Maturation of hepatic lipase. Formation of functional enzyme in the endoplasmic reticulum is the rate-limiting step in its secretion.
Among three lipases in the lipase gene family, hepatic lipase (HL), lipoprotein lipase, and pancreatic lipase, HL exhibits the lowest intracellular specific activity (i.e. minimal amounts of catalytic activity accompanied by massive amounts of inactive lipase mass in the endoplasmic reticulum (ER)). In addition, HL has a distinctive sedimentation profile, where the inactive mass overlaps the region containing active dimeric HL and trails into progressively larger molecular forms. Eventually, at least half of the HL inactive mass in the ER reaches an active, dimeric conformation (t(1/2) = 2 h) and is rapidly secreted. The remaining inactive mass is degraded. HL maturation occurs in the ER and is strongly dependent on binding to calnexin in the early co-/post-translational stages. Later stages of HL maturation occur without calnexin assistance, although inactive HL at all stages appears to be associated in distinct complexes with other ER proteins. Thus, unlike other lipases in the gene family, HL maturation is the rate-limiting step in its secretion as a functional enzyme.
Ben-Zeev
Osnat
O
Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073, USA.
Doolittle
Mark H
MH
D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D037281:Calnexin / Q000737:chemistry; D002460:Cell Line; D002499:Centrifugation, Density Gradient; D006224:Cricetinae; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D019281:Dimerization; D004591:Electrophoresis, Polyacrylamide Gel; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007212:Indolizines / Q000494:pharmacology; D008049:Lipase / Q000737:chemistry* / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D011233:Precipitin Tests; D011487:Protein Conformation; D017510:Protein Folding; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013395:Sucrose / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D054836:Indolizidines
D037281:Calnexin; D003432:Cross-Linking Reagents; D003513:Cycloheximide; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D007212:Indolizines; D008049:Lipase; D011500:Protein Synthesis Inhibitors; D013395:Sucrose; C037806:castanospermine; D054836:Indolizidines