REVIEW URRENT C OPINION
Dietary fatty acids, dietary patterns, and lipoprotein metabolism Benoıˆt Lamarche and Patrick Couture
Purpose of review Few studies have reviewed the impact of dietary fat and dietary patterns on lipoprotein metabolism. This review intends to provide perspective on this topic, while focusing primarily on the studies that assessed intravascular lipoprotein kinetics in humans using isotope methodologies. Recent findings Data suggest that dietary saturated fatty acids slow the clearance of LDL apolipoprotein (apo)B-100 and of apoA-I from the circulation, whereas possibly increasing also apoA-I production. Dietary trans fats reduce the clearance of LDL apoB-100, whereas increasing the clearance of apoA-I. n3 polyunsaturated fatty acids (PUFAs) intake reduces the production of apoB-48-containing lipoproteins as well as of VLDL apoB100 and increases their conversion into smaller lipoproteins. Medium-chain triglycerides appear to have no significant effect on lipoprotein kinetics. Finally, Mediterranean diet in the absence of weight loss reduces LDL cholesterol, primarily by enhancing its clearance from the circulation. Summary Kinetic studies with tracers allow a better appreciation of the impact of specific dietary factors on plasma lipid risk factors. However, additional studies are required to better document the effect of monounsaturated fatty acids, n6 PUFAs, and of whole diets on lipoprotein metabolism. Keywords dietary fat, diets, lipoprotein kinetics
INTRODUCTION Since the early studies of Keys and colleagues in the 1950s, we have accrued considerable knowledge on how dietary fats and dietary patterns influence key cardiometabolic risk factors, including LDL, HDL, and VLDL. Tracer-based metabolic studies that have allowed the investigation of in-vivo lipoprotein metabolism in humans have provided perspective on how dietary modifications modulate each of these key lipid risk factors. This article reviews the evidence pertaining to how individual categories of dietary fatty acids as well as whole dietary patterns influence the intravascular metabolism of lipoproteins in humans. We have focused our analysis primarily on the studies that have used methods involving tracers, when such data were available.
the time, modulate in-vivo lipoprotein metabolism in humans. Using radiolabeled lipoproteins, Shepherd et al. [1] and Turner et al. [2] have provided the first evidence that total fat and SFAs increase plasma LDL cholesterol (LDL-C), primarily by reducing the fractional catabolic rate (FCR) of these lipoproteins. We have come a long way since these early pioneer studies. Table 1 summarizes the impact of various dietary fats on lipoprotein kinetics and diets as discussed in the sections that follow.
Total fat and saturated fatty acids In 1986, Zimmerman et al. [12] have shown that feeding normotriglyceride and hypertriglyceride Institute of Nutrition and Functional Foods, Laval University, Quebec City, Quebec, Canada
DIETARY FATTY ACIDS AND LIPOPROTEIN METABOLISM Studies published in 1980 have provided the first evidence on how dietary fat and saturated fatty acids (SFAs), the two main features of dietary guidelines at www.co-lipidology.com
Correspondence to Benoıˆt Lamarche, PhD, Institute of Nutrition and Functional Foods, Laval University, 2440, Boulevard Hochelaga, Que´bec City, QC, Canada G1V 0A6. Tel: +1 418 656 3527; fax: +1 418 656 5877; e-mail: [email protected] Curr Opin Lipidol 2015, 26:42–47 DOI:10.1097/MOL.0000000000000139 Volume 26 Number 1 February 2015
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KEY POINTS Kinetic studies with tracers have been very informative to better understand the impact of specific dietary factors on cardiometabolic risk factors. Dietary SFAs slows the clearance of LDL apoB and apoA-I from the circulation, whereas increasing apoA-I production. Dietary trans fat reduces the clearance of LDL apoB-100, whereas increasing the catabolism of apoA-I. Long-chain n3 PUFAs decrease nonfasting plasma TRL apoB-100 concentrations, TRL apoB-100 production rate, and direct catabolism of these particles, and accelerate the conversion of TRL to LDL. n3 PUFAs also decrease the concentration, catabolism, and production rate of TRL apoB-48. Further metabolic and kinetic studies are required to shed more light on how dietary MUFAs, n6 PUFAs, and specific dietary patterns such as the MedDiet and the portfolio diet influence lipoprotein metabolism in vivo.
individuals a high-fat and low-carbohydrate (CHO) diet (41–45% of calories from fat) vs. a low-fat and high-CHO diet (29% from fat) significantly reduced
plasma triglyceride and VLDL apolipoprotein (apo) B-100 levels, and increased LDL-C and HDL-C concentrations. ApoA-I kinetic studies using radiolabeling techniques revealed that both the production rate and the FCR of apoA-I were reduced after the high-fat diet; hence, the increase in HDL-C concentrations after a high-fat diet appeared to be attributed primarily to the reduced rate of clearance of these particles. On the other hand, Brinton et al. [3] have later shown that the increase in plasma HDL-C upon switching from a low to a high SFA and cholesterol diet was primarily because of an increase in the production rate of apoA-I. However, they have also shown that patients’ HDL-C levels on any of the low or high fat diet correlated more strongly with variations in FCR rather than with variations in production rate. The authors suggested that whereas diet-induced changes in HDL-C levels may be determined primarily by the changes in lipoprotein synthesis rather than by changes in clearance, differences in HDL-C levels between individuals on a given diet may be better predicted by differences in clearance rates than by differences in synthesis. Taken together, results from these studies suggest that changes in both the synthesis (increase) as well as clearance (reduction) may account to various extents for the increase in HDL-C concentrations
Table 1. Summary of the available evidence on the effect of dietary fatty acids and whole diets on metrics of lipoprotein kinetics based on studies with radio or stable isotopes in humans TRL apoB-48 Fatty acids SFAa
VLDL apoB-100
Pool size
Production rate
FCR
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
Pool size
LDL apoB-100
Production rate
FCR
nd
nd
b
MCT
MUFAc
HDL, apoAI
Pool size
Production rate
FCR
Pool size
Production rate
FCR
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
TFAd n3 PUFAe n6 PUFAf
nd
nd
nd
Whole diets MedDietg High MUFA Portfolioh FCR, fractional catabolic rate; IDL, intermediate density lipoprotein; MCT, medium-chain triglyceride; MUFA, monounsaturated fatty acid; ND, not yet determined; PUFA, polyunsaturated fatty acid; SFA, saturated fatty acid; TFA, trans fatty acid; TRL, triglyceride-rich lipoprotein; , no change; , increase; , reduction. a Vs. low-fat and carbohydrate-rich diet [1–3]. && b Vs. corn oil [4 ]. c Both a reduction in production rate and increase in FCR contribute to the reduced VLDL apoB-100 mass with MUFA. The increased LDL apoB-100 FCR was seen in small, dense LDL containing both apoE and apoC-III [5,6]. d Vs. sunflower oil or SFA [7]. e Long-chain n3 PUFA vs. baseline values. The increased VLDL apoB-100 FCR was primarily because of an accelerated conversion to IDL/LDL, which also translated into an increased production rate of LDL apoB-100 [8]. f No kinetic study with tracers available yet. & && g Mediterranean diet (MedDiet) in the absence of weight loss [9 ,10 ]. h Dietary Portfolio of cholesterol-lowering foods, enriched in MUFA [11].
