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Responses of Plasma Lipoproteins and Sex Hormones to the Consumption of Lean Fish Incorporated in a Prudent-Type Diet in Normolipidemic Men

Département des sciences des aliments et de nutrition (B.L., C.L., H.J.), Université Laval, Sainte-Foy, Québec, CANADA
Département de physiologie (Y.D.), Université Laval, Sainte-Foy, Québec, CANADA
Centre de recherche sur les maladies lipidiques (P.J., L.-D.B.), Centre Hospitalier de l’Université Laval, Sainte-Foy, Québec, CANADA

Address reprint requests to: Hélène Jacques, Ph.D., Département des sciences des aliments et de nutrition, FSAA, Pavillon Paul-Comtois, Université Laval, Québec, G1K 7P4, CANADA. E-mail: helene.jacques{at}aln.ulaval.ca.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
Objective: The effects of lean fish on plasma lipoproteins, postheparin plasma lipolytic activities and sex hormones were examined in 11 normolipidemic male subjects.

Methods: This study was a randomized crossover trial of two isoenergetic prudent-type diets, lean fish diet and beef, pork, veal, eggs and milk (nonfish) diet. Experimental diets provided approximately 11800 kJ—18% as proteins, 50% as carbohydrates, 32% as lipids [ratio of polyunsaturated to saturated fatty acids (P:S) of 1:1 compared with 0.5:1 in preexperimental diet], and 260 mg cholesterol/day.

Results: Compared with the nonfish diet, the lean fish diet induced higher plasma total and LDL apolipoprotein (apo) B and apo B:apo A-1 ratio, indicating that the substitution of lean fish for beef, veal, pork, eggs and milk provides little benefits with regard to plasma apo B concentrations in a low-fat high P:S diet. Moreover, triglycerides:apo B and cholesterol:apo B ratios of VLDL were lower following the lean fish diet than the nonfish diet, suggesting the presence of smaller very low-density lipoprotein (VLDL) particles following the consumption of lean fish. Higher plasma concentrations of sex hormone-binding globulin (SHBG), HDL₂ cholesterol and HDL₂:HDL₃ cholesterol ratio were found with the lean fish diet compared with the nonfish diet. Negative correlations between plasma postheparin lipoprotein lipase (LPL) activity and VLDL triglycerides (n = 11, r = -0.53, p = 0.02), and between plasma postheparin LPL activity and VLDL triglycerides:apo B ratio (n = 11, r = -0.64, p = 0.02) were also observed following the lean fish diet.

Conclusion: These results suggest that the effects of substituting lean fish for beef, veal, pork, eggs and milk on plasma lipoproteins may be partly associated with variations in plasma sex hormone status and plasma LPL activity in normolipidemic men.

Key words: fish, lipoproteins, lipases, sex hormones, prudent diet, men

Abbreviations: apo = apolipoprotein • BMI = body mass index • nonfish = beef,pork,veal,eggs and milk • CHD = coronary heart disease • HDL = high-density lipoproteins • HTGL= hepatic triglyceride lipase • LDL = low-density lipoproteins • LPL = lipoprotein lipase • lean fish = lean white fish • n-3 = omega -3 • n-6 = omega-6 • NCEP = National Cholesterol Education Program • P:S ratio = polyunsaturated to saturated fatty acid ratio • P:M:S ratio = polyunsaturated to monounsaturated to saturated fatty acid ratio • PUFA = polyunsaturated fatty acids

