Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1984 Nov;74(5):1658–1668. doi: 10.1172/JCI111582

Pathogenesis of hepatic steatosis in the parenterally fed rat.

R I Hall, J P Grant, L H Ross, R A Coleman, M G Bozovic, S H Quarfordt
PMCID: PMC425343  PMID: 6438155

Abstract

Hepatic steatosis frequently complicates total parenteral nutrition (TPN). Some of the mechanisms responsible were examined in rats receiving calories as dextrose (CHO-TPN) or dextrose plus lipid emulsion (Lipid-TPN). Hepatic triglyceride content increased approximately threefold after CHO-TPN and twofold after Lipid-TPN (P less than 0.02). Hepatic triglyceride fatty acid composition reflected endogenous synthesis. Hepatic acetyl-Coenzyme A carboxylase specific activity increased fourfold after CHO-TPN and twofold after Lipid-TPN, and it correlated positively with hepatic lipid content (r = 0.82). The activities of the microsomal enzymes of complex lipid synthesis were unchanged in the TPN groups. Both TPN regimens suppressed hepatic triglyceride secretion, measured by the rise in plasma triglyceride and the incorporation of [14C]palmitic acid into plasma triglyceride after intravenous Triton. Hepatic triglyceride secretion correlated negatively with total hepatic lipid content (r = -0.89). CHO-TPN increased the uptake of a radiolabeled triglyceride emulsion and increased hepatic lipase activity, whereas Lipid-TPN decreased both. Both adipose and cardiac lipase were higher for Lipid-TPN animals than for CHO-TPN or control animals. Hepatic 14C-triglyceride content was increased in both TPN groups as compared with controls after the injection of 1-[14C]-palmitic acid. This increment was proportional to the decreased hepatic secretion. Triglyceride fatty acid oxidation was significantly suppressed by CHO-TPN, less so by Lipid-TPN. Free fatty acid oxidation was suppressed only by CHO-TPN. The results suggest that the steatosis induced by TPN in rats was due to enhanced hepatic synthesis of fatty acid and reduced triglyceride secretion. Reduced hepatic triglyceride uptake, enhanced fatty acid oxidation, and enhanced peripheral tissue plasma triglyceride lipolysis when CHO-TPN is supplemented with lipid may modulate the accumulation of hepatic triglyceride and, along with reduced synthesis of fatty acid, lead to a lower hepatic triglyceride content.