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generally after consumption of a high-fat/highSFA diet.
Medium-chain triglycerides Medium-chain triglycerides (MCTs) are 6–12 carbon fatty acids of interest because of their unique metabolism [13]. Although the therapeutic use of MCTs to reduce plasma triglyceride is well accepted in patients with severe hypertriglyceridemia, their efficacy in patients with other forms of lipid disorders remains equivocal. Inconsistencies in results may be due in part to the different doses of MCTs that have been given to patients in the various studies [14,15]. We have recently shown that supplementing obese insulin-resistant men with 20 g/ day MCTs for 4 weeks compared with corn oil had no impact on plasma lipids, triglyceride-rich lipoprotein (TRL) apoB-48 and VLDL apoB-100 kinetics, and on intestinal mRNA expression levels of key genes involved in lipid metabolism [4 ]. Kinetics of LDL apoB-100 and of apoA-I were not investigated in that study. Further studies are needed to examine the impact of different doses of MCTs on plasma lipids as well as on lipoprotein kinetics in various at-risk populations. &&
Monounsaturated fatty acids The impact of dietary monounsaturated fatty acids (MUFAs) on cardiometabolic risk factors remains somewhat controversial. Indeed, whereas several lines of indirect evidence from clinical trials [16] as well as epidemiology [17 ] indicate that dietary MUFAs may have beneficial effects on atherogenesis in humans, data from animal models suggest the opposite [18]. Interestingly, the significant beneficial impacts of MUFAs on HDL-C (increase) and triglyceride and LDL-C concentrations (reductions) seen in the meta-analysis by Mensink et al. [19] have not been reproduced in the most recent meta-analysis of studies comparing high vs. low MUFA diets specifically [20]. Few studies have examined the effects of MUFAs on lipoprotein metabolism in humans. The reduction in VLDL apoB-100 and triglyceride levels after a 6-week high-MUFA diet in men with abdominal obesity has been related primarily to variations in VLDL apoB-100 production rate [5] and to variations in plasma apoC-III production rate [21]. There was no change in plasma HDL-C concentrations after the high-MUFA diet, which was consistent with the lack of change in apoA-I kinetics. LDL apoB-100 kinetics were not investigated in this small study. Zheng et al. [6] have shown that replacing 17% of total energy intake from complex CHO with MUFAs increased VLDL and intermediate density &
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lipoprotein (IDL) apoB-100 catabolism, with no overall change in LDL apoB-100 kinetics. The high-MUFA diet doubled the proportion of TRL that are cleared directly from the circulation rather than being converted into LDL, and this was related to a large extent to the apoE and C-III content of the TRL. The authors also showed increased clearance rate of small, dense LDL (sdLDL) that contained both apoE and apoC-III after the high-MUFA diet. They concluded that a high vs. low MUFA diet stimulates the catabolism of TRL and LDL that contain both apoE and apoC-III and suppresses the metabolism of TRL that do not contain these apolipoproteins [6].
Trans fatty acids Increased consumption of trans fatty acids (TFAs) has been associated consistently with an increased risk of CHD [22]. Consumption of TFAs from hydrogenated vegetable oil has been shown to increase plasma LDLC and to reduce HDL-C concentrations, resulting in a less favorable LDL-C/HDL-C ratio even compared with SFAs [22]. High TFA consumption has also been associated with increased plasma triglyceride [23] and lipoprotein (a) concentrations [24]. The elevated LDL-C levels associated with dietary TFAs have been attributed to a reduced LDL apoB-100 FCR, with no significant effects on the production rate of these lipoproteins [7]. Increased apoA-I catabolism appears to be the primary determinant of the reduction in plasma HDL-C levels with TFAs [7]. Consumption of TFAs has no effect on TRL apoB-48 and TRL apoB-100 kinetics [7]. This is the only study available so far on this topic and additional investigations, with particular interest on TFAs for natural sources, are needed.
n-3 Polyunsaturated fatty acids Long-chain n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have unique cardioprotective properties, including potent triglyceride-lowering effects [25]. A high n3 PUFA diet (1.23 g/day EPA and DHA) has been show to decrease nonfasting plasma TRL apoB100 concentrations, TRL apoB-100 production rate, and direct catabolism of these particles, and to accelerate the conversion of TRL to LDL in nonobese men and women [8]. Supplementation with n3 PUFAs also decreased the concentration, FCR, and production rate of intestinally derived TRL apoB-48; reduced LDL apoB-100 concentrations by increasing LDL apoB-100 FCR; and reduced HDL apoA-I concentrations by decreasing HDL apoA-I production rate. The impact of n3 fatty acids from vegetable sources (primarily alpha-linolenic acid) on lipoprotein kinetics is yet unknown. Volume 26 Number 1 February 2015
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nS6 Polyunsaturated fatty acids The LDL-C-lowering effect of n6 PUFAs vs. SFAs is well established from the clinical studies [19]. Data suggest that chronic intake of n6 PUFAs may also exert beneficial effects on cardiovascular disease (CVD) risk by reducing postprandial lipemia. Weintraub et al. [26] found that 25 days of an n6 PUFArich diet markedly attenuated the postprandial lipid response to a fat load compared with an SFA-rich diet in normolipidemic individuals. Bergeron and Havel [27] found no evidence that levels of SFAs and n6 PUFAs in the diet or in challenge meal have different effects on the clearance of TRL apoB-48 in healthy young men. However, they have shown that postprandial hepatic TRL apoB-100 levels were reduced in individuals who consumed n6 PUFAs for 30 days compared with SFAs, and this was independent of the fatty acid composition of the fat load [27]. Thus, studies suggest that chronic intake of n6 PUFAs has a favorable effect on the postprandial TRL metabolism compared with SFAs. Additional studies are needed to better understand how dietary n6 PUFAs modulate lipoprotein metabolism using tracer methodologies in humans.
DIETARY PATTERNS AND LIPOPROTEIN METABOLISM Very few studies have examined the impact of whole diets on lipoprotein kinetics. To the best of our knowledge, such data are available only for the Mediterranean diet (MedDiet) and the Portfolio diet.
Mediterranean diet The cardiovascular benefits of the traditional MedDiet have been scrutinized extensively over the years.
