod protein was stronger in the postprandial than in the food-deprived state (30 ). Second, the effects of dietary proteins on plasma TG levels in rats are attenuated by cornstarch compared with sucrose (29 ). Nevertheless, the present results indicate that the combination of cod protein and menhaden oil had a more beneficial effect on triglyceridemia than menhaden oil added to casein. Indeed, cod protein-menhaden oil induced a 50% decrease in triglyceridemia compared with casein-beef tallow, whereas casein-menhaden oil did not significantly decrease plasma TG.
Triglyceridemia is also modulated by the intravascular hydrolysis of TG, and our earlier studies have suggested that LPL may contribute to the TG-lowering effect of cod protein in rodents (14 ,16 ). In the present study, the diets did not affect postheparin plasma LPL activity, indicating that the hypotriglyceridemic effect of cod protein and menhaden oil in food-deprived rats was not due to absolute changes in the intravascular availability of LPL. In contrast, the activity of HTGL was significantly lower in rats fed menhaden oil–based diets than in those fed beef tallow. However, the lowering of HTGL activity by menhaden oil has been suggested to be a consequence, rather than a cause of the decrease in plasma concentrations of TG-rich lipoproteins (6 ,31 ). Although lipase activities did not appear to strongly determine triglyceridemia, the contribution of a subtle but sustained elevation in postheparin LPL activity resulting from tissue-specific changes in muscle and adipose tissues (14 ,16 ) cannot be excluded a priori.
Fish oil is hypocholesterolemic in rats compared with saturated fatty acids (6 ,25 ) or (n-6) PUFA (25 ,32 ,33 ), an effect that was reproduced in this study. There was, however, no effect of the lipid source on hepatic cholesterol concentrations, suggesting that the hypocholesterolemic effect of menhaden oil was not mediated by a reduction in hepatic cholesterol synthesis. The hypocholesterolemic effect of fish oil in rats appears to be due mainly to a reduction in LDL cholesterol concentrations resulting from an increase in hepatic receptor–dependent LDL uptake (34 ). Other possible contributors include reduced liver VLDL secretion and increased liver receptor–mediated VLDL clearance (35 ), as well as increased cholesterol excretion into bile (36 ).
As observed previously in rats, fish protein reduced both plasma (13 ,14 ,37 ) and hepatic (14 ) cholesterol concentrations in the present study. The hypocholesterolemic effect of fish protein in rats may be caused by a decrease in liver cholesterol output into the circulation due to a stimulation of cholesterol to bile acid conversion and to increased excretion of cholesterol and its metabolites into feces (37 ). Because LDL are derived mainly from the catabolism of VLDL by lipases (38 ), and because cod protein reduced VLDL-TG secretion rates, it is possible that a reduction in liver secretion of cholesterol into TG-rich lipoproteins may account in part for the hypocholesterolemic effect of cod protein in rats. In humans, however, the effects of cod protein on cholesterol metabolism compared with other animal proteins appear to be different from those observed in rats. Indeed, fish protein did not affect total plasma cholesterol concentrations in men (12 ) or in premenopausal women (10 ). The low content of (n-3) PUFA in the fish protein diets could explain this absence of effect in humans. Fundamental differences between rat and human lipid metabolism (17 ,39 –41 ) may also be the cause of these species-specific effects of cod protein on cholesterolemia.
Dietary proteins and lipids exerted main effects on several lipid variables but did not interact, indicating that their actions were independent of one another. It is also worth noting that the combination of cod protein and menhaden oil reduced plasma and hepatic TG concentrations as well as TG secretion rates compared with the casein-beef tallow mixture, whereas the addition of menhaden oil to casein did not have such an effect. The present results therefore suggest that fish protein, in combination with fish oil, may contribute to the beneficial effects of fish consumption on the lipid profile. Interestingly, a reduction in VLDL-TG was observed in premenopausal women fed a lean fish diet containing large amounts of fish protein and small quantities of fish oil (10 ). Whether the effects of cod protein on TG metabolism in humans play a role in the overall reduction in CHD risk that has been associated with fish consumption in epidemiologic studies (1 –3 ) remains to be determined.
In conclusion, this study showed that cod protein lowers TG secretion rates in rats, and that this effect is independent of that of menhaden oil. As is the case for menhaden oil, cod protein may reduce TG secretion rates through reduced hepatic lipid synthesis, as suggested by its effect on liver lipid concentration. This remains to be tested experimentally, along with possible effects of fish components on lipoprotein composition, which may affect their intravascular hydrolysis, and on postprandial lipoprotein metabolism.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: CHD: coronary heart disease; HTGL, hepatic triglyceride lipase; TG, triglyceride; VLDL-TG, VLDL triglycerides.
Manuscript received 13 August 2002. Initial review completed 9 October 2002. Revision accepted 28 January 2003.
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