Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1992 Apr;89(4):1133–1141. doi: 10.1172/JCI115694

Regulatory effects of the saturated fatty acids 6:0 through 18:0 on hepatic low density lipoprotein receptor activity in the hamster.

L A Woollett 1, D K Spady 1, J M Dietschy 1
PMCID: PMC442970  PMID: 1556178

Abstract

The plasma concentration of cholesterol carried in low density lipoproteins is principally determined by the level of LDL receptor activity (Jm) and the LDL-cholesterol production rate (Jt) found in animals or man. This study delineates which saturated fatty acids alter Jm and Jt and so increase the plasma LDL-cholesterol level. Jm and Jt were measured in vivo in hamsters fed a constant level of added dietary cholesterol (0.12%) and triacylglycerol (10%), where the triacylglycerol contained only a single saturated fatty acid varying in chain length from 6 to 18 carbon atoms. After feeding for 30 d, the 12:0, 14:0, 16:0, and 18:0 fatty acids, but not the 6:0, 8:0, and 10:0 compounds, became significantly enriched in the liver total lipid fraction of the respective groups fed these fatty acids. However, only the 12:0, 14:0, and 16:0 fatty acids, but not the 6:0, 8:0, 10:0, and 18:0 compounds, suppressed Jm, increased Jt, and essentially doubled plasma LDL-cholesterol concentrations. Neither the 16:0 nor 18:0 compound altered rates of cholesterol synthesis in the extrahepatic organs, and both lowered the hepatic total cholesterol pool. Thus, the different effects of the 16:0 and 18:0 fatty acids could not be attributed to a difference in cholesterol delivery to the liver. Since these changes in LDL kinetics took place without an apparent alteration in external sterol balance, the regulatory effects of the 12:0, 14:0, and 16:0 fatty acids presumably are mediated through some change in a putative intrahepatic regulatory pool of sterol in the liver.