The recent cardiovascular outcome study ‘PREDIMED’ (Prevencio´n con Dieta Mediterra´nea) [16] has provided hardly disputable evidence confirming that MedDiet is an effective dietary approach to reduce CVD risk. This is consistent with a wealth of data having demonstrated the favorable impact of the MedDiet on numerous cardiometabolic risk factors, including plasma lipids [28]. To our knowledge, only one study so far has documented the impact of MedDiet on lipoprotein kinetics. Under isocaloric conditions, 5-week consumption of the MedDiet by men with metabolic syndrome (MetS) increased VLDL apoB-100 FCR (þ26.3%, Fig. 1) compared with a North American control diet, part of which was attributable to a concurrent reduction in apoC-III concentrations in this fraction (41.5%). However, this had no effect on VLDL apoB-100 pool size or triglyceride concentrations, probably because of a compensating small but nonsignificant increase in VLDL apo-100 production rate (þ15.5%). Consistent with the data from previous meta-analyses, MedDiet combined with weight loss (10% body weight) significantly reduced plasma VLDL–triglyceride concentrations (28.5%) and VLDL apoB-100 pool size (10.8%), most likely because of enhanced FCR of these particles (þ30.7%) along with a further reduction in VLDL apoC-III concentrations (58.3%) compared with the control diet. Short-term consumption of the MedDiet reduced plasma LDL-C by 9.9%, primarily through an increase in the FCR of LDL apoB100 (þ32.3%, Fig. 1), with no significant change in LDL apoB100 production rate [10 ]. Endogenous cholesterol synthesis estimated by plasma lathosterol concentration was unchanged with MedDiet, but proprotein convertase subtilisin/ kexin type 9 (PCSK9) concentrations were significantly reduced [29], consistent with the role of this &&
60% Weight loss
MedDiet vs. control diet
50%
No
Yes
*
40% 30%
*
20%
*
*
*
10% 0% –10%
PS
PS *
FCR
PR
PR
*
–20% –30%
FCR *
VLDL apoB-100
LDL apoB-100
FIGURE 1. Impact of short-term consumption of the Mediterranean diet (MedDiet) on VLDL and LDL apoB-100 kinetics in men with metabolic syndrome. FCR, fractional catabolic rate; PR, production rate; PS, pool size. P < 0.05 vs. the control North American diet. Reproduced with permission from [10 ]. &&
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protein in regulating LDL receptor activity and hence LDL clearance [30]. sdLDL particles compared with large LDL are known to have a lower affinity for the LDL receptor and hence to be cleared less rapidly from the circulation [31]. Consumption of the MedDiet in the absence of weight loss reduced the proportion of sdLDL compared with the control diet. The concomitant reductions in cholesteryl ester transfer protein (7.0%) and hepatic lipase concentrations (7.1%) in plasma may have contributed to this phenomenon [10 ]. The fact that LDL were larger after MedDiet is therefore another factor potentially responsible for the enhanced clearance of LDL. We suspect that the reduced amount of SFAs and TFAs and increased amount of MUFAs are key dietary features responsible for the enhanced clearance of LDL particles with MedDiet. Interestingly, MedDiet combined with significant weight loss increased the production rate of LDL apoB-100 vs. the North American control diet, but had no further effect on LDL concentration [10 ]. This increase in the production of LDL with the combination of MedDiet and weight loss is likely to be attributable, at least in part, to a parallel enhancement of VLDL particle turnover, that is, an accelerated conversion rate of VLDL to IDL (þ74%) and IDL to LDL (þ52%) [10 ]. Short-term consumption of the MedDiet by men with MetS had no major impact on plasma HDL-C concentrations, but the response was highly heterogeneous [9 ]. Those among whom HDL-C increased with MedDiet (DHDL-C: þ9.9%, n ¼ 11) had a reduction in apoA-I FCR and VLDL–triglyceride concentrations compared with those among whom HDL-C levels were reduced after the MedDiet (DHDL-C: 12.0%, n ¼ 8). Variations in apoA-I FCR (r ¼ 0.48, P ¼ 0.01) and in plasma VLDL–triglyceride (r ¼ 0.45, P ¼ 0.03) concentrations also correlated with the individual’s HDL-C response to the MedDiet. These data suggest that the primary determinant of the highly variable HDL response to MedDiet relates to the diet-induced variations in HDL catabolism rather than the rate of synthesis.
of reduction in apoA-I FCR [11]. Sample size was relatively limited in that study, but data suggested that the reduction in VLDL apoB-100 pool size with the high MUFA portfolio diet compared with baseline values on a prudent NCEP diet was because of an enhanced channeling of these particles toward IDL and LDL [11]. The FCR of LDL apoB-100 with the high MUFA portfolio diet was also increased compared with baseline. This suggests that replacing CHOs with MUFAs in a dietary portfolio of cholesterol-lowering foods may contribute to enhancing LDL clearance rate and reducing HDL catabolism, thus potentiating further the well known cholesterol-lowering effect of this diet.
Portfolio diet
Conflicts of interest B.L. and P.C. have received research grants from the Agriculture and Agri-Food Canada Dairy Cluster, the Dairy Famers of Canada, Merck Canada, and the Canadian Institutes for Health Research. P.C. has received research funding from Amgen, Sanofi, Aegerion, and Kaneka Pharma America LLC, and honoraria from Merck Canada, Amgen, and Aegerion. B.L. has received research funding from the Danone Institute and Atrium Innovations, and honoraria from Unilever, Danone Institute, and the Dairy Farmers of Canada. B.L. is Laval
&&
&&
&&
&
The portfolio diet combines different foods with established cholesterol-lowering properties, namely soluble fibers, phytosterols, nuts, and soy protein [32]. This diet has been shown to be particularly potent in reducing plasma LDL-C but has little effect on plasma HDL-C concentrations [33,34]. Unlike a regular portfolio diet, a MUFA-rich portfolio diet increases plasma HDL-C concentrations [35]. This increase in HDL and in apoA-I pool size with a high MUFA portfolio diet appears to be primarily because 46
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CONCLUSION A relatively small number of studies have investigated and compared the impact of different fatty acids on lipoprotein kinetics in humans using modern tracer technologies. Nevertheless, the impact of SFAs, TFAs, and of n3 PUFAs on lipoprotein metabolism in humans has been fairly well characterized. On the other hand, we are lacking valuable information regarding the impact of MUFAs and n-6 PUFAs, for which associations with cardiovascular risk remains controversial. Additional metabolic and kinetic studies are therefore needed to shed more light on those specific topics. A few reports from our group have provided insightful information on how cardioprotective diets such as the MedDiet and the portfolio diet influence lipoprotein kinetics in vivo. But kinetic studies of other heart healthy diets such as the Dietary Approach to Stop Hypertension (DASH) would be extremely helpful in the future to better appreciate their impact on cardiometabolic health. Acknowledgements None. Financial support and sponsorship None.
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University’s Chair of Nutrition, supported in part by the Provigo/Loblaws, Pfizer and la Banque Royale du Canada.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Shepherd J, Packard CJ, Grundy SM, et al. Effects of saturated and polyunsaturated fat diets on the chemical composition and metabolism of low density lipoproteins in man. J Lipid Res 1980; 21:91–99. 2. Turner JD, Le NA, Brown WV. Effect of changing dietary fat saturation on low-density lipoprotein metabolism in man. Am J Physiol 1981; 241:E57– E63. 3. Brinton EA, Eisenberg S, Breslow JL. A low-fat diet decreases high density lipoprotein (HDL) cholesterol levels by decreasing HDL apolipoprotein transport rates. J Clin Invest 1990; 85:144–151. 4. Tremblay AJ, Lamarche B, Labonte´ ME, et al. Dietary medium-chain triglycer&& ide supplementation has no effect on apolipoprotein B-48 and apolipoprotein B-100 kinetics in insulin-resistant men. Am J Clin Nutr 2014; 99:54–61. A randomized, double-blind, placebo-controlled study showing no significant impact of a dietary MCT supplementation on TRL apoB-48 and VLDL apoB-100 kinetics and intestinal expression of key genes involved in lipoprotein metabolism. 5. Desroches S, Paradis ME, Perusse M, et al. Apolipoprotein A-I, A-II, and VLDL-B-100 metabolism in men: comparison of a low-fat diet and a highmonounsaturated fatty acid diet. J Lipid Res 2004; 45:2331–2338. 6. Zheng C, Khoo C, Furtado J, et al. Dietary monounsaturated fat activates metabolic pathways for triglyceride-rich lipoproteins that involve apolipoproteins E and C-III. Am J Clin Nutr 2008; 88:272–281. 7. Matthan NR, Welty FK, Barrett PH, et al. Dietary hydrogenated fat increases high-density lipoprotein apoA-I catabolism and decreases low-density lipoprotein apoB-100 catabolism in hypercholesterolemic women. Arterioscler Thromb Vasc Biol 2004; 24:1092–1097. 8. Ooi EM, Lichtenstein AH, Millar JS, et al. Effects of therapeutic lifestyle change diets high and low in dietary fish-derived FAs on lipoprotein metabolism in middle-aged and elderly subjects. J Lipid Res 2012; 53:1958–1967. 9. Richard C, Couture P, Desroches S, et al. Effect of an isoenergetic traditional & Mediterranean diet on apolipoprotein A-I kinetic in men with metabolic syndrome. Nutr J 2013; 12:76. This study reported that short-term consumption of the MedDiet by men with metabolic syndrome was associated with highly heterogeneous response in HDLC concentrations and HDL apoA-I kinetics. 10. Richard C, Couture P, Ooi EM, et al. Effect of Mediterranean diet with and && without weight loss on apolipoprotein B100 metabolism in men with metabolic syndrome. Arterioscler Thromb Vasc Biol 2014; 34:433–438. The first study demonstrating that short-term consumption of the MedDiet reduces plasma LDL-C primarily through an increase in the clearance of LDL apoB-100, with no significant change in LDL apoB-100 production rate. 11. Labonte ME, Jenkins DJ, Lewis GF, et al. Adding MUFA to a dietary portfolio of cholesterol-lowering foods reduces apoAI fractional catabolic rate in subjects with dyslipidaemia. Br J Nutr 2013; 110:426–436. 12. Zimmerman J, Eisenberg S, Kaufmann NA, et al. Effect of moderate isocaloric modification of dietary carbohydrate on high-density lipoprotein composition and apolipoprotein A-1 turnover in humans. Isr J Med Sci 1986; 22:95–104. 13. Babayan VK. Medium chain triglycerides and structured lipids. Lipids 1987; 22:417–420. 14. Swift LL, Hill JO, Peters JC, Greene HL. Plasma lipids and lipoproteins during 6 d of maintenance feeding with long-chain, medium-chain, and mixed-chain triglycerides. Am J Clin Nutr 1992; 56:881–886.
15. St-Onge MP, Bosarge A, Goree LL, Darnell B. Medium chain triglyceride oil consumption as part of a weight loss diet does not lead to an adverse metabolic profile when compared to olive oil. J Am Coll Nutr 2008; 27:547 – 552. 16. Estruch R, Ros E, Salas-Salvado J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013; 368:1279–1290. 17. Martinez-Gonzalez MA, Bes-Rastrollo M. Dietary patterns, Mediterranean diet, & and cardiovascular disease. Curr Opin Lipidol 2014; 25:20–26. A critical review of the current knowledge of the Mediterranean diet and CVD risk. 18. Rudel LL, Kelley K, Sawyer JK, et al. Dietary monounsaturated fatty acids promote aortic atherosclerosis in LDL receptor-null, human ApoB100-overexpressing transgenic mice. Arterioscler Thromb Vasc Biol 1998; 18:1818–1827. 19. Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr 2003; 77:1146–1155. 20. Schwingshackl L, Strasser B, Hoffmann G. Effects of monounsaturated fatty acids on cardiovascular risk factors: a systematic review and meta-analysis. Ann Nutr Metab 2011; 59:176–186. 21. Desroches S, Ruel IL, Deshaies Y, et al. Kinetics of plasma apolipoprotein C-III as a determinant of diet-induced changes in plasma triglyceride levels. Eur J Clin Nutr 2008; 62:10–17. 22. Mozaffarian D, Katan MB, Ascherio A, et al. Trans fatty acids and cardiovascular disease. N Engl J Med 2006; 354:1601–1613. 23. Aronis KN, Khan SM, Mantzoros CS. Effects of trans fatty acids on glucose homeostasis: a meta-analysis of randomized, placebo-controlled clinical trials. Am J Clin Nutr 2012; 96:1093–1099. 24. Mozaffarian D, Clarke R. Quantitative effects on cardiovascular risk factors and coronary heart disease risk of replacing partially hydrogenated vegetable oils with other fats and oils. Eur J Clin Nutr 2009; 63 (Suppl. 2):S22–S33. 25. Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol 2011; 58:2047–2067. 26. Weintraub MS, Zechner R, Brown A, et al. Dietary polyunsaturated fats of the W6 and W3 series reduce postprandial lipoprotein levels. Chronic and acute effects of fat saturation on postprandial lipoprotein metabolism. J Clin Invest 1988; 82:1884–1893. 27. Bergeron N, Havel RJ. Influence of diets rich in saturated and omega-6 polyunsaturated fatty acids on the postprandial responses of apolipoproteins B-48, B-100, E, and lipids in triglyceride-rich lipoproteins. Arterioscler Thromb Vasc Biol 1995; 15:2111–2121. 28. Kastorini CM, Milionis HJ, Esposito K, et al. The effect of Mediterranean diet on metabolic syndrome and its components: a meta-analysis of 50 studies and 534,906 individuals. J Am Coll Cardiol 2011; 57:1299–1313. 29. Richard C, Couture P, Desroches S, et al. Effect of the Mediterranean diet with and without weight loss on surrogate markers of cholesterol homeostasis in men with the metabolic syndrome. Br J Nutr 2012; 107:705–711. 30. Chan DC, Lambert G, Barrett PH, et al. Plasma proprotein convertase subtilisin/kexin type 9: a marker of LDL apolipoprotein B-100 catabolism? Clin Chem 2009; 55:2049–2052. 31. Lamarche B, Lemieux I, Despres JP. The small, dense LDL phenotype and the risk of coronary heart disease: epidemiology, patho-physiology and therapeutic aspects. Diabetes Metab 1999; 25:199–211. 32. Jenkins DJ, Josse AR, Wong JM, et al. The portfolio diet for cardiovascular risk reduction. Curr Atheroscler Rep 2007; 9:501–507. 33. Jenkins DJ, Jones PJ, Lamarche B, et al. Effect of a dietary portfolio of cholesterol-lowering foods given at 2 levels of intensity of dietary advice on serum lipids in hyperlipidemia: a randomized controlled trial. JAMA 2011; 306:831–839. 34. Jenkins DJ, Kendall CW, Marchie A, et al. Effects of a dietary portfolio of cholesterol-lowering foods vs lovastatin on serum lipids and C-reactive protein. JAMA 2003; 290:502–510. 35. Jenkins DJ, Chiavaroli L, Wong JM, et al. Adding monounsaturated fatty acids to a dietary portfolio of cholesterol-lowering foods in hypercholesterolemia. CMAJ 2010; 182:1961–1967.