Full text

PDF
1658

Selected References

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

  1. BORTZ W., ABRAHAM S., CHAIKOFF I. L. Localization of the block in lipogenesis resulting from feeding fat. J Biol Chem. 1963 Apr;238:1266–1272. [PubMed] [Google Scholar]
  2. BYERS S. O., FRIEDMAN M. Site of origin of plasma triglyceride. Am J Physiol. 1960 Mar;198:629–631. doi: 10.1152/ajplegacy.1960.198.3.629. [DOI] [PubMed] [Google Scholar]
  3. Banis R. J., Tove S. B. Solubilization of a long chain fatty acyl-CoA synthetase from chicken adipose tissue microsomes. Biochim Biophys Acta. 1974 May 29;348(2):210–220. doi: 10.1016/0005-2760(74)90232-x. [DOI] [PubMed] [Google Scholar]
  4. Bloch K., Vance D. Control mechanisms in the synthesis of saturated fatty acids. Annu Rev Biochem. 1977;46:263–298. doi: 10.1146/annurev.bi.46.070177.001403. [DOI] [PubMed] [Google Scholar]
  5. Borensztajn J., Samols D. R., Rubenstein A. H. Effects of insulin on lipoprotein lipase activity in the rat heart and adipose tissue. Am J Physiol. 1972 Dec;223(6):1271–1275. doi: 10.1152/ajplegacy.1972.223.6.1271. [DOI] [PubMed] [Google Scholar]
  6. Burke J. F., Wolfe R. R., Mullany C. J., Mathews D. E., Bier D. M. Glucose requirements following burn injury. Parameters of optimal glucose infusion and possible hepatic and respiratory abnormalities following excessive glucose intake. Ann Surg. 1979 Sep;190(3):274–285. doi: 10.1097/00000658-197909000-00002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Buzby G. P., Mullen J. L., Stein T. P., Rosato E. F. Manipulation of TPN caloric substrate and fatty infiltration of liver. J Surg Res. 1981 Jul;31(1):46–54. doi: 10.1016/0022-4804(81)90028-7. [DOI] [PubMed] [Google Scholar]
  8. Cohen C., Olsen M. M. Pediatric total parenteral nutrition. Liver histopathology. Arch Pathol Lab Med. 1981 Mar;105(3):152–156. [PubMed] [Google Scholar]
  9. Coleman R., Bell R. M. Phospholipid synthesis in isolated fat cells. Studies of microsomal diacylglycerol cholinephosphotransferase and diacylglycerol ethanolaminephosphotransferase activities. J Biol Chem. 1977 May 10;252(9):3050–3056. [PubMed] [Google Scholar]
  10. Coleman R., Bell R. M. Triacylglycerol synthesis in isolated fat cells. Studies on the microsomal diacylglycerol acyltransferase activity using ethanol-dispersed diacylglycerols. J Biol Chem. 1976 Aug 10;251(15):4537–4543. [PubMed] [Google Scholar]
  11. Craig M. C., Dugan R. E., Muesing R. A., Slakey L. L., Porter J. W. Comparative effects of dietary regimens on the levels of enzymes regulating the synthesis of fatty acids and cholesterol in rat liver. Arch Biochem Biophys. 1972 Jul;151(1):128–136. doi: 10.1016/0003-9861(72)90481-x. [DOI] [PubMed] [Google Scholar]
  12. DOLE V. P., MEINERTZ H. Microdetermination of long-chain fatty acids in plasma and tissues. J Biol Chem. 1960 Sep;235:2595–2599. [PubMed] [Google Scholar]
  13. Dahms B. B., Halpin T. C., Jr Serial liver biopsies in parenteral nutrition-associated cholestasis of early infancy. Gastroenterology. 1981 Jul;81(1):136–144. [PubMed] [Google Scholar]
  14. Dudrick S. J., Wilmore D. W., Vars H. M., Rhoads J. E. Can intravenous feeding as the sole means of nutrition support growth in the child and restore weight loss in an adult? An affirmative answer. Ann Surg. 1969 Jun;169(6):974–984. doi: 10.1097/00000658-196906000-00018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Dudrick S. J., Wilmore D. W., Vars H. M., Rhoads J. E. Long-term total parenteral nutrition with growth, development, and positive nitrogen balance. Surgery. 1968 Jul;64(1):134–142. [PubMed] [Google Scholar]
  16. Grant J. P., Cox C. E., Kleinman L. M., Maher M. M., Pittman M. A., Tangrea J. A., Brown J. H., Gross E., Beazley R. M., Jones R. S. Serum hepatic enzyme and bilirubin elevations during parenteral nutrition. Surg Gynecol Obstet. 1977 Oct;145(4):573–580. [PubMed] [Google Scholar]
  17. Jeejee hoy K. N., Anderson G. H., Nakhooda A. F., Greenberg G. R., Sanderson I., Marliss E. B. Metabolic studies in total parenteral nutrition with lipid in man. Comparison with glucose. J Clin Invest. 1976 Jan;57(1):125–136. doi: 10.1172/JCI108252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jeejeebhoy K. N., Zohrab W. J., Langer B., Phillips M. J., Kuksis A., Anderson G. H. Total parenteral nutrition at home for 23 months, without complication, and with good rehabilitation. A study of technical and metabolic features. Gastroenterology. 1973 Nov;65(5):811–820. [PubMed] [Google Scholar]
  19. KARMEN A., WHYTE M., GOODMAN D. S. FATTY ACID ESTERIFICATION AND CHYLOMICRON FORMATION DURING FAT ABSORPTION. 1. TRIGLYCERIDES AND CHOLESTEROL ESTERS. J Lipid Res. 1963 Jul;4:312–321. [PubMed] [Google Scholar]