	INTRODUCTION

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Atherosclerosis is a multifactorial disorder associated with the development of coronary heart disease (CHD), which has become the commonest cause of disability and death in industrialized countries. Dietary recommendations have been proposed in order to prevent or reduce the development of atherosclerosis in the general population [1,2]. According to the recommendations for a prudent diet from the 1994 National Cholesterol Education Program (NCEP) [2], the proportion of lipids consumed should be limited to 30% or less of total energy, consumption of saturated fatty acids should be 8% to 10% of total energy, consumption of omega-6 (n-6) polyunsaturated fatty acids (PUFA) up to 10% of total energy, and cholesterol consumption should be limited to less than 300 mg per day. Low-fat high polyunsaturated/saturated fat ratio (P:S) diets can contribute to reduce the incidence of CHD risk factors, such as elevated concentrations of cholesterol and apolipoprotein (apo) B in total plasma and low-density lipoproteins (LDL) and reduced concentrations of cholesterol in high-density lipoproteins (HDL). The NCEP [2] also recommends including fish in the diet because it is relatively low in saturated fat and is a natural source of omega-3 (n-3) polyunsaturated fatty acids (PUFA) known to reduce blood clotting and serum triglycerides [3]. In this respect, it has been suggested that fish oil lowers triglyceride concentrations by inhibiting VLDL triglyceride synthesis [4]. More recently, it has been also shown that n-3 fatty acids can stimulate endogenous activities of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) in normolipidemic subjects [5], but not plasma postheparin LPL or HTGL [6,7].

Early epidemiological studies of Greenland Eskimos [8] and Japanese [9] who consume large amounts of fish and marine foods, indicated a very low incidence of ischemic heart disease in these populations. Since then, evidences from studies in human populations generally indicated that the risk of death from CHD is lower among people who consume low to moderate quantity of fish compared with those who avoid it [10,11]. However when fish intake is relatively high, no relationship between fish intake and rates of total or fatal CHD is observed [12,13]. An epidemiological study conducted in the United States [14] also reported that increasing fish intake from 1–2 servings/wk to 5–6 servings/wk does not substantially reduce the risk of CHD in healthy men. The explanation for this lack of increased protection against CHD with high fish intake is not clear. This could be attributed to the type of fish or diet consumed, the subjects studied, the experimental designs or the presence of other components in fish. Other nutrients present in fish may indeed influence plasma lipids and lipoproteins. Factorial experiments conducted in rabbits [15,16] demonstrated that defatted fish consisting of 92% fish protein can maintain unchanged total and high-density-lipoprotein (HDL) cholesterol even in combination with n-6 PUFA, which usually reduce these concentrations. Moreover the higher HDL cholesterol concentration induced by fish protein, compared with soy protein, has been associated with decrease in very low-density lipoprotein (VLDL) triglycerides and increase in postheparin plasma LPL activity [16].

The effects of lean fish, whose major constituent is fish protein containing 1% or less of fish oil (0.45% or less of total energy derived from n-3 PUFA), have also been examined in premenopausal [17] and postmenopausal [18] women fed well-controlled low-fat (30%) high P:S (1:1) ratio diets. In premenopausal [17] and postmenopausal [18] women, lean fish induced higher concentrations of LDL-apo B in plasma than other animal protein sources, resulting perhaps from increased conversion of VLDL to LDL, which is LPL mediated. In postmenopausal women [18], lean fish, compared with other animal protein sources, induced higher concentrations of plasma total and HDL cholesterol as well as sex hormone-binding globulin (SHBG), referred to as circulating testosterone-estradiol-binding globulin. Interestingly, the testosterone-estradiol balance, mainly regulated by circulating SHBG [19], influences the lipid profile in men. Thus, it was deemed of interest to determine whether lean fish compared to other animal protein sources influences lipid and lipoprotein concentrations through postheparin plasma lipolytic activities and sex hormone variations in men.

	MATERIALS AND METHODS

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Subjects
After physical examination and medical history, 11 normolipidemic French-Canadian men, between 19 and 27 years of age and students at Laval University, were selected. Subjects were encouraged to maintain their normal lifestyles. They practiced regular physical activity (e.g., 2–5 h/wk of muscular training, cycling or jogging) and were nonsmokers. Exclusion criteria included dyslipoproteinemias, LPL gene defects, use of medication known to affect lipid metabolism, important weight loss within the previous six months, chronic, metabolic or acute disease or major surgery within the previous three months, and dietary incompatibility with calcium supplementation and/or fish consumption (allergy, intolerance, dislike). Based on genetic analyses as previously described [20], carriers of LPL gene mutations (G188E, P207L and D250N) were also excluded. All subjects had normal body mass index (BMI) and normal lipid profiles (Table 1). According to data from the third National Health and Nutrition Examination Survey, individual plasma total and LDL cholesterol values were distributed between the 5^th and 50^th percentiles of the population for the corresponding group age [2]. These subjects with low levels of circulating total and LDL cholesterol were selected to determine clearly the effects of the lean fish diet in normolipidemic subjects and not in borderline hypercholesterolemic subjects. This study was approved by the Clinical Research Ethical Committee of Laval University. Each participant gave written informed consent and was free to withdraw at any time.