Full text

PDF
1133

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. AHRENS E. H., Jr, INSULL W., Jr, BLOMSTRAND R., HIRSCH J., TSALTAS T. T., PETERSON M. L. The influence of dietary fats on serum-lipid levels in man. Lancet. 1957 May 11;272(6976):943–953. doi: 10.1016/s0140-6736(57)91280-1. [DOI] [PubMed] [Google Scholar]
  2. Bilheimer D. W., Eisenberg S., Levy R. I. The metabolism of very low density lipoprotein proteins. I. Preliminary in vitro and in vivo observations. Biochim Biophys Acta. 1972 Feb 21;260(2):212–221. doi: 10.1016/0005-2760(72)90034-3. [DOI] [PubMed] [Google Scholar]
  3. Bilheimer D. W., Goldstein J. L., Grundy S. M., Starzl T. E., Brown M. S. Liver transplantation to provide low-density-lipoprotein receptors and lower plasma cholesterol in a child with homozygous familial hypercholesterolemia. N Engl J Med. 1984 Dec 27;311(26):1658–1664. doi: 10.1056/NEJM198412273112603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bilheimer D. W., Stone N. J., Grundy S. M. Metabolic studies in familial hypercholesterolemia. Evidence for a gene-dosage effect in vivo. J Clin Invest. 1979 Aug;64(2):524–533. doi: 10.1172/JCI109490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bonanome A., Grundy S. M. Effect of dietary stearic acid on plasma cholesterol and lipoprotein levels. N Engl J Med. 1988 May 12;318(19):1244–1248. doi: 10.1056/NEJM198805123181905. [DOI] [PubMed] [Google Scholar]
  6. Connor W. E., Cerqueira M. T., Connor R. W., Wallace R. B., Malinow M. R., Casdorph H. R. The plasma lipids, lipoproteins, and diet of the Tarahumara indians of Mexico. Am J Clin Nutr. 1978 Jul;31(7):1131–1142. doi: 10.1093/ajcn/31.7.1131. [DOI] [PubMed] [Google Scholar]
  7. Crook D., Weisgraber K. H., Boyles J. K., Mahley R. W. Isolation and characterization of plasma lipoproteins of common marmoset monkey. Comparison of effects of control and atherogenic diets. Arteriosclerosis. 1990 Jul-Aug;10(4):633–647. doi: 10.1161/01.atv.10.4.633. [DOI] [PubMed] [Google Scholar]
  8. Dawson P. A., Metherall J. E., Ridgway N. D., Brown M. S., Goldstein J. L. Genetic distinction between sterol-mediated transcriptional and posttranscriptional control of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem. 1991 May 15;266(14):9128–9134. [PubMed] [Google Scholar]
  9. Dietschy J. M., Brown M. S. Effect of alterations of the specific activity of the intracellular acetyl CoA pool on apparent rates of hepatic cholesterogenesis. J Lipid Res. 1974 Sep;15(5):508–516. [PubMed] [Google Scholar]
  10. Dietschy J. M., Kita T., Suckling K. E., Goldstein J. L., Brown M. S. Cholesterol synthesis in vivo and in vitro in the WHHL rabbit, an animal with defective low density lipoprotein receptors. J Lipid Res. 1983 Apr;24(4):469–480. [PubMed] [Google Scholar]
  11. Dietschy J. M., Spady D. K. Measurement of rates of cholesterol synthesis using tritiated water. J Lipid Res. 1984 Dec 15;25(13):1469–1476. [PubMed] [Google Scholar]
  12. Hegsted D. M., McGandy R. B., Myers M. L., Stare F. J. Quantitative effects of dietary fat on serum cholesterol in man. Am J Clin Nutr. 1965 Nov;17(5):281–295. doi: 10.1093/ajcn/17.5.281. [DOI] [PubMed] [Google Scholar]
  13. Hornick C. A., Kita T., Hamilton R. L., Kane J. P., Havel R. J. Secretion of lipoproteins from the liver of normal and Watanabe heritable hyperlipidemic rabbits. Proc Natl Acad Sci U S A. 1983 Oct;80(19):6096–6100. doi: 10.1073/pnas.80.19.6096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jeske D. J., Dietschy J. M. Regulation of rates of cholesterol synthesis in vivo in the liver and carcass of the rat measured using [3H]water. J Lipid Res. 1980 Mar;21(3):364–376. [PubMed] [Google Scholar]
  15. Johnson F. L., St Clair R. W., Rudel L. L. Effects of the degree of saturation of dietary fat on the hepatic production of lipoproteins in the African green monkey. J Lipid Res. 1985 Apr;26(4):403–417. [PubMed] [Google Scholar]
  16. Kita T., Brown M. S., Bilheimer D. W., Goldstein J. L. Delayed clearance of very low density and intermediate density lipoproteins with enhanced conversion to low density lipoprotein in WHHL rabbits. Proc Natl Acad Sci U S A. 1982 Sep;79(18):5693–5697. doi: 10.1073/pnas.79.18.5693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lepage G., Roy C. C. Direct transesterification of all classes of lipids in a one-step reaction. J Lipid Res. 1986 Jan;27(1):114–120. [PubMed] [Google Scholar]
  18. Mattson F. H., Grundy S. M. Comparison of effects of dietary saturated, monounsaturated, and polyunsaturated fatty acids on plasma lipids and lipoproteins in man. J Lipid Res. 1985 Feb;26(2):194–202. [PubMed] [Google Scholar]
  19. McGarry J. D., Foster D. W. Regulation of hepatic fatty acid oxidation and ketone body production. Annu Rev Biochem. 1980;49:395–420. doi: 10.1146/annurev.bi.49.070180.002143. [DOI] [PubMed] [Google Scholar]
  20. McIlhinney R. A. The fats of life: the importance and function of protein acylation. Trends Biochem Sci. 1990 Oct;15(10):387–391. doi: 10.1016/0968-0004(90)90237-6. [DOI] [PubMed] [Google Scholar]
  21. Metherall J. E., Goldstein J. L., Luskey K. L., Brown M. S. Loss of transcriptional repression of three sterol-regulated genes in mutant hamster cells. J Biol Chem. 1989 Sep 15;264(26):15634–15641. [PubMed] [Google Scholar]
