Nutritional Regulation of Apolipoprotein Genes: Effect of Dietary Carbohydrates and Fatty Acids

  • Agnès Ribciro
  • Marise Mangeney
  • Philippe Cardot
  • Claude Loriette
  • Jean Chambaz
  • Yves Rayssiguier
  • Gilbert Béréziat
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 285)


The effect of nutritional factors on apolipoprotein gene expression by rat liver were studied. Dietary carbohydrates or fatty acids regulate the expression of apo E gene, by altering either gene transcription or mRNA stability. Conversely, apo AT regulation occurs at a post transcriptional level. In vivo and in vitro experiments gave contradictory results concerning apo B gene expression. The more dramatic changes in plasma lipids and apolipoproteins are obtained under dietary fish oil. Hepatocytes from fish oil-fed rats retain for several days modification in fatty acid metabolism, i.e. a shift in oleic acid channeling towards oxidation at the expense of csterification and a reduced ability to synthesize and secrete triacylglycerol. These modifications are paralleled with a decrease in the synthesis and in the secretion of apo Bs. Hepatocytes from fish oil fed rats secrete degradative forms of apo B which might result from either a sluggish VLDL synthesis and secretion or a more specific effect of n-3 long chain polyunsaturated fatty acid peroxidative products. Hepatocytes from fish oil fed rats exhibit a reduced ability to synthesize cholesterol, associated with a decrease in apo AT synthesis and secretion without any modification in apo AI mRNA. In contrast, the hepatocytes exhibit a concomitent decrease in apo E synthesis and secretion and in cellular apo E mRNA levels.


Oleic Acid Essential Fatty Acid Dietary Carbohydrate Essential Fatty Acid Deficiency Plasma Triacylglycerol 
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  1. 1.
    Sinrlair, A.J. and Collins ,F.D. Fatty livers in rats deficient in essential fatty acids. Biochim. Biophys. Acta 152:498–510 (1968).Google Scholar
  2. 2.
    Trugnan ,G, Thomas ,G ,Cardot, P, Rayssiguier, Y and Bereziat, G. Short-term essential fatty acid deficiency in rats. Influence of dietary carbohydrates. Lipids 20:862–868 (1985).PubMedCrossRefGoogle Scholar
  3. 3.
    Williams MA, Tinoco, J, Hincenbergs, I and Thomas ,B. Increased plasma triglyceride secretion in EFA-deficient rats fed diets with or without saturated fat. Lipids 24:448–453 (1989).PubMedCrossRefGoogle Scholar
  4. 4.
    Sugano ,M and Portman OW. Essential fatty acid deficiency and cholesterol esterification activity of plasma and liver in vitro and in vivo. Arch. Biochim. Biophys. 109:312–315 (1965).CrossRefGoogle Scholar
  5. 5.
    Ney ,DM, Ziboh, VA and Schneeman, BO. Reduction in plasma apolipoprotein E and HDL1 levels in rats with essential fatty acid deficiency. J. Nutr. 117:2016–2020 (1987).PubMedGoogle Scholar
  6. 6.
    Kannan, R, Baker, N and Bruckdorfer, KR. Secretion and turnover of very low density lipoprotein triacylglycerols in rats fed chronically diets rich in glucose and fructose. J. Nutr. 111:1216–1223 (1981).PubMedGoogle Scholar
  7. 7.
    Yamamoto, M, Yamamoto, I, Tanaka, Y and Ontko, JA. Fatty acid metabolism and lipid secretion by perfused livers from rats fed laboratory stock and sucrcse-rich diets. J. Lipid Res. 28 :1156–1165 (1987).PubMedGoogle Scholar
  8. 8.
    Cardot, P, Chambaz, J, Thomas, G, Rayssiguier, Y and Béréziat, G. Essential fatty acid deficiency during pregnancy in the rat: influence of dietary carbohydrates. J. Nutr. 117 :1504–1513 (1987).PubMedGoogle Scholar
  9. 9.
    Boogaerts, JR, Malone-Mc Neal, M, Archambault-Schexnayder, J and Davis, RA. Dietary carbohydrate induces lipogenenis and very-low-density lipoprotein synthesis. Am. J. Physiol. 246:E77–E83 (1984).PubMedGoogle Scholar
  10. 10.
    Witztum, JL and Schonfeld, G. Carbohydrate diet-induced changes in very low-density lipoprotein composition and structure. Diabetes 27:1215–1229 (1978).PubMedCrossRefGoogle Scholar
  11. 11.
    Sanders, TAB, Vickers, M and Haines, AP. Effect on blood lipids and haemostasis of a supplement of cold-liver, rich in eicosapentaenoic and docosahexaenoic acid, in healthy young men. Clin. Sci.61:317–324 (1981).PubMedGoogle Scholar
  12. 12.
    Harris, WS. Fish oils and plasma lipid and lipoprotein metabolism in humans:a critical review. J. Lipid Res. 30:785–807 (1989).PubMedGoogle Scholar
  13. 13.
    Sorci-Thomas, M, Wilson, MD, Johnson, FL, Williams, DL and Rudel, LL. Studies on the expression of genes encoding apolipoproteins B100 and B48 and the low density lipoproteins receptor in nonhuman primates. J. Biol. Chem. 264:9039–9045 (1989).PubMedGoogle Scholar
  14. 14.
    Parks, JS, Wilson, MD, Johnson, FL and Rudel, LL. Fish oil decreases hepatic cholesteryl ester secretion but not apo B secretion in african green monkeys. J. Lipid Res. 30:1535–1544 (1989).PubMedGoogle Scholar
  15. 15.
    Wong, SH, Nestel, JP, Timble, RP, Storer, GB, Illman, RJ and Topping, DL. The adaptive effects of dietary fish and safflower oil on lipid and lipoprotein metabolism in perfused rat liver. Biochim. Biophys. Acta 792 :103–109 (1984).PubMedGoogle Scholar
  16. 16.
    Wong, SH and Marsh, JB. Inhibition of apolipoprotein secretion and phosphatidate phosphohydrolase activity by eicosapentaenoic and docosahexaenoic acids in the perfused rat liver. Metabolism 37 :1177–1181 (1988).PubMedCrossRefGoogle Scholar
  17. 17.
    Wong, S, Reardon, M and Nestel, PJ. Reduced triglyceride formation from long chain polyenoic fatty acids in rat hepatocytes. Metabolism 43:900–905 (1985).CrossRefGoogle Scholar
  18. 18.
    Strum-Odin, R, Adkins-Finke, B, Blake, WL, Phinney, SD and Clarke, SD. Modification of fatty acid composition of membrane phospholipid in hepatocyte monolayer with n-3, n-6 and n 9 fatty acid and its relationship to triacylglycerol production. Biochim. Biophys. Acta 921:378–391 (1987).PubMedGoogle Scholar
  19. 19.
    Wong, S and Nestel PJ. Eicosapentaenoic acid inhibits the secretion of triacyl glycerol and of apoprotein B and the binding of LDL in HepG2 cells. Atherosclerosis 64 :139–146 (1987).PubMedCrossRefGoogle Scholar
  20. 20.
    Nossen, JO, Rustan, AC, Gloppestad, SH, Malbakken, S and Drevon, CA. Eicosapentaenoic acid inhibits synthesis and secretion of triacylglycerols by cultured rat hepatocytes. Biochim. Biophys. Acta 879:56–65 (1986).PubMedGoogle Scholar
  21. 21.
    Bieri, JG, Stoewsand, GS, Briggs, GM, Phillips, RW, Woodard, JC and Knapka, JJ. Report of the american institution of nutrition ad hoc. Committee on standards for nutritional studies. J. Nutr. 107 :1340–1348 (1977).Google Scholar
  22. 22.
    Biigh, EG and Dyer, WJ. A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol. 37:911–917 (1959).CrossRefGoogle Scholar
  23. 23.
    Havel, RJ, Eder, HA and Bragdon JH. The distribution and chemical composition of ultracentrifigally separated lipoproteins in human serum. J. Clin. Invest. 34:1345–1447 (1955).PubMedCrossRefGoogle Scholar
  24. 24.
    Lowry, OH, Rosebrough, NJ, Farr, AL and Randall, RJ. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193:265–275 (1951).PubMedGoogle Scholar
  25. 25.
    Laemmli, UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685 (1970).PubMedCrossRefGoogle Scholar
  26. 26.
    Chambaz, J, Guillouzo, A, Cardot, P, Pepin, D and Bereziat, G. Essential fatty acid uptake and esterification in primary culture of rat hepatocytes. Biochim. Biophys. Acta 878:310–319 (1986).PubMedGoogle Scholar
  27. 27.
    Mangeney, M, Sire, 0, Montagne, J and Nordmann, J. Effect of D-galactosamine in vitro on [U-14C]palmitate oxidation, triacylglycerol synthesis and secretion in isolated hepatocytes. Biochem. Biophys. Acta 833 :119–127 (1985).PubMedGoogle Scholar
  28. 28.
    Andus, T, Gross, V, Tran-Thi, TA, Schreiber, G, Nagashima, M and Heinrich, PC. The biosynthesis of acute-phase proteins in primary cultures of rat hepatocytes. Eur. J. Biochem. 133:561–571 (1983).PubMedCrossRefGoogle Scholar
  29. 29.
    Ribeiro, A, Mangeney ,M ,Cardot, P, Loriette, C, Rayssiguier, Y, Chambaz, J and Bereziat ,G. Effect of dietary fish oil and corn oil on lipid metabolism and apolipoprotein gene expression by rat liver. Soumis a publication.Google Scholar
  30. 30.
    Lenich ,C ,Brecher, P, Makrides, S, Chobanian, A and Zannis, VI. Apolipoprotein gene expression in the rabbit:abundance, size and distribution of apolipoprotein mRNA species in different tissues. J. Lipid Res. 29:755–764 (1988).PubMedGoogle Scholar
  31. 31.
    Chomczynski, P and Sacchi, N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extration. Anal. Biochem. 162 :156–159 (1987).PubMedCrossRefGoogle Scholar
  32. 32.
    Mangeney ,M ,Cardot ,P ,Lyonnet ,S ,Coupe ,C ,Benarous, R, Munnich, A, Girard, J, Chambaz, J and Bereziat ,G. Apolipoprotein-E-gene expression in rat liver during development in relation to insulin and glucagon. Eur. J. Biochem. 181:225–230 (1989).PubMedCrossRefGoogle Scholar
  33. 33.
    Strobl, W, Gorder, NL, Fienup ,GA ,Lin-Lee ,YC ,Gotto ,Jr AM and Patsch, W. Effect of sucrose diet on apolipoprotein biosynthesis in rat liver (increase in apolipoprotein E gene transcription). J. Biol. Chem. 264 :1190–1194 (1989).PubMedGoogle Scholar
  34. 34.
    Davis ,RA ,Diuz ,SM ,Leighton, JK and Brengaze, VA. Increased translatable mRNA and decreased lipogenesis are responsible for the augmented secretion of lipid-deflcient apolipoprotein E by hepatocytes from fasted rats. J. Biol. Chem. 264:8970–8977 (1989).PubMedGoogle Scholar
  35. 35.
    Cotran RS and Munro JM. Pathogenesis of atherosclerosis. In Recent concept in the role of cholesterol in atherosclerosis. Grundy SM and Beam AG eds Hanley and Belfus inc. Philadelphia, pp 5–24 (1987).Google Scholar
  36. 36.
    Ruderman NB, Richards KC, De Bourges VN and Jones AL. Regulation of production and release of lipoprotein by the perfused rat liver. J. Lipid Res. 9:613–619 (1988).Google Scholar
  37. 37.
    Davis, RA and Boogaerts JR. Intrahepatic assembly of very-low-density lipoproteins:effects of fatty acids on triacylglycerol and apolipoprotein synthesis. J. Biol. Chem. 257 :10908–10913 (1982).PubMedGoogle Scholar
  38. 38.
    Kim, MH, Nakayama, R, Manos, P, Tomlinson JE, Choi, E, Joseph, D.Ng, and Holten D. Regulation of apolipoprotein E synthesis and mRNA by diet and hormones. J. Lipid Res. 30:663–671 (1989).PubMedGoogle Scholar
  39. 39.
    Cardot, P, Ribeiro ,A ,Lablanquie, C, Mangeney, M, Rayssiguier, Y and Chambaz, J. Effect of dietary sucrose or glucose on apolipoprotein B and E gene exprassicn in rat liver. Influence of fasting and essential fatty acid deficiency. Soumis a publication.Google Scholar
  40. 40.
    Lin-Lee YC, Tanaka, Y, Lin, CT and Chan, L. Effect of an atherogenic diet on apolipoprotein E biosynthesis in the rat. Biochemistry 20:6474–6480 (1981).PubMedCrossRefGoogle Scholar
  41. 41.
    Davis, RA and Malone-Mc Neal M. Dietary cholesterol does not affect the synthesis of apolipoproteins B and E by rat hepatocytes. Biochem. J. 227:29–35 (1985).PubMedGoogle Scholar
  42. 42.
    Kosykh, VA, Preobrazhensky, SN, Fuki, IV, Zaikina OE, Tsibulski, VP, Repin, VS and Smirnov, VN. Cholesterol can stimulate secretion of apolipoprotein B by cultured human hepatocytes. Biochim. Biophys. Acta 836:385–389 (1985).PubMedGoogle Scholar
  43. 43.
    Apostopoulos, JJ, Howlett GJ and Fidge N. Effect of dietary cholesterol and hypothyroidism on rat apolipoprotein mRNA metabolism. J. Lipid Res. 28:642–648 (1987).Google Scholar
  44. 44.
    Bergseth, S, Christiansen, EN and Bremer, J. The effect of feeding fish oils, vegetable oils and clofibrate on the ketogenesis from long chain fatty acids in hepatocytes. Lipids ,21:508–514 (1986).PubMedCrossRefGoogle Scholar
  45. 45.
    Yamasaki, RK, Shen, T and Shade, GB. A diet rich in (n-3) fatty acids increases peroxisomal p-oxidation activity and lowers plasma triacylglycerols without inhibiting glutathionedependent detoxification activities in the rat liver. Biochim. Biophys. Acta 920:62–67 (1987).Google Scholar
  46. 46.
    Patsch, W, Tama, T and Schonfeld, G. Effect of fatty acids on lipid and apoprotein secretion and association in hepatocyte cultures. J. Clin. Invest. 72:371–378 (1983).PubMedCrossRefGoogle Scholar
  47. 47.
    Situa-Manango, P, Janero, DR and Lane MD. Association and assembly of triglyceride and phospholipid with glycosylated and un glycosylated apoproteins of very-low-density lipoprotein in the intact liver cell. J. Biol. Chem. 257 :11463–11467 (1982).Google Scholar
  48. 48.
    Borchardt, RA and Davis, RA. Intrahepatic assembly of very-low-density lipoproteins (rate of transport out of the endoplasmic reticulum determines rat of secretion). J. Biol. Chem. 262:16394–16402 (1987).PubMedGoogle Scholar
  49. 49.
    Van Rollins, M. Cytochrome P-450 metabolites of eicosapentaenoic acids are strong inhibitors of lipid synthesis in rat hepatocytes. Circulation 80:A2467 (1989).Google Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • Agnès Ribciro
    • 1
  • Marise Mangeney
    • 1
  • Philippe Cardot
    • 2
  • Claude Loriette
    • 1
  • Jean Chambaz
    • 1
  • Yves Rayssiguier
    • 2
  • Gilbert Béréziat
    • 1
  1. 1.Laboratoire de biochimie (CNRS URA 1283) CHU Saint-AntoineUniversité Pierre et Marie CurieParisFrance
  2. 2.Laboratoire des maladies métaboliquesINRATheixFrance

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