  20. Kaminski D. L., Adams A., Jellinek M. The effect of hyperalimentation on hepatic lipid content and lipogenic enzyme activity in rats and man. Surgery. 1980 Jul;88(1):93–100. [PubMed] [Google Scholar]
  21. Koga Y., Ikeda K., Inokuchi K. Effect of complete parenteral nutrition using fat emulsion on liver. Ann Surg. 1975 Feb;181(2):186–190. doi: 10.1097/00000658-197502000-00011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Krauss R. M., Windmueller H. G., Levy R. I., Fredrickson D. S. Selective measurement of two different triglyceride lipase activities in rat postheparin plasma. J Lipid Res. 1973 May;14(3):286–295. [PubMed] [Google Scholar]
  23. LANDS W. E., HART P. METABOLISM OF GLYCEROLIPIDS. VI. SPECIFICITIES OF ACYL COENZYME A: PHOSPHOLIPID ACYLTRANSFERASES. J Biol Chem. 1965 May;240:1905–1911. [PubMed] [Google Scholar]
  24. LOMBARDI B., RECKNAGEL R. O. Interference with secretion of triglycerides by the liver as a common factor in toxic liver injury with some observations on choline deficiency fatty liver. Am J Pathol. 1962 May;40:571–586. [PMC free article] [PubMed] [Google Scholar]
  25. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  26. MacFadyen B. V., Jr, Dudrick S. J., Baquero G., Gum E. T. Clinical and biological changes in liver function during intravenous hyperalimentation. JPEN J Parenter Enteral Nutr. 1979 Nov-Dec;3(6):438–443. doi: 10.1177/014860717900300607. [DOI] [PubMed] [Google Scholar]
  27. Mavis R. D., Finkelstein J. N., Hall B. P. Pulmonary surfactant synthesis. A highly active microsomal phosphatidate phosphohydrolase in the lung. J Lipid Res. 1978 May;19(4):467–477. [PubMed] [Google Scholar]
  28. Mookerjea S. Action of choline in lipoprotein metabolism. Fed Proc. 1971 Jan-Feb;30(1):143–150. [PubMed] [Google Scholar]
  29. Numa S., Yamashita S. Regulation of lipogenesis in animal tissues. Curr Top Cell Regul. 1974;8(0):197–246. doi: 10.1016/b978-0-12-152808-9.50012-2. [DOI] [PubMed] [Google Scholar]
  30. Ockner R. K., Hughes F. B., Isselbacher K. J. Very low density lipoproteins in intestinal lymph: origin, composition, and role in lipid transport in the fasting state. J Clin Invest. 1969 Nov;48(11):2079–2088. doi: 10.1172/JCI106174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Popp M. B., Brennan M. F. Long-term vascular access in the rat: importance of asepsis. Am J Physiol. 1981 Oct;241(4):H606–H612. doi: 10.1152/ajpheart.1981.241.4.H606. [DOI] [PubMed] [Google Scholar]
  32. Postuma R., Trevenen C. L. Liver disease in infants receiving total parenteral nutrition. Pediatrics. 1979 Jan;63(1):110–115. [PubMed] [Google Scholar]
  33. Schlossman D. M., Bell R. M. Triacylglycerol synthesis in isolated fat cells. Evidence that the sn-glycerol-3-phosphate and dihydroxyacetone phosphate acyltransferase activities are dual catalytic functions of a single microsomal enzyme. J Biol Chem. 1976 Sep 25;251(18):5738–5744. [PubMed] [Google Scholar]
  34. Schotz M. C., Garfinkel A. S., Huebotter R. J., Stewart J. E. A rapid assay for lipoprotein lipase. J Lipid Res. 1970 Jan;11(1):68–69. [PubMed] [Google Scholar]
  35. Shelburne F., Hanks J., Meyers W., Quarfordt S. Effect of apoproteins on hepatic uptake of triglyceride emulsions in the rat. J Clin Invest. 1980 Mar;65(3):652–658. doi: 10.1172/JCI109710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Sheldon G. F., Peterson S. R., Sanders R. Hepatic dysfunction during hyperalimentation. Arch Surg. 1978 Apr;113(4):504–508. doi: 10.1001/archsurg.1978.01370160162028. [DOI] [PubMed] [Google Scholar]
  37. Sinclair A. J., Collins F. D. Fatty livers in rats deficient in essential fatty acids. Biochim Biophys Acta. 1968 May 1;152(3):498–510. doi: 10.1016/0005-2760(68)90090-8. [DOI] [PubMed] [Google Scholar]
  38. Stein T. P., Buzby G. P., Hargrove W. C., 3rd, Leskiw M. J., Mullen J. L. Essential fatty acid deficiency in patients receiving simultaneous parenteral and oral nutrition. JPEN J Parenter Enteral Nutr. 1980 Jul-Aug;4(4):343–345. doi: 10.1177/014860718000400401. [DOI] [PubMed] [Google Scholar]
  39. Touloukian R. J., Seashore J. H. Hepatic secretory obstruction with total parenteral nutrition in the infant. J Pediatr Surg. 1975 Jun;10(3):353–360. doi: 10.1016/0022-3468(75)90098-6. [DOI] [PubMed] [Google Scholar]
  40. Truswell A. S., Hansen J. D., Watson C. E., Wannenburg P. Relation of serum lipids and lipoproteins to fatty liver in kwashiorkor. Am J Clin Nutr. 1969 May;22(5):568–576. doi: 10.1093/ajcn/22.5.568. [DOI] [PubMed] [Google Scholar]
  41. Tulikoura I., Huikuri K. Morphological fatty changes and function of the liver, serum free fatty acids, and triglycerides during parenteral nutrition. Scand J Gastroenterol. 1982 Mar;17(2):177–185. doi: 10.3109/00365528209182037. [DOI] [PubMed] [Google Scholar]

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

RESOURCES