  22. Pittman R. C., Carew T. E., Glass C. K., Green S. R., Taylor C. A., Jr, Attie A. D. A radioiodinated, intracellularly trapped ligand for determining the sites of plasma protein degradation in vivo. Biochem J. 1983 Jun 15;212(3):791–800. doi: 10.1042/bj2120791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ruff P., Speicher D. W., Husain-Chishti A. Molecular identification of a major palmitoylated erythrocyte membrane protein containing the src homology 3 motif. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6595–6599. doi: 10.1073/pnas.88.15.6595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Sallee V. L., Dietschy J. M. Determinants of intestinal mucosal uptake of short- and medium-chain fatty acids and alcohols. J Lipid Res. 1973 Jul;14(4):475–484. [PubMed] [Google Scholar]
  25. Schulz H. Beta oxidation of fatty acids. Biochim Biophys Acta. 1991 Jan 28;1081(2):109–120. doi: 10.1016/0005-2760(91)90015-a. [DOI] [PubMed] [Google Scholar]
  26. Shames D. M., Havel R. J. De novo production of low density lipoproteins: fact or fancy. J Lipid Res. 1991 Jul;32(7):1099–1112. [PubMed] [Google Scholar]
  27. Smith J. R., Osborne T. F., Goldstein J. L., Brown M. S. Identification of nucleotides responsible for enhancer activity of sterol regulatory element in low density lipoprotein receptor gene. J Biol Chem. 1990 Feb 5;265(4):2306–2310. [PubMed] [Google Scholar]
  28. Spady D. K., Bilheimer D. W., Dietschy J. M. Rates of receptor-dependent and -independent low density lipoprotein uptake in the hamster. Proc Natl Acad Sci U S A. 1983 Jun;80(11):3499–3503. doi: 10.1073/pnas.80.11.3499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Spady D. K., Dietschy J. M. Dietary saturated triacylglycerols suppress hepatic low density lipoprotein receptor activity in the hamster. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4526–4530. doi: 10.1073/pnas.82.13.4526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Spady D. K., Dietschy J. M. Interaction of dietary cholesterol and triglycerides in the regulation of hepatic low density lipoprotein transport in the hamster. J Clin Invest. 1988 Feb;81(2):300–309. doi: 10.1172/JCI113321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Spady D. K., Huettinger M., Bilheimer D. W., Dietschy J. M. Role of receptor-independent low density lipoprotein transport in the maintenance of tissue cholesterol balance in the normal and WHHL rabbit. J Lipid Res. 1987 Jan;28(1):32–41. [PubMed] [Google Scholar]
  32. Spady D. K., Meddings J. B., Dietschy J. M. Kinetic constants for receptor-dependent and receptor-independent low density lipoprotein transport in the tissues of the rat and hamster. J Clin Invest. 1986 May;77(5):1474–1481. doi: 10.1172/JCI112460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Spady D. K., Turley S. D., Dietschy J. M. Dissociation of hepatic cholesterol synthesis from hepatic low-density lipoprotein uptake and biliary cholesterol saturation in female and male hamsters of different ages. Biochim Biophys Acta. 1983 Oct 11;753(3):381–392. doi: 10.1016/0005-2760(83)90062-0. [DOI] [PubMed] [Google Scholar]
  34. Spady D. K., Turley S. D., Dietschy J. M. Rates of low density lipoprotein uptake and cholesterol synthesis are regulated independently in the liver. J Lipid Res. 1985 Apr;26(4):465–472. [PubMed] [Google Scholar]
  35. Spady D. K., Turley S. D., Dietschy J. M. Receptor-independent low density lipoprotein transport in the rat in vivo. Quantitation, characterization, and metabolic consequences. J Clin Invest. 1985 Sep;76(3):1113–1122. doi: 10.1172/JCI112066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Südhof T. C., Russell D. W., Brown M. S., Goldstein J. L. 42 bp element from LDL receptor gene confers end-product repression by sterols when inserted into viral TK promoter. Cell. 1987 Mar 27;48(6):1061–1069. doi: 10.1016/0092-8674(87)90713-6. [DOI] [PubMed] [Google Scholar]
  37. Takeda A., Maizel A. L. An unusual form of lipid linkage to the CD45 peptide. Science. 1990 Nov 2;250(4981):676–679. doi: 10.1126/science.2146743. [DOI] [PubMed] [Google Scholar]
  38. Turley S. D., Andersen J. M., Dietschy J. M. Rates of sterol synthesis and uptake in the major organs of the rat in vivo. J Lipid Res. 1981 May;22(4):551–569. [PubMed] [Google Scholar]
  39. Westergaard H., Dietschy J. M. The mechanism whereby bile acid micelles increase the rate of fatty acid and cholesterol uptake into the intestinal mucosal cell. J Clin Invest. 1976 Jul;58(1):97–108. doi: 10.1172/JCI108465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Woollett L. A., Spady D. K., Dietschy J. M. Mechanisms by which saturated triacylglycerols elevate the plasma low density lipoprotein-cholesterol concentration in hamsters. Differential effects of fatty acid chain length. J Clin Invest. 1989 Jul;84(1):119–128. doi: 10.1172/JCI114131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Woollett L. A., Spady D. K., Dietschy J. M. Saturated and unsaturated fatty acids independently regulate low density lipoprotein receptor activity and production rate. J Lipid Res. 1992 Jan;33(1):77–88. [PubMed] [Google Scholar]
  42. Yamada N., Shames D. M., Stoudemire J. B., Havel R. J. Metabolism of lipoproteins containing apolipoprotein B-100 in blood plasma of rabbits: heterogeneity related to the presence of apolipoprotein E. Proc Natl Acad Sci U S A. 1986 May;83(10):3479–3483. doi: 10.1073/pnas.83.10.3479. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES