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Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269 and * Custom Learning Designs, Inc., 375 Concord Avenue, Belmont, MA 02478
2To whom correspondence should be addressed. E-mail: maria-luz.fernandez{at}uconn.edu.
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ABSTRACT |
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 TOP ABSTRACT Fat saturation and cholesterol...Fat saturation and LDL...Fatty acids and molecular...LITERATURE CITED |
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KEY WORDS: • dietary fat saturation • plasma cholesterol • plasma triglycerides • LDL receptor • molecular regulation
Dietary fat saturation plays a considerable role in modulating plasma cholesterol concentrations and determining the risk for coronary heart disease (CHD).3 In fact, SFAs are recognized as the single dietary factor that has the greatest negative effect on LDL cholesterol (LDL-C) concentrations (1). In contrast, monounsaturated fatty acids (MUFAs) and PUFAs of the (n-6) family have been shown to decrease plasma cholesterol concentrations in clinical studies (2,3) and in various animal models (4–6). According to Hu et al. (7), replacing 5% of the energy of SFAs by unsaturated fatty acids results in a 43% decrease in CHD. Recently trans fatty acids (TFAs) have emerged as the most detrimental type of fat relative to increased risk for CHD, since some studies demonstrated that in addition to increasing plasma LDL-C, TFAs also decrease plasma HDL cholesterol (HDL-C) and may increase lipoprotein (a) (8). PUFAs of the (n-3) family have multiple beneficial effects on CHD risk (9). The present review discusses only the effects of (n-3) PUFAs in modulating VLDL metabolism and reducing plasma triglycerides (TGs).
The concentration of LDL in blood is determined by the production of this lipoprotein via VLDL through the delipidation cascade and the efficiency of its removal from circulation by LDL receptor or nor-receptor mechanisms (6). In addition, the secretion of VLDL is influenced by the availability of apolipoprotein (apo) B in the liver and the activities of regulatory enzymes involved in the assembly and transport of VLDL, including microsomal transfer protein and acyl-coenzyme A (CoA):cholesterol acyltransferase (ACAT). Moreover, the effects of fatty acids in regulating gene expression (10) may also contribute to the mechanisms that determine plasma LDL-C. Fatty acids regulate at least 4 families of transcription factors: the peroxisome proliferator activated receptors (PPARs), liver X receptors (LXRs), hepatic nuclear factor-4 (HNF-4), and sterol regulatory element binding proteins (SREBPs) (10). A brief review of the postulated effects of fatty acids in regulating plasma cholesterol follows.
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Fat saturation and cholesterol synthesis. |
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TOPABSTRACTFat saturation and cholesterol...Fat saturation and LDL...Fatty acids and molecular...LITERATURE CITED |
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Fat saturation and LDL receptors. |
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TOPABSTRACTFat saturation and cholesterol...Fat saturation and LDL...Fatty acids and molecular...LITERATURE CITED |
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Mustad et al. (18) demonstrated that dietary SFA (palmitic acid) markedly decreased LDL receptor protein levels in pigs fed a diet containing 0.25% cholesterol, compared to pigs fed a diet with cholesterol only or to controls fed a low-fat, cholesterol-free diet. In contrast, pigs fed a diet high in PUFA (linoleic acid) had increased LDL receptor levels compared to pigs fed a diet with cholesterol only or a low-fat, cholesterol-free diet (18). These distinct effects of dietary fatty acids were accompanied by parallel changes in LDL receptor mRNA levels. These data provide strong evidence for an independent and positive effect of PUFAs on the regulation of LDL receptor expression. It is important to note that these differential effects of dietary fatty acids were observed only in pigs fed the lowest level of dietary cholesterol, suggesting that high cholesterol intake has a dominant and repressive effect on LDL receptor mRNA levels that cannot be alleviated by fatty acids.
Cholesterol-raising SFAs (12:0, 14:0, 16:0) decrease LDL receptor activity, protein, and mRNA abundance, while unsaturated fatty acids increase these variables. Dietary modification of hepatocyte membrane fluidity may be one way in which diets high in PUFAs affect LDL receptor activity differently than diets enriched in SFAs. Support for this suggestion comes from in vitro studies (19) and studies in rats (20), which showed significant alterations in LDL binding to the LDL receptor as a result of changes in membrane fluidity. It has also been suggested that dietary fatty acids can directly influence the number of receptors available for uptake of circulating LDL by specifically affecting LDL receptor synthesis. In vitro binding studies demonstrated that alterations in LDL uptake associated with dietary fatty acid composition can be attributed to changes in LDL maximal binding (Bmax), an indicator of receptor number (13).
In support of the in vitro studies, PUFAs decreased LDL apo B pool size by 50% and increased LDL fractional catabolic rate (FCR) 2-fold when compared to SFA intake in guinea pigs (16). The differences in plasma LDL-C concentrations, as influenced by the chain length of the saturated fatty acid, were also correlated to both receptor expression (Bmax) and LDL FCR (17). Guinea pigs fed the long-chain SFA had lower plasma LDL-C concentrations, which correlated with the fastest LDL FCR when compared to guinea pigs fed diets high in lauric or myristic acids (16). Similarly, in hamsters lauric, myristic, and pamitic acids increased plasma LDL-C concentrations compared to a diet high in stearic acid by decreasing LDL apo B/E receptor activity and increasing LDL production rate (21).
In vitro studies with different cell types (22) and studies with hamsters (23,24) showed that fatty acids can affect the storage of cholesterol esters and influence sterol distribution. It has been suggested that dietary fatty acids and cholesterol regulate hepatic LDL receptor activity via cholesteryl ester and free cholesterol regulatory pools. These cholesterol regulatory pools are affected by ACAT, the rate-limiting enzyme of cholesterol esterification. SFAs suppress this enzyme, which may result in a greater proportion of cholesterol remaining in the regulatory pool. An increase in hepatic cholesteryl ester is negatively correlated with LDL receptor activity in hamsters (23). However, data from many animal studies are not consistent with this hypothesis. For example, in African green monkeys, an increase in ACAT activity is correlated with increases in plasma LDL cholesterol and increased deposition of cholesterol in the aorta (25).
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Fatty acids and molecular regulation. |
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TOPABSTRACTFat saturation and cholesterol...Fat saturation and LDL...Fatty acids and molecular...LITERATURE CITED |
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PPAR
interacts with both saturated and unsaturated fatty acids, although SFAs have a lower affinity (26). Transcriptional regulation is mediated through peroxisome proliferator response elements (PPREs) in the promoter regions of target genes Target genes in the liver include apoA-I, apoA-II, apoC-III, and lipoprotein lipase (LPL) (27). The coordinated changes in the expression of these genes contribute to hepatic lipid homeostasis by regulating, either directly or indirectly, lipid flux into and out of the liver.
The TG- and cholesterol-lowering action of certain fatty acids is attributable to an enhanced catabolism of TG-rich lipoproteins (TGRLs) and inhibition of hepatic VLDL secretion (27). Effects of fatty acids on TG and cholesterol metabolism are partly mediated by changes in the expression of LPL and apoC-III. LPL hydrolyzes the TG component of chylomicron and VLDL particles, which enables the removal of the remaining lipoprotein remnants from circulation by the liver. In hepatocytes and preadipocytes, fatty acids stimulate the transcription of the LPL gene by binding to a PPRE in the LPL promoter (28). In addition, most human studies report that dietary (n-3) PUFAs decrease the residence time of VLDL in serum (9). However, dietary PUFAs have little or no effect on LPL or hepatic lipase activity in postheparin serum in humans (29). LPL may be more reactive toward VLDL with PUFA TGs as substrate, leading to more rapid lipolysis of TGRLs with dietary PUFAs (30). In addition, dietary (n-3) PUFAs accelerate chylomicrons clearance in rats (31) and enhance the conversion of VLDL apoB to LDL apoB in pigs (32). Overall, the marked decrease in plasma LDL concentrations in animals fed (n-3) PUFAs could be due to reductions in the rate of LDL entry into the plasma, resulting from increased VLDL catabolism (30).
Due to its action in blocking LPL activity, apoC-III levels are positively correlated with plasma TG concentrations (33). Metabolic studies suggest that high levels of apoC-III impair the clearance of TGRLs due to interference with apoE-mediated uptake of these particles by cellular receptors (34). The reduction in apoC-III levels in response to fatty acid intake is thought to enhance the LPL-mediated effects on lipoprotein metabolism, leading to increased catabolism of VLDL particles. Consequentially, the dual action of fatty acids on the expression of the LPL and apoC-III genes provides a potential model by which fatty acids reduce plasma TG concentrations.
HNF-4 is a key regulator of genes involved in glucose, cholesterol, and fatty acid metabolism (35). The promoters of apoA-I, apoA-II, apoA-IV, apoB, apoC-II, and apoC-III all contain binding sites for HNF-4 (35). Increased levels of HDL are correlated with a decreased risk for coronary artery disease. The protective effects of HDL on atherosclerosis are correlated with levels of specific HDL particles. Fatty acids exert a negative effect on apoA-I transcription (36) via a sequence located in the proximal promoter region of the human apoA-I gene. However, this negative effect is counteracted by a positive regulatory site that responds to PPAR. This regulatory site is localized in the apoA-I promoter A site and binds to other nuclear receptors, such as the retinoid X receptor (37). The subtle interaction between these two opposing mechanisms determines the overall effect of fatty acids on apoA-I gene expression.
The liver X receptor (LXR) may act as a sterol sensor that functions to help an organism cope with high free cholesterol levels in the blood (38). Tobin et al. (39) demonstrated that in the liver, LXR expression is induced by PUFAs. This effect occurs as a result of a direct (40) induction of LXR gene transcription. Due to the established ability of fatty acids to serve as ligands for the PPARs, it is possible that PPARs are involved in mediating the effect of fatty acids on LXR expression (39).
LXR regulates intracellular cholesterol levels by inducing the expression of cholesterol 7-hydroxylase (CYP7), the initial and rate-limiting enzyme in the conversion of cholesterol to bile acids. Fatty acids not only enhance PPAR activity; they also induce LXR protein, mRNA, and gene transcription. Through induction of LXR via PUFAs, the LXR-regulatory pathway facilitates the elimination of excess cholesterol by stimulating CYP7, thereby resulting in the conversion of cholesterol to bile acids. Conversion of cholesterol into bile acids is an irreversible and terminal process of cholesterol catabolism. In addition to the increase in CYP7 activity, unsaturated fatty acid synthesis is prevented through the suppression of SREBP-1c expression via the antagonistic effect of PUFAs (41). This could be an indirect mechanism by which PUFAs increase LDL receptor expression by the elimination of cholesterol from the liver via increased bile acid synthesis. A summary of the possible mechanisms by which (n-6) PUFAs may lower plasma cholesterol is depicted in Figure 1.
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A study by Vasandani et al. (30) showed that dietary (n-3) PUFAs markedly decreased triglyceride and cholesterol ester levels in the liver and the concentration of apoB-containing lipoproteins in the plasma of LDL-receptor–deficient mice. These results suggest an important mechanism by which dietary (n-3) PUFAs lower plasma TGs. The potential mechanisms of action by (n-3) PUFAs include the following: 1) suppression of SREBP-1 expression and processing, leading to decreased lipogenesis and decreased VLDL secretion; 2) enhanced hepatic clearance of lipoproteins through increased LPL expression and decreases in apoC-III levels; and 3) increased reverse cholesterol transport (Fig. 2).
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FOOTNOTES |
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-hydroxylase; FCR, fractional catabolic rate; HDL-C, HDL cholesterol; HNF-4, hepatic nuclear factor 4; LDL-C, LDL cholesterol; LPL, lipoprotein lipase; LXR, liver X receptor; MUFA, monounsaturated fatty acid; PPAR, peroxisome proliferator activated receptor; PPRE, peroxisome proliferator response element; SREBP, sterol regulatory element binding protein; TFA, trans fatty acid; TG, triglyceride; TGRL, triglyceride-rich lipoprotein. 
Manuscript received 3 June 2005.
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LITERATURE CITED |
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TOPABSTRACTFat saturation and cholesterol...Fat saturation and LDL...Fatty acids and molecular...LITERATURE CITED |
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1. Hu, FB, Manson, JE & Willett, WC (2001) Types of dietary fat and risk of coronary heart disease: a critical review. J Am Coll Nutr. 20:5-19.
2. Kris-Etherton, P & Yu, S (1997) Individual fatty acids on plasma lipids and lipoproteins: human studies. Am J Clin Nutr. 65 Suppl:1628-144S.
3. Temme, E, Mensik, RP & Hornstra, G (1996) Comparison of the effects of diets enriched in lauric, palmitic, or oleic acids on serum lipids and lipoproteins in healthy women and men. Am J Clin Nutr. 63:897-903.
4. Fernandez, ML & McNamara, DJ (1994) Dietary fat saturation and chain length modulate guinea pig hepatic cholesterol metabolism. J Nutr. 124:331-339.
5. Nicolosi, RJ (1997) Dietary fat saturation effects on low density lipoprotein concentration and metabolism in various animal models. Am J Clin Nutr. 65 Suppl:1617-127S.
6. Woollett, LA, Spady, DK & Dietschy, JM (1992) Saturated and unsaturated fatty acids independently regulate low density lipoprotein receptor activity and production rate. J Lipid Res. 33:77-88.[Abstract]
7. Hu, FB, Stampfer, MJ, Manson, JE, Ascherio, A, Colditz, GA, Speizer, FE, Hennekens, CH & Willett, WC (1999) Dietary saturated fats and their food sources in relation to the risk of coronary heart disease in women. Am J Clin Nutr. 70:1001-1008.
8. Mensink, RP, Zock, PL, Kester, ADM & Katan, MB (2003) Effects of dietary fatty acids and carbohydrates on serum lipids and apolipoproteins: a meta analysis of 60 controlled trials. Am J Clin Nutr. 77:1146-1155.
9. Illingworth, DR & Schmidt, EB (1993) The influence of dietary n-3 fatty acids on plasma lipids and lipoproteins. Ann NY Acad Sci. 676:60-69.[Abstract]
10. Jump, DB (2002) Dietary polyunsaturated fatty acids and regulation of gene transcription. Curr Opin Lipidol. 13:155-164.[Medline]
11. Matson, FH & Grundy, SM (1985) Comparison of effects of dietary saturated, monounsaturated and polyunsaturated fatty acids on plasma lipids and lipoproteins in man. J Lipid Res. 26:194-202.[Abstract]
12. Jones, PJH, Ausaman, LM, Croll, DH, Feng, JY, Schaefer, EA & Lichtenstein, AH (1998) Validation of deuterium incorporation against sterol balance for measurement of human cholesterol biosynthesis. J Lipid Res. 39:1111-1117.
13. Fernandez, ML & McNamara, DJ (1989) Dietary fat-mediated changes in hepatic apoprotein B/E receptor in the guinea pig: effect of polyunsaturated, monounsaturated, and saturated fat. Metabolism. 38:1094-1102.[Medline]
14. Sundram, K, French, MA & Clandinin, TA (2003) Exchanging partially hydrogenated fat for palmitic acid in the diet increases LDL-cholesterol and endogenous cholesterol synthesis in normocholesterolemic women. Eur J Nutr. 42:188-194.[Medline]
15. Fernandez, ML & McNamara, DJ (1991) Regulation of cholesterol and lipoprotein metabolism in guinea pigs mediated by dietary fat quality and quantity. J Nutr. 121:934-943.
16. Fernandez, ML, Lin, ECK & McNamara, DJ (1992) Differential effects of saturated fatty acids on low density lipoprotein metabolism in the guinea pig. J Lipid Res. 33:1833-1842.[Abstract]
17. Fernandez, ML, Lin, ECK & McNamara, DJ (1992) Regulation of guinea pig plasma low density lipoprotein kinetics by dietary fat saturation. J Lipid Res. 33:97-109.[Abstract]
18. Mustad, VA, Ellsworth, JL, Cooper, AD, Kris-Etherton, PM & Etherton, TD (1996) Dietary linoleic acid increases and palmitic acid decreases hepatic LDL receptor protein and mRNA abundance in young pigs. J Lipid Res. 37:2310-2323.[Abstract]
19. Kuo, P, Weinfeld, M & Loscalzo, J (1990) Effect of membrane fatty acyl composition on LDL metabolism in Hep G2 hepatocytes. Biochemistry. 29:6626-6632.[Medline]
20. Tripodi, A, Loria, P, Dilengite, MA & Carulli, N (1991) Effect of fish oil and coconut oil diet on the LDL receptor activity of rat liver plasma membranes. Biochim Biophys Acta. 1083:298-304.[Medline]
21. Woollett, LA, Spady, DK & Dietschy, JM (1992) Regulatory effects of the saturated fatty acids 6:0 through 18:0 on hepatic low density lipoprotein receptor activity in the hamster. J Clin Invest. 89:1133-1141.
22. Rumsey, SC, Galeano, NF, Lipschitz, B & Deckelbaum, RJ (1995) Oleate and other long chain fatty acids stimulate low density lipoprotein receptor activity by enhancing acyl coenzyme A:cholesterol acyltransferase activity and altering intracellular regulatory cholesterol pools in cultured cells. J Biol Chem. 270:10008-10016.
23. Spady, DK, Woollett, LA & Dietschy, JM (1993) Regulation of plasma LDL-cholesterol levels by dietary cholesterol and fatty acids. Annu Rev Nutr. 13:355-381.[Medline]
24. Daumerie, CM, Woollett, LA & Dietschy, JM (1992) Fatty acids regulate hepatic low density lipoprotein receptor activity through redistribution of intracellular cholesterol pools. Proc Natl Acad Sci USA. 89:10797-10801.
25. Carr, TP, Parks, JS & Rudel, LL (1992) Hepatic ACAT activity in African green monkeys is highly correlated to plasma LDL cholesteryl ester enrichment and coronary artery atherosclerosis. Arterioscler Thromb. 12:1274-1283.
26. Ferre, P (2004) The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes. 53(Suppl 1):S43-S50.
27. Schoonjans, K, Staels, B & Auwerx, J (1996) Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res. 37:907-925.[Abstract]
28. Schoonjans, K, Peinado-Onsurbe, J, Lefebvre, AM, Heyman, RA, Briggs, M, Deeb, S, Staels, B & Auwerx, J (1996) PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J. 15:5336-5348.[Medline]
29. Kasim-Karakas, SE, Herrmann, R & Almario, R (1995) Effects of omega-3 fatty acids on intravascular lipolysis of very-low-density lipoproteins in humans. Metabolism. 44:1223-1230.[Medline]
30. Vasandi, C, Kafrouni, AI, Caronna, A, Bashmakov, Y, Gotthard, M, Horton, JD & Spady, DK (2002) Upregulation of hepatic LDL transport by n-3 fatty acids in LDL receptor knock out mice. J Lipid Res. 43:772-784.
31. Harris, WS, Hustvedt, BE, Hagen, E, Green, MH, Lu, G & Drevon, CA (1997) N-3 fatty acids and chylomicron metabolism in the rat. J Lipid Res. 38:503-515.[Abstract]
32. Huff, MW & Telford, DE (1989) Regulation of low density lipoprotein apoprotein B metabolism by lovastatin and cholestyramine in miniature pigs: effects on LDL composition and synthesis of LDL subfractions. Metabolism. 38:256-264.[Medline]
33. Shachter, NS (2001) Apolipoproteins C-I and C-III as important modulators of lipoprotein metabolism. Curr Opin Lipidol. 12:297-304.[Medline]
34. Aalto-Setala, K, Fisher, EA, Chen, X, Chajek-Shaul, T, Hayek, T, Zechner, R, Walsh, A, Ramakrishnan, R, Ginsberg, HN & Breslow, JL (1992) Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles. J Clin Invest. 90:1889-1900.
35. Ladias, JA, Hadzopoulou-Cladaras, M, Kardassis, D, Cardot, P, Cheng, J, Zannis, V & Cladaras, C (1992) Transcriptional regulation of human apolipoprotein genes ApoB, ApoCIII, and ApoAII by members of the steroid hormone receptor superfamily HNF-4, ARP-1, EAR-2, and EAR-3. J Biol Chem. 267:15849-15860.
36. Vu-Dac, N, Schoonjans, K, Kosykh, V, Dallongeville, J, Fruchart, JC, Staels, B & Auwerx, J (1995) Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor. J Clin Invest. 96:741-750.
37. Widom, RL, Ladias, JA, Kouidou, S & Karathanasis, SK (1991) Synergistic interactions between transcription factors control expression of the apolipoprotein AI gene in liver cells. Mol Cell Biol. 11:677-687.
38. Repa, JJ & Mangelsdorf, DJ (1999) Nuclear receptor regulation of cholesterol and bile acid metabolism. Curr Opin Biotechnol. 10:557-563.[Medline]
39. Tobin, KA, Steineger, HH, Alberti, S, Spydevold, O, Auwerx, J, Gustafsson, JA & Nebb, HI (2000) Cross-talk between fatty acid and cholesterol metabolism mediated by liver X receptor-alpha. Mol Endocrinol. 14:741-752.
40. Ide, T, Shimano, H, Yoshikawa, T, Yahagi, N, Amemiya-Kudo, M, Matsusaka, T, Yatoh, S, Iisuka, Y & Tomita, S, et al (2003) Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. II. LXRs suppress lipid degradation gene promoters through inhibition of PPAR signaling. Mol Endocrinol. 17:1255-1267.
41. Xu, J, Nakamura, MT, Cho, HP & Clark, SD (1999) Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids. A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats. J Biol Chem. 274:23577-23583.
42. Shimomura, I, Bashmakov, Y, Ikemoto, S, Horton, JD, Brown, MS & Goldstein, JL (1999) Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Natl Acad Sci USA. 96:13656-13661.
43. Field, FJ, Born, E & Mathur, SN (2003) Fatty acid flux suppresses fatty acids synthesis in hamster intestine independently of SREBP-1 expression. J Lipid Res. 44:1199-1208.
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