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Vol. 16, Issue 2, 984-996, February 2005
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* Department of Cell Biology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada;
Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2E1, Canada;
Department of Pediatrics, University of Alberta, Edmonton, Alberta T6G 2E1, Canada; and
the CIHR Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
Submitted March 16, 2004;
Revised November 29, 2004;
Accepted November 30, 2004
Monitoring Editor: Jennifer Lippincott-Schwartz
The majority of hepatic intracellular triacylglycerol (TG) is mobilized by lipolysis followed by reesterification to reassemble TG before incorporation into a very-low-density lipoprotein (VLDL) particle. Triacylglycerol hydrolase (TGH) is a lipase that hydrolyzes TG within hepatocytes. Immunogold electron microscopy in transfected cells revealed a disparate distribution of this enzyme within the endoplasmic reticulum (ER), with particularly intense localization in regions surrounding mitochondria. TGH is localized to the lumen of the ER by the C-terminal tetrapeptide sequence HIEL functioning as an ER retention signal. Deletion of HIEL resulted in secretion of catalytically active TGH. Mutation of HIEL to KDEL, which is the consensus ER retrieval sequence in animal cells, also resulted in ER retention and conservation of lipolytic activity. However, KDEL-TGH was not as efficient at mobilizing lipids for VLDL secretion and exhibited an altered distribution within the ER. TGH is a glycoprotein, but glycosylation is not required for catalytic activity. TGH does not hydrolyze apolipoprotein B–associated lipids. This suggests a mechanism for vectored movement of TGs onto developing VLDL in the ER as TGH may mobilize TG for VLDL assembly, but will not access this lipid once it is associated with VLDL.
Abbreviations used: Apo, apolipoprotein; BiP, ER-binding protein; CE, cholesteryl ester; ER, endoplasmic reticulum; HS, horse serum; HSL, hormone-sensitive lipase; LPL, microbial lipoprotein lipase; MUH, 4-methylumbelliferyl heptanoate; PBS, phosphate-buffered saline; TG, triacylglycerol; TGH, triacylglycerol hydrolase; U, enzymatic unit; VLDL, very-low-density lipoprotein.
|| Scientist of the Alberta Heritage Foundation for Medical Research and Canada Research Chair in Molecular and Cell Biology of Lipids.
¶ Senior Scholar of the Alberta Heritage Foundation for Medical Research.
# Corresponding author. E-mail address: richard.lehner{at}ualberta.ca.
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