Diets
Before the beginning of the study, participants filled a three-day dietary record, including two weekdays and a weekend day, in order to estimate their individual energy intake and to build seven-day rotating menus which respected their food preferences as much as possible. The formulation of experimental diets was based on the guidelines for a prudent diet recommended by the 1994 NCEP [2]. Nutrient composition of diets and dietary records were calculated with the computed-assisted analysis of the Canadian Nutrient File database [21] and the US Department of Agriculture’s Agricultural Handbook No. 8 [22].

The lean fish diet was formulated using cod and sole which contained less than 1% fat. The nonfish diet consisted of lean beef, pork and veal, eggs, skim and partially skimmed milk and milk products. Approximately 70% to 75% of dietary protein came from fish protein or beef, pork, veal, eggs and milk proteins, the remaining being of vegetable origin. Table 2 provides a sample one-day menu for both experimental diets. Because no milk products were allowed during the lean fish diet, a calcium (500 mg) and vitamin D (125 I.U.) supplement was given daily to subjects on this diet. Alcohol consumption was strictly prohibited two weeks prior to and during both experimental periods. Table 3 compares the mean nutrient composition of lean fish and nonfish diets to the preexperimental diet. In order to obtain 70% of the daily protein intake from fish or beef, veal, pork, eggs and milk, the protein content of experimental diets was increased by 2% compared to the preexperimental diet. The major differences between the two experimental diets (lean fish and nonfish) and the preexperimental diet were an increase in P:S ratio from 0.5:1 to 1.1:1 and a 55 mg decrease in dietary cholesterol. The mean fatty acid content of experimental diets is presented in Table 4. The proportions of saturated, monounsaturated and polyunsaturated fatty acids, and therefore the P:M:S ratio, were similar between the two experimental diets. The main differences between the two experimental diets were the protein source, either from fish or from other animal protein sources, and a slightly higher (1%) content of n-3 long-chain fatty acids in the lean fish diet (Table 4).

All meals, except breakfast, were prepared under the supervision of two qualified dietitians. Breakfasts and snacks were prepared at home by subjects using a predetermined food list. Lunches and dinners were prepared and served by professional dietitians at our experimental nutrition laboratory. Weekend meals were prepared in advance and distributed on Friday evenings.

Blood analysis
Fasting blood samples were taken at the beginning and at the end of each experimental four-week period. A catheter was inserted in the antecubital vein from which 7 mL of blood were collected in tubes with and without ethylenediamine tetraacetic acid (EDTA) in order to obtain plasma and serum, respectively. Ten minutes after the injection of 60 U of heparin/kg of body weight, postheparin blood samples were collected in EDTA tubes. Centrifugations were performed immediately at 4°C for 10 min at 1500 X g. Plasma samples were stored at 4°C and analysed within five days for lipoproteins or were kept at -80°C until lipases were assayed. Serum samples were stored at -80°C until sex hormones were measured. Lipoprotein fractions (VLDL, LDL and HDL) were separated and assayed for their cholesterol, triglyceride, apo A-I and B contents, according to methods previously described by Gascon et al. [17] and Jacques et al. [18].

Serum total and free testosterone and SHBG were measured by radioimmunoassay (Diagnostic Products Corporation, Los Angeles, USA). LPL and HTGL activities were determined in postheparin plasma after preincubation with sodium dodecyl sulfate (SDS) as previously described by Watson et al. [23].