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Dietary fatty acids, dietary patterns, and lipoprotein metabolism Benoıˆt Lamarche and Patrick Couture
Purpose of review Few studies have reviewed the impact of dietary fat and dietary patterns on lipoprotein metabolism. This review intends to provide perspective on this topic, while focusing primarily on the studies that assessed intravascular lipoprotein kinetics in humans using isotope methodologies. Recent findings Data suggest that dietary saturated fatty acids slow the clearance of LDL apolipoprotein (apo)B-100 and of apoA-I from the circulation, whereas possibly increasing also apoA-I production. Dietary trans fats reduce the clearance of LDL apoB-100, whereas increasing the clearance of apoA-I. n3 polyunsaturated fatty acids (PUFAs) intake reduces the production of apoB-48-containing lipoproteins as well as of VLDL apoB100 and increases their conversion into smaller lipoproteins. Medium-chain triglycerides appear to have no significant effect on lipoprotein kinetics. Finally, Mediterranean diet in the absence of weight loss reduces LDL cholesterol, primarily by enhancing its clearance from the circulation. Summary Kinetic studies with tracers allow a better appreciation of the impact of specific dietary factors on plasma lipid risk factors. However, additional studies are required to better document the effect of monounsaturated fatty acids, n6 PUFAs, and of whole diets on lipoprotein metabolism. Keywords dietary fat, diets, lipoprotein kinetics
INTRODUCTION Since the early studies of Keys and colleagues in the 1950s, we have accrued considerable knowledge on how dietary fats and dietary patterns influence key cardiometabolic risk factors, including LDL, HDL, and VLDL. Tracer-based metabolic studies that have allowed the investigation of in-vivo lipoprotein metabolism in humans have provided perspective on how dietary modifications modulate each of these key lipid risk factors. This article reviews the evidence pertaining to how individual categories of dietary fatty acids as well as whole dietary patterns influence the intravascular metabolism of lipoproteins in humans. We have focused our analysis primarily on the studies that have used methods involving tracers, when such data were available.
the time, modulate in-vivo lipoprotein metabolism in humans. Using radiolabeled lipoproteins, Shepherd et al. [1] and Turner et al. [2] have provided the first evidence that total fat and SFAs increase plasma LDL cholesterol (LDL-C), primarily by reducing the fractional catabolic rate (FCR) of these lipoproteins. We have come a long way since these early pioneer studies. Table 1 summarizes the impact of various dietary fats on lipoprotein kinetics and diets as discussed in the sections that follow.
Total fat and saturated fatty acids In 1986, Zimmerman et al. [12] have shown that feeding normotriglyceride and hypertriglyceride Institute of Nutrition and Functional Foods, Laval University, Quebec City, Quebec, Canada
DIETARY FATTY ACIDS AND LIPOPROTEIN METABOLISM Studies published in 1980 have provided the first evidence on how dietary fat and saturated fatty acids (SFAs), the two main features of dietary guidelines at www.co-lipidology.com
Correspondence to Benoıˆt Lamarche, PhD, Institute of Nutrition and Functional Foods, Laval University, 2440, Boulevard Hochelaga, Que´bec City, QC, Canada G1V 0A6. Tel: +1 418 656 3527; fax: +1 418 656 5877; e-mail: [email protected] Curr Opin Lipidol 2015, 26:42–47 DOI:10.1097/MOL.0000000000000139 Volume 26 Number 1 February 2015
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Li poprotein metabolism Lamarche and Couture
KEY POINTS Kinetic studies with tracers have been very informative to better understand the impact of specific dietary factors on cardiometabolic risk factors. Dietary SFAs slows the clearance of LDL apoB and apoA-I from the circulation, whereas increasing apoA-I production. Dietary trans fat reduces the clearance of LDL apoB-100, whereas increasing the catabolism of apoA-I. Long-chain n3 PUFAs decrease nonfasting plasma TRL apoB-100 concentrations, TRL apoB-100 production rate, and direct catabolism of these particles, and accelerate the conversion of TRL to LDL. n3 PUFAs also decrease the concentration, catabolism, and production rate of TRL apoB-48. Further metabolic and kinetic studies are required to shed more light on how dietary MUFAs, n6 PUFAs, and specific dietary patterns such as the MedDiet and the portfolio diet influence lipoprotein metabolism in vivo.
individuals a high-fat and low-carbohydrate (CHO) diet (41–45% of calories from fat) vs. a low-fat and high-CHO diet (29% from fat) significantly reduced
plasma triglyceride and VLDL apolipoprotein (apo) B-100 levels, and increased LDL-C and HDL-C concentrations. ApoA-I kinetic studies using radiolabeling techniques revealed that both the production rate and the FCR of apoA-I were reduced after the high-fat diet; hence, the increase in HDL-C concentrations after a high-fat diet appeared to be attributed primarily to the reduced rate of clearance of these particles. On the other hand, Brinton et al. [3] have later shown that the increase in plasma HDL-C upon switching from a low to a high SFA and cholesterol diet was primarily because of an increase in the production rate of apoA-I. However, they have also shown that patients’ HDL-C levels on any of the low or high fat diet correlated more strongly with variations in FCR rather than with variations in production rate. The authors suggested that whereas diet-induced changes in HDL-C levels may be determined primarily by the changes in lipoprotein synthesis rather than by changes in clearance, differences in HDL-C levels between individuals on a given diet may be better predicted by differences in clearance rates than by differences in synthesis. Taken together, results from these studies suggest that changes in both the synthesis (increase) as well as clearance (reduction) may account to various extents for the increase in HDL-C concentrations
Table 1. Summary of the available evidence on the effect of dietary fatty acids and whole diets on metrics of lipoprotein kinetics based on studies with radio or stable isotopes in humans TRL apoB-48 Fatty acids SFAa
VLDL apoB-100
Pool size
Production rate
FCR
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
Pool size
LDL apoB-100
Production rate
FCR
nd
nd
b
MCT
MUFAc
HDL, apoAI
Pool size
Production rate
FCR
Pool size
Production rate
FCR
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
TFAd n3 PUFAe n6 PUFAf
nd
nd
nd
Whole diets MedDietg High MUFA Portfolioh FCR, fractional catabolic rate; IDL, intermediate density lipoprotein; MCT, medium-chain triglyceride; MUFA, monounsaturated fatty acid; ND, not yet determined; PUFA, polyunsaturated fatty acid; SFA, saturated fatty acid; TFA, trans fatty acid; TRL, triglyceride-rich lipoprotein; , no change; , increase; , reduction. a Vs. low-fat and carbohydrate-rich diet [1–3]. && b Vs. corn oil [4 ]. c Both a reduction in production rate and increase in FCR contribute to the reduced VLDL apoB-100 mass with MUFA. The increased LDL apoB-100 FCR was seen in small, dense LDL containing both apoE and apoC-III [5,6]. d Vs. sunflower oil or SFA [7]. e Long-chain n3 PUFA vs. baseline values. The increased VLDL apoB-100 FCR was primarily because of an accelerated conversion to IDL/LDL, which also translated into an increased production rate of LDL apoB-100 [8]. f No kinetic study with tracers available yet. & && g Mediterranean diet (MedDiet) in the absence of weight loss [9 ,10 ]. h Dietary Portfolio of cholesterol-lowering foods, enriched in MUFA [11].
