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Journal of Lipid Research, Vol 31, 2045-2055, Copyright © 1990 by Lipid Research, Inc.
ARTICLES |
KM Cianflone, Z Yasruel, MA Rodriguez, D Vas and AD Sniderman
McGill Unit, Royal Victoria Hospital, Montreal, Quebec, Canada.
Secretion of hepatic apoB lipoproteins removes excess triglyceride from the liver. However, the mechanism by which synthesis of apoB, which occurs on the rough endoplasmic reticulum, is coordinated with synthesis of triglyceride, which takes place in the smooth endoplasmic reticulum, is not known. To examine this question, we have manipulated intracellular synthesis of triglyceride and cholesteryl ester in HepG2 cells and determined the impact of these maneuvers on apoB secretion. Since cholesteryl ester is the only major lipid class synthesized in the rough endoplasmic reticulum, our hypothesis was that, in response to a fatty acid challenge, synthesis of cholesteryl ester rather than synthesis of triglyceride would be the immediate trigger to apoB secretion. Oleate complexed to bovine serum albumin caused intracellular triglyceride synthesis to increase 6-fold and cholesteryl ester synthesis to increase almost 3-fold, while apoB secretion into the medium increased by 2.5-fold (P less than 0.0125) at all time points between 4 and 24 h. Addition of acylation stimulating protein to the medium further stimulated both triglyceride and cholesteryl ester synthesis (58% and 108%, respectively) above oleate alone and this resulted in a 50% increase in apoB secretion (P less than 0.0025). By contrast, both progesterone and 2-bromooctanoate inhibited triglyceride and cholesteryl ester synthesis and these effects were associated with reduced apoB secretion. Lovastatin inhibited cholesteryl ester synthesis (45%, P less than 0.0025); however, at the doses used, triglyceride formation was unaffected. Under these circumstances, apoB secretion was reduced by 25% (P less than 0.05). Similarly, 58-035 (an inhibitor of acyl CoA:cholesterol acyltransferase) on the one hand reduced cholesteryl ester synthesis markedly (59%, P less than 0.005), but on the other increased triglyceride synthesis though not statistically significantly (65%, P NS), and again this resulted in decreased apoB secretion (25%, P less than 0.005). Control experiments established that changes in low density lipoprotein catabolism did not contribute importantly to the quantity of apoB in the medium. Taken together, the data indicate that, at least in HepG2 cells, there are parallel changes in cholesteryl ester synthesis and apoB secretion and suggest that it is cholesteryl ester synthesis, not triglyceride synthesis, that is the immediate regulator of apoB secretion when these cells are exposed to an increased influx of fatty acids. However, alternative or additional regulatory mechanisms, such as, for example, a role for acylation of apoB, are not excluded by these studies.
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A. E. Rusinol, H. Jamil, and J. E. Vance In Vitro Reconstitution of Assembly of Apolipoprotein B48-containing Lipoproteins J. Biol. Chem., March 21, 1997; 272(12): 8019 - 8025. [Abstract] [Full Text] [PDF]
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I.J. Martins, B.-C. Mortimer, and T.G. Redgrave Effect of the ACAT Inhibitor CL 277,082 on Apolipoprotein B48 Transport in Mesenteric Lymph and on Plasma Clearance of Chylomicrons and Remnants Arterioscler. Thromb. Vasc. Biol., January 1, 1997; 17(1): 211 - 216. [Abstract] [Full Text]
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F. Benoist and T. Grand-Perret ApoB-100 Secretion by HepG2 Cells Is Regulated by the Rate of Triglyceride Biosynthesis but Not by Intracellular Lipid Pools Arterioscler. Thromb. Vasc. Biol., October 1, 1996; 16(10): 1229 - 1235. [Abstract] [Full Text]
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P. J. Uelmen, K. Oka, M. Sullivan, C. C. Y. Chang, T. Y. Chang, and L. Chan Tissue-specific Expression and Cholesterol Regulation of Acylcoenzyme A:Cholesterol Acyltransferase (ACAT) in Mice J. Biol. Chem., November 3, 1995; 270(44): 26192 - 26201. [Abstract] [Full Text] [PDF]
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S. L. Selby and Z. Yao Level of Apolipoprotein B mRNA Has an Important Effect on the Synthesis and Secretion of Apolipoprotein B–Containing Lipoproteins : Studies on Transfected Hepatoma Cell Lines Expressing Recombinant Human Apolipoprotein B Arterioscler. Thromb. Vasc. Biol., November 1, 1995; 15(11): 1900 - 1910. [Abstract] [Full Text]
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G. J. Warner, G. Stoudt, M. Bamberger, W. J. Johnson, and G. H. Rothblat Cell Toxicity Induced by Inhibition of Acyl Coenzyme A:Cholesterol Acyltransferase and Accumulation of Unesterified Cholesterol J. Biol. Chem., March 17, 1995; 270(11): 5772 - 5778. [Abstract] [Full Text] [PDF]
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