Statistical analysis
Statistical analyses were performed using SAS (Statistical Analysis System Institute, Cary, NC, USA) programs. The results are expressed as mean ± standard error of the mean (SEM) and the significance level is p < 0.05 unless otherwise specified. To compare the effects of lean fish and nonfish diets, analysis of variance was performed according to the crossover design as described by Hills and Armitage [24]. Because no significant effect of either experimental period or sequence was observed and no residual effect of the first experimental period over the second was noted for all lipid and sex hormone variables, the data for experimental period, sequence and dietary treatment were pooled. Statistical comparisons of nutrient intake between the lean fish and the nonfish diets were performed using Student’s t test. The relationships between lipoprotein variations and either LPL or SHBG variations were estimated with Pearson’s correlation coefficient (r).

	RESULTS

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Mean initial body weights were 75 ± 2 kg and 74 ± 2 kg for the lean fish and nonfish groups respectively. Mean initial body mass index (BMI) was 24 ± 1 kg/m² for both diet groups. At the end of experimental diets, mean body weight and BMI remained unchanged.

Mean concentrations of plasma lipids, lipoproteins and apolipoproteins measured before and after lean fish and nonfish diets are indicated in Table 5. The nonfish diet decreased total and LDL cholesterol by 10% and 11%, respectively and the lean fish diet by 4% and 1%, respectively. However, no significant differences were observed on plasma total and LDL cholesterol concentrations between the lean fish and nonfish diets. Plasma concentrations of HDL₂ cholesterol increased by 30% after lean fish ingestion and remained unchanged after ingestion of beef, veal, pork, eggs and milk. Likewise, the HDL₂:HDL₃ cholesterol ratio increased by 59% with the lean fish diet but to a lower extent (19%) with the nonfish diet. Consequently, plasma HDL₂ cholesterol and HDL₂:HDL₃ cholesterol ratio were significantly (p < 0.05) higher following the lean fish diet than the nonfish diet. Although the lean fish diet decreased plasma total and VLDL triglycerides by 27% and 34%, respectively, and the nonfish diet only by 11% and 13%, respectively, there was no significant difference in plasma total (p = 0.14) and VLDL (p = 0.19) triglyceride concentrations between the lean fish and nonfish diets.

As shown in Table 6, plasma triglycerides:apo B and cholesterol: apo B ratios of VLDL decreased by 33% and 26%, respectively, during the lean fish diet and increased by 27% and 26%, respectively, during the nonfish diet. Therefore, plasma triglycerides:apo B and cholesterol:apo B ratios of VLDL were significantly (p < 0.05) lower when the lean fish diet was compared with the nonfish diet. On the other hand, HDL cholesterol:apo A-1 ratio was significantly (p < 0.05) higher after the lean fish diet than after the nonfish diet.

	DISCUSSION

In the present study, all participants showed reductions in plasma total cholesterol, although these varied in magnitude according to the diet consumed. In fact, the lean fish diet induced a 4% reduction from baseline, and the nonfish diet a 10% reduction. The lipid-lowering responses to these diets were close to the 5% to 10% cholesterol reduction expected from the NCEP Step I diet intervention [2]. The observed decreases of plasma total cholesterol concentrations, due to increased P:S ratio and decreased cholesterol content in the nonfish and lean fish diets vs. preexperimental diet, are consistent with those reported in previous studies [25,26]. Reductions in LDL cholesterol values reflected those in total cholesterol, decreasing by 11% when the nonfish diet was followed and by 1% when the lean fish diet was consumed. Despite these apparent divergences, there were no significant differences on plasma total and LDL cholesterol concentrations between subjects fed either lean fish or beef, veal, pork, eggs and milk. Interestingly, NCEP Step 2 diets relatively high or relatively low in fish have also been shown to be both effective in significantly reducing total and LDL cholesterol concentrations under controlled weight-stable conditions in middle-aged and elderly subjects [27].