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generally after consumption of a high-fat/highSFA diet.
Medium-chain triglycerides Medium-chain triglycerides (MCTs) are 6–12 carbon fatty acids of interest because of their unique metabolism [13]. Although the therapeutic use of MCTs to reduce plasma triglyceride is well accepted in patients with severe hypertriglyceridemia, their efficacy in patients with other forms of lipid disorders remains equivocal. Inconsistencies in results may be due in part to the different doses of MCTs that have been given to patients in the various studies [14,15]. We have recently shown that supplementing obese insulin-resistant men with 20 g/ day MCTs for 4 weeks compared with corn oil had no impact on plasma lipids, triglyceride-rich lipoprotein (TRL) apoB-48 and VLDL apoB-100 kinetics, and on intestinal mRNA expression levels of key genes involved in lipid metabolism [4 ]. Kinetics of LDL apoB-100 and of apoA-I were not investigated in that study. Further studies are needed to examine the impact of different doses of MCTs on plasma lipids as well as on lipoprotein kinetics in various at-risk populations. &&
Monounsaturated fatty acids The impact of dietary monounsaturated fatty acids (MUFAs) on cardiometabolic risk factors remains somewhat controversial. Indeed, whereas several lines of indirect evidence from clinical trials [16] as well as epidemiology [17 ] indicate that dietary MUFAs may have beneficial effects on atherogenesis in humans, data from animal models suggest the opposite [18]. Interestingly, the significant beneficial impacts of MUFAs on HDL-C (increase) and triglyceride and LDL-C concentrations (reductions) seen in the meta-analysis by Mensink et al. [19] have not been reproduced in the most recent meta-analysis of studies comparing high vs. low MUFA diets specifically [20]. Few studies have examined the effects of MUFAs on lipoprotein metabolism in humans. The reduction in VLDL apoB-100 and triglyceride levels after a 6-week high-MUFA diet in men with abdominal obesity has been related primarily to variations in VLDL apoB-100 production rate [5] and to variations in plasma apoC-III production rate [21]. There was no change in plasma HDL-C concentrations after the high-MUFA diet, which was consistent with the lack of change in apoA-I kinetics. LDL apoB-100 kinetics were not investigated in this small study. Zheng et al. [6] have shown that replacing 17% of total energy intake from complex CHO with MUFAs increased VLDL and intermediate density &
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lipoprotein (IDL) apoB-100 catabolism, with no overall change in LDL apoB-100 kinetics. The high-MUFA diet doubled the proportion of TRL that are cleared directly from the circulation rather than being converted into LDL, and this was related to a large extent to the apoE and C-III content of the TRL. The authors also showed increased clearance rate of small, dense LDL (sdLDL) that contained both apoE and apoC-III after the high-MUFA diet. They concluded that a high vs. low MUFA diet stimulates the catabolism of TRL and LDL that contain both apoE and apoC-III and suppresses the metabolism of TRL that do not contain these apolipoproteins [6].
Trans fatty acids Increased consumption of trans fatty acids (TFAs) has been associated consistently with an increased risk of CHD [22]. Consumption of TFAs from hydrogenated vegetable oil has been shown to increase plasma LDLC and to reduce HDL-C concentrations, resulting in a less favorable LDL-C/HDL-C ratio even compared with SFAs [22]. High TFA consumption has also been associated with increased plasma triglyceride [23] and lipoprotein (a) concentrations [24]. The elevated LDL-C levels associated with dietary TFAs have been attributed to a reduced LDL apoB-100 FCR, with no significant effects on the production rate of these lipoproteins [7]. Increased apoA-I catabolism appears to be the primary determinant of the reduction in plasma HDL-C levels with TFAs [7]. Consumption of TFAs has no effect on TRL apoB-48 and TRL apoB-100 kinetics [7]. This is the only study available so far on this topic and additional investigations, with particular interest on TFAs for natural sources, are needed.
n-3 Polyunsaturated fatty acids Long-chain n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have unique cardioprotective properties, including potent triglyceride-lowering effects [25]. A high n3 PUFA diet (1.23 g/day EPA and DHA) has been show to decrease nonfasting plasma TRL apoB100 concentrations, TRL apoB-100 production rate, and direct catabolism of these particles, and to accelerate the conversion of TRL to LDL in nonobese men and women [8]. Supplementation with n3 PUFAs also decreased the concentration, FCR, and production rate of intestinally derived TRL apoB-48; reduced LDL apoB-100 concentrations by increasing LDL apoB-100 FCR; and reduced HDL apoA-I concentrations by decreasing HDL apoA-I production rate. The impact of n3 fatty acids from vegetable sources (primarily alpha-linolenic acid) on lipoprotein kinetics is yet unknown. Volume 26 Number 1 February 2015
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Li poprotein metabolism Lamarche and Couture
nS6 Polyunsaturated fatty acids The LDL-C-lowering effect of n6 PUFAs vs. SFAs is well established from the clinical studies [19]. Data suggest that chronic intake of n6 PUFAs may also exert beneficial effects on cardiovascular disease (CVD) risk by reducing postprandial lipemia. Weintraub et al. [26] found that 25 days of an n6 PUFArich diet markedly attenuated the postprandial lipid response to a fat load compared with an SFA-rich diet in normolipidemic individuals. Bergeron and Havel [27] found no evidence that levels of SFAs and n6 PUFAs in the diet or in challenge meal have different effects on the clearance of TRL apoB-48 in healthy young men. However, they have shown that postprandial hepatic TRL apoB-100 levels were reduced in individuals who consumed n6 PUFAs for 30 days compared with SFAs, and this was independent of the fatty acid composition of the fat load [27]. Thus, studies suggest that chronic intake of n6 PUFAs has a favorable effect on the postprandial TRL metabolism compared with SFAs. Additional studies are needed to better understand how dietary n6 PUFAs modulate lipoprotein metabolism using tracer methodologies in humans.
DIETARY PATTERNS AND LIPOPROTEIN METABOLISM Very few studies have examined the impact of whole diets on lipoprotein kinetics. To the best of our knowledge, such data are available only for the Mediterranean diet (MedDiet) and the Portfolio diet.
Mediterranean diet The cardiovascular benefits of the traditional MedDiet have been scrutinized extensively over the years.