Although lean fish induced greater reductions (27% and 34%, respectively) in total and VLDL triglyceride concentrations than beef, veal, pork, eggs and milk (11% and 13%, respectively), no differences in total and VLDL triglycerides were observed between the lean fish and nonfish diets. Generally, normal individuals fed marine n-3 fatty acids demonstrate a reduction in plasma triglycerides. But the hypotriglyceridemic effects of n-3 fatty acids are not only dose dependent, but can also be affected by the composition of the diet [28]. In the present study, the lean fish diet provided approximately 2.78 g n-3 fatty acids/day, 1.02 g more n-3 fatty acids than the amount found in the nonfish diet, mainly due to higher content of eicosapentænoic and docosahexænoic acids. Layne et al. [28] recently demonstrated that a dietary supplementation of 35 mg of eicosapentænoic and docosahexænoic acids/kg of body weight (approximately 2.5 g n-3 fatty acids/day) does not reduce plasma triglycerides in normal subjects consuming a high P:S ratio diet (0.87), whereas it does in subjects consuming a low P:S ratio diet (0.48). Indeed, high levels of linoleate present in high P:S ratio diet would compete more with n-3 long-chain fatty acids for incorporation into plasma lipid and lipoprotein fractions.

Based on significant (p < 0.05) lower VLDL triglycerides:apo B and VLDL cholesterol:apo B ratios (Table 4) with lean fish, the present study however suggests that, lean fish may have produced smaller and denser VLDL particles compared with beef, pork, veal, eggs and milk. Inagaki and Harris [29] found that fish oil can reduce the pool of large triglyceride-rich VLDL to a greater extent than small VLDL in hypertriglyceridemic subjects, resulting in smaller VLDL particles. Small VLDL particles are distinguished metabolically from large VLDL particles in that either they can bind to the LDL receptor [30] or they can progress down the lipolytic cascade, ultimately to form normal LDL. Indeed, Packard et al. [31] demonstrated that LDL-apo B is derived from small VLDL and very slightly from large VLDL particles. The presence of smaller VLDL particles could be the explanation for the higher LDL-apo B concentrations observed with lean fish as compared to beef, veal, pork, eggs and milk in the present study as well as in studies on pre- and post-menopausal women [17,18].

There is scientific evidence that n-3 long-chain fatty acids decrease serum triglycerides primarily by reducing the synthesis of triglycerides in the liver [4]. In the present study, n-3 long-chain fatty acids were present in slightly higher amounts (1.02 g n-3 fatty acids) in the lean fish diet than in the nonfish diet (Table 4). Although reduced triglyceride production would play an important mechanistic role, it does not exclude a contribution from enhanced clearance by LPL, an insulin responsive enzyme. Indeed, although neither plasma total triglycerides nor postheparin LPL activity were significantly different between the lean fish and nonfish diets, we found significant negative correlations between variations in plasma VLDL triglyceride concentrations and those in plasma postheparin LPL activity (r = -0.53; n = 11; p = 0.04), and variations in plasma VLDL triglyceride:apo B ratio and those in plasma postheparin LPL activity (r = -0.64; n = 11; p = 0.04) in subjects fed the lean fish diet, suggesting the possibility that repeated exposure to modest increases in LPL activity, although not significant, over extended periods of time could long-term contribute to the production of smaller VLDL following the lean fish diet compared with the nonfish diet. Further studies are however needed to verify this assumption.

We observed in the present study a rise in the HDL₂ cholesterol concentrations in subjects fed the lean fish diet. There has been some published evidence in a previous n-3 fatty acid trial [32] that an increase in HDL₂ cholesterol concentrations may be mediated by an inhibition of lipid transfer protein activity. Such inhibition could slow the exchange of HDL cholesterol esters for triglycerides, resulting in higher HDL₂ cholesterol concentrations. The eventual presence of small and dense VLDL particles could also reduce the substrate available for transfer mediated by lipid transfer protein and thereby allow HDL₂ cholesterol concentrations to increase. Alternatively, the LPL-mediated hydrolysis of triglyceride-rich lipoproteins and transfer of their surface components to HDL precursors is a major pathway for the assembly of circulating HDL particles, particularly HDL₂ [33]. Yet, a close relationship between postheparin LPL activity, levels of HDL cholesterol and VLDL triglycerides already observed in rabbits fed fish protein [16] suggest that the presence of fish protein in lean fish could also have contributed to increase the formation of circulating HDL₂ particles when the lean fish diet was consumed.

This study also showed an elevation of plasma SHBG concentrations with the lean fish diet as compared to the nonfish diet, supporting the observation of Gates et al. [34] in Chinese women that fish consumption is positively associated with SHBG concentrations. Jacques et al. [18] have demonstrated similar increases in plasma SHBG concentrations in postmenopausal women consuming the lean fish diet. Interestingly, in the present study, a positive correlation between SHBG and HDL₂-C (r = 0.80; n = 22; p = 0.01) and negative correlations between SHBG and total triacylglycerols (r = -0.72; n = 22; p = 0.01), VLDL-triacylglycerols (r = 0.70; n = 22; p = 0.02) and plasma VLDL triglycerides:apo B ratio (r = -0.51; n = 22; p = 0.02) have been observed, suggesting that the lipoprotein profile induced by experimental diets is closely related to plasma SHBG concentrations. The mechanism by which SHBG is associated with lipoprotein metabolism remains unclear. On one hand, the positive correlation of SHBG with HDL₂ cholesterol levels suggests that SHBG influence the metabolism and/or the production of HDL₂ cholesterol; this effect could be direct or indirect through the equilibrium of the estradiol-testosterone balance and in association with the activity of hepatic triglyceride lipase, which is stimulated by androgens and inhibited by estrogens [35]. On the other hand, SHBG, VLDL and immature HDL are synthetised by the liver, and a similar mechanism may be responsible for their hepatic production [36].

The evidence that insulin is an inhibitor of SHBG production in vitro [37] and suppresses SHBG production in normal and obese men [38] suggests that low insulin levels may upregulate SHBG and HDL concentrations. According to Haffner et al. [39], higher SHBG is associated with both higher total and nonoxidative glucose disposal. Taken together, higher plasma SHBG and HDL₂-C concentrations, as observed with the lean fish diet compared with the nonfish diet, could be the result of an improvement in insulin sensitivity. In support of this hypothesis, a recent study conducted in our laboratory with rats fed cod protein, soy protein or casein indicated that insulin sensitivity was improved in fasted rats fed cod or soy protein compared with those fed casein [40]. However, further studies are required to confirm the effect of fish protein and lean fish on insulin sensitivity in healthy and non-insulin-dependent diabetic subjects.

Although most studies [29,32] support the evidence that the presence of small quantities of n-3 fatty acids in lean fish would be responsible for the lipid and lipoprotein variations observed in the present study, they do not preclude a contribution from fish protein, another nutrient present in lean fish. Indeed, fish protein has been already shown to reduce plasma triglyceride concentrations, to increase plasma postheparin LPL activity and HDL cholesterol concentrations in rabbits [16] and to improve glucose tolerance and insulin sensitivity in rats [40]. Fish protein is rich in essential amino acids and contains more arginine than casein and more lysine than casein, beef and soy protein [41], two amino acids shown by Vahouny et al. [42] to influence serum insulin and lipids in the rat. However, the relative contributions of n-3 fatty acids and fish protein remain unknown, and it could be worthwhile to evaluate the distinct and interactive metabolic effects of fish oil and fish protein on plasma lipids, lipoproteins and insulin sensitivity in future trials.

In conclusion, the present study indicates that lean fish compared with beef, veal, pork, eggs and milk produced higher LDL apo B and HDL₂-C concentrations when included in a prudent-type diet in normolipidemic men. The present results further suggest that the effects of substituting lean fish for beef, veal, pork, eggs and milk on plasma lipoproteins may be partly associated with variations in VLDL size, sex hormone status and plasma LPL activity. These results were obtained from a group of young men whose plasma lipids are usually less responsive to dietary alterations than those of subjects with elevated plasma lipids. Thus it appears of interest to determine in further studies whether larger effects would be observed in hyperlipidemic patients.

	ACKNOWLEDGMENTS

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We thank Annie Gascon, Lise Pratte, André Lamothe, Jocelyne Piché, Édith Dufour and Lucie Bérubé for preparing meals. We also express our appreciation to the subjects for their enthusiastic cooperation. This work was supported by a grant from Quebec Heart Foundation. The authors wish to thank the Ayerst Laboratories (Montréal, Canada) who kindly provided the calcium supplements.

Received September 3, 1999. Accepted September 9, 2000.

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TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 

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