The recent cardiovascular outcome study ‘PREDIMED’ (Prevencio´n con Dieta Mediterra´nea) [16] has provided hardly disputable evidence confirming that MedDiet is an effective dietary approach to reduce CVD risk. This is consistent with a wealth of data having demonstrated the favorable impact of the MedDiet on numerous cardiometabolic risk factors, including plasma lipids [28]. To our knowledge, only one study so far has documented the impact of MedDiet on lipoprotein kinetics. Under isocaloric conditions, 5-week consumption of the MedDiet by men with metabolic syndrome (MetS) increased VLDL apoB-100 FCR (þ26.3%, Fig. 1) compared with a North American control diet, part of which was attributable to a concurrent reduction in apoC-III concentrations in this fraction (41.5%). However, this had no effect on VLDL apoB-100 pool size or triglyceride concentrations, probably because of a compensating small but nonsignificant increase in VLDL apo-100 production rate (þ15.5%). Consistent with the data from previous meta-analyses, MedDiet combined with weight loss (10% body weight) significantly reduced plasma VLDL–triglyceride concentrations (28.5%) and VLDL apoB-100 pool size (10.8%), most likely because of enhanced FCR of these particles (þ30.7%) along with a further reduction in VLDL apoC-III concentrations (58.3%) compared with the control diet. Short-term consumption of the MedDiet reduced plasma LDL-C by 9.9%, primarily through an increase in the FCR of LDL apoB100 (þ32.3%, Fig. 1), with no significant change in LDL apoB100 production rate [10 ]. Endogenous cholesterol synthesis estimated by plasma lathosterol concentration was unchanged with MedDiet, but proprotein convertase subtilisin/ kexin type 9 (PCSK9) concentrations were significantly reduced [29], consistent with the role of this &&
60% Weight loss
MedDiet vs. control diet
50%
No
Yes
*
40% 30%
*
20%
*
*
*
10% 0% –10%
PS
PS *
FCR
PR
PR
*
–20% –30%
FCR *
VLDL apoB-100
LDL apoB-100
FIGURE 1. Impact of short-term consumption of the Mediterranean diet (MedDiet) on VLDL and LDL apoB-100 kinetics in men with metabolic syndrome. FCR, fractional catabolic rate; PR, production rate; PS, pool size. P < 0.05 vs. the control North American diet. Reproduced with permission from [10 ]. &&
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Nutrition and metabolism
protein in regulating LDL receptor activity and hence LDL clearance [30]. sdLDL particles compared with large LDL are known to have a lower affinity for the LDL receptor and hence to be cleared less rapidly from the circulation [31]. Consumption of the MedDiet in the absence of weight loss reduced the proportion of sdLDL compared with the control diet. The concomitant reductions in cholesteryl ester transfer protein (7.0%) and hepatic lipase concentrations (7.1%) in plasma may have contributed to this phenomenon [10 ]. The fact that LDL were larger after MedDiet is therefore another factor potentially responsible for the enhanced clearance of LDL. We suspect that the reduced amount of SFAs and TFAs and increased amount of MUFAs are key dietary features responsible for the enhanced clearance of LDL particles with MedDiet. Interestingly, MedDiet combined with significant weight loss increased the production rate of LDL apoB-100 vs. the North American control diet, but had no further effect on LDL concentration [10 ]. This increase in the production of LDL with the combination of MedDiet and weight loss is likely to be attributable, at least in part, to a parallel enhancement of VLDL particle turnover, that is, an accelerated conversion rate of VLDL to IDL (þ74%) and IDL to LDL (þ52%) [10 ]. Short-term consumption of the MedDiet by men with MetS had no major impact on plasma HDL-C concentrations, but the response was highly heterogeneous [9 ]. Those among whom HDL-C increased with MedDiet (DHDL-C: þ9.9%, n ¼ 11) had a reduction in apoA-I FCR and VLDL–triglyceride concentrations compared with those among whom HDL-C levels were reduced after the MedDiet (DHDL-C: 12.0%, n ¼ 8). Variations in apoA-I FCR (r ¼ 0.48, P ¼ 0.01) and in plasma VLDL–triglyceride (r ¼ 0.45, P ¼ 0.03) concentrations also correlated with the individual’s HDL-C response to the MedDiet. These data suggest that the primary determinant of the highly variable HDL response to MedDiet relates to the diet-induced variations in HDL catabolism rather than the rate of synthesis.
of reduction in apoA-I FCR [11]. Sample size was relatively limited in that study, but data suggested that the reduction in VLDL apoB-100 pool size with the high MUFA portfolio diet compared with baseline values on a prudent NCEP diet was because of an enhanced channeling of these particles toward IDL and LDL [11]. The FCR of LDL apoB-100 with the high MUFA portfolio diet was also increased compared with baseline. This suggests that replacing CHOs with MUFAs in a dietary portfolio of cholesterol-lowering foods may contribute to enhancing LDL clearance rate and reducing HDL catabolism, thus potentiating further the well known cholesterol-lowering effect of this diet.
Portfolio diet
Conflicts of interest B.L. and P.C. have received research grants from the Agriculture and Agri-Food Canada Dairy Cluster, the Dairy Famers of Canada, Merck Canada, and the Canadian Institutes for Health Research. P.C. has received research funding from Amgen, Sanofi, Aegerion, and Kaneka Pharma America LLC, and honoraria from Merck Canada, Amgen, and Aegerion. B.L. has received research funding from the Danone Institute and Atrium Innovations, and honoraria from Unilever, Danone Institute, and the Dairy Farmers of Canada. B.L. is Laval
&&
&&
&&
&
The portfolio diet combines different foods with established cholesterol-lowering properties, namely soluble fibers, phytosterols, nuts, and soy protein [32]. This diet has been shown to be particularly potent in reducing plasma LDL-C but has little effect on plasma HDL-C concentrations [33,34]. Unlike a regular portfolio diet, a MUFA-rich portfolio diet increases plasma HDL-C concentrations [35]. This increase in HDL and in apoA-I pool size with a high MUFA portfolio diet appears to be primarily because 46
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CONCLUSION A relatively small number of studies have investigated and compared the impact of different fatty acids on lipoprotein kinetics in humans using modern tracer technologies. Nevertheless, the impact of SFAs, TFAs, and of n3 PUFAs on lipoprotein metabolism in humans has been fairly well characterized. On the other hand, we are lacking valuable information regarding the impact of MUFAs and n-6 PUFAs, for which associations with cardiovascular risk remains controversial. Additional metabolic and kinetic studies are therefore needed to shed more light on those specific topics. A few reports from our group have provided insightful information on how cardioprotective diets such as the MedDiet and the portfolio diet influence lipoprotein kinetics in vivo. But kinetic studies of other heart healthy diets such as the Dietary Approach to Stop Hypertension (DASH) would be extremely helpful in the future to better appreciate their impact on cardiometabolic health. Acknowledgements None. Financial support and sponsorship None.
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Li poprotein metabolism Lamarche and Couture
University’s Chair of Nutrition, supported in part by the Provigo/Loblaws, Pfizer and la Banque Royale du Canada.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Shepherd J, Packard CJ, Grundy SM, et al. Effects of saturated and polyunsaturated fat diets on the chemical composition and metabolism of low density lipoproteins in man. J Lipid Res 1980; 21:91–99. 2. Turner JD, Le NA, Brown WV. Effect of changing dietary fat saturation on low-density lipoprotein metabolism in man. Am J Physiol 1981; 241:E57– E63. 3. Brinton EA, Eisenberg S, Breslow JL. A low-fat diet decreases high density lipoprotein (HDL) cholesterol levels by decreasing HDL apolipoprotein transport rates. J Clin Invest 1990; 85:144–151. 4. Tremblay AJ, Lamarche B, Labonte´ ME, et al. Dietary medium-chain triglycer&& ide supplementation has no effect on apolipoprotein B-48 and apolipoprotein B-100 kinetics in insulin-resistant men. Am J Clin Nutr 2014; 99:54–61. A randomized, double-blind, placebo-controlled study showing no significant impact of a dietary MCT supplementation on TRL apoB-48 and VLDL apoB-100 kinetics and intestinal expression of key genes involved in lipoprotein metabolism. 5. Desroches S, Paradis ME, Perusse M, et al. Apolipoprotein A-I, A-II, and VLDL-B-100 metabolism in men: comparison of a low-fat diet and a highmonounsaturated fatty acid diet. J Lipid Res 2004; 45:2331–2338. 6. Zheng C, Khoo C, Furtado J, et al. Dietary monounsaturated fat activates metabolic pathways for triglyceride-rich lipoproteins that involve apolipoproteins E and C-III. Am J Clin Nutr 2008; 88:272–281. 7. Matthan NR, Welty FK, Barrett PH, et al. Dietary hydrogenated fat increases high-density lipoprotein apoA-I catabolism and decreases low-density lipoprotein apoB-100 catabolism in hypercholesterolemic women. Arterioscler Thromb Vasc Biol 2004; 24:1092–1097. 8. Ooi EM, Lichtenstein AH, Millar JS, et al. Effects of therapeutic lifestyle change diets high and low in dietary fish-derived FAs on lipoprotein metabolism in middle-aged and elderly subjects. J Lipid Res 2012; 53:1958–1967. 9. Richard C, Couture P, Desroches S, et al. Effect of an isoenergetic traditional & Mediterranean diet on apolipoprotein A-I kinetic in men with metabolic syndrome. Nutr J 2013; 12:76. This study reported that short-term consumption of the MedDiet by men with metabolic syndrome was associated with highly heterogeneous response in HDLC concentrations and HDL apoA-I kinetics. 10. Richard C, Couture P, Ooi EM, et al. Effect of Mediterranean diet with and && without weight loss on apolipoprotein B100 metabolism in men with metabolic syndrome. Arterioscler Thromb Vasc Biol 2014; 34:433–438. The first study demonstrating that short-term consumption of the MedDiet reduces plasma LDL-C primarily through an increase in the clearance of LDL apoB-100, with no significant change in LDL apoB-100 production rate. 11. Labonte ME, Jenkins DJ, Lewis GF, et al. Adding MUFA to a dietary portfolio of cholesterol-lowering foods reduces apoAI fractional catabolic rate in subjects with dyslipidaemia. Br J Nutr 2013; 110:426–436. 12. Zimmerman J, Eisenberg S, Kaufmann NA, et al. Effect of moderate isocaloric modification of dietary carbohydrate on high-density lipoprotein composition and apolipoprotein A-1 turnover in humans. Isr J Med Sci 1986; 22:95–104. 13. Babayan VK. Medium chain triglycerides and structured lipids. Lipids 1987; 22:417–420. 14. Swift LL, Hill JO, Peters JC, Greene HL. Plasma lipids and lipoproteins during 6 d of maintenance feeding with long-chain, medium-chain, and mixed-chain triglycerides. Am J Clin Nutr 1992; 56:881–886.
15. St-Onge MP, Bosarge A, Goree LL, Darnell B. Medium chain triglyceride oil consumption as part of a weight loss diet does not lead to an adverse metabolic profile when compared to olive oil. J Am Coll Nutr 2008; 27:547 – 552. 16. Estruch R, Ros E, Salas-Salvado J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013; 368:1279–1290. 17. Martinez-Gonzalez MA, Bes-Rastrollo M. Dietary patterns, Mediterranean diet, & and cardiovascular disease. Curr Opin Lipidol 2014; 25:20–26. A critical review of the current knowledge of the Mediterranean diet and CVD risk. 18. Rudel LL, Kelley K, Sawyer JK, et al. Dietary monounsaturated fatty acids promote aortic atherosclerosis in LDL receptor-null, human ApoB100-overexpressing transgenic mice. Arterioscler Thromb Vasc Biol 1998; 18:1818–1827. 19. Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr 2003; 77:1146–1155. 20. Schwingshackl L, Strasser B, Hoffmann G. Effects of monounsaturated fatty acids on cardiovascular risk factors: a systematic review and meta-analysis. Ann Nutr Metab 2011; 59:176–186. 21. Desroches S, Ruel IL, Deshaies Y, et al. Kinetics of plasma apolipoprotein C-III as a determinant of diet-induced changes in plasma triglyceride levels. Eur J Clin Nutr 2008; 62:10–17. 22. Mozaffarian D, Katan MB, Ascherio A, et al. Trans fatty acids and cardiovascular disease. N Engl J Med 2006; 354:1601–1613. 23. Aronis KN, Khan SM, Mantzoros CS. Effects of trans fatty acids on glucose homeostasis: a meta-analysis of randomized, placebo-controlled clinical trials. Am J Clin Nutr 2012; 96:1093–1099. 24. Mozaffarian D, Clarke R. Quantitative effects on cardiovascular risk factors and coronary heart disease risk of replacing partially hydrogenated vegetable oils with other fats and oils. Eur J Clin Nutr 2009; 63 (Suppl. 2):S22–S33. 25. Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol 2011; 58:2047–2067. 26. Weintraub MS, Zechner R, Brown A, et al. Dietary polyunsaturated fats of the W6 and W3 series reduce postprandial lipoprotein levels. Chronic and acute effects of fat saturation on postprandial lipoprotein metabolism. J Clin Invest 1988; 82:1884–1893. 27. Bergeron N, Havel RJ. Influence of diets rich in saturated and omega-6 polyunsaturated fatty acids on the postprandial responses of apolipoproteins B-48, B-100, E, and lipids in triglyceride-rich lipoproteins. Arterioscler Thromb Vasc Biol 1995; 15:2111–2121. 28. Kastorini CM, Milionis HJ, Esposito K, et al. The effect of Mediterranean diet on metabolic syndrome and its components: a meta-analysis of 50 studies and 534,906 individuals. J Am Coll Cardiol 2011; 57:1299–1313. 29. Richard C, Couture P, Desroches S, et al. Effect of the Mediterranean diet with and without weight loss on surrogate markers of cholesterol homeostasis in men with the metabolic syndrome. Br J Nutr 2012; 107:705–711. 30. Chan DC, Lambert G, Barrett PH, et al. Plasma proprotein convertase subtilisin/kexin type 9: a marker of LDL apolipoprotein B-100 catabolism? Clin Chem 2009; 55:2049–2052. 31. Lamarche B, Lemieux I, Despres JP. The small, dense LDL phenotype and the risk of coronary heart disease: epidemiology, patho-physiology and therapeutic aspects. Diabetes Metab 1999; 25:199–211. 32. Jenkins DJ, Josse AR, Wong JM, et al. The portfolio diet for cardiovascular risk reduction. Curr Atheroscler Rep 2007; 9:501–507. 33. Jenkins DJ, Jones PJ, Lamarche B, et al. Effect of a dietary portfolio of cholesterol-lowering foods given at 2 levels of intensity of dietary advice on serum lipids in hyperlipidemia: a randomized controlled trial. JAMA 2011; 306:831–839. 34. Jenkins DJ, Kendall CW, Marchie A, et al. Effects of a dietary portfolio of cholesterol-lowering foods vs lovastatin on serum lipids and C-reactive protein. JAMA 2003; 290:502–510. 35. Jenkins DJ, Chiavaroli L, Wong JM, et al. Adding monounsaturated fatty acids to a dietary portfolio of cholesterol-lowering foods in hypercholesterolemia. CMAJ 2010; 182:1961–1967.
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