Davis_1990_J.Biol.Chem_265_17960

Newborn combined lipase-deficient (cld) mice have severe hypertriglyceridemia associated with a marked decrease of lipoprotein lipase (LPL) and hepatic lipase (HL) activities. Since the cld mutation and lipase genes reside on separate chromosomes, combined lipase deficiency cannot result from defects occurring within the LPL or HL structural genes. To elucidate the biochemical basis of this trans-acting defect, cld mice were compared to unaffected littermates for changes in lipase mRNA levels, rates of synthesis, and posttranslational processing and secretion. LPL and HL mRNA levels in cld liver and LPL in cld heart were comparable to controls; corresponding lipase synthetic rates were modestly decreased by about 30%. However, these reduced synthetic rates were not lipase-specific, since the rates of apolipoprotein (apo) A-I and apoA-II synthesis in cld liver were similarly decreased. Despite LPL synthetic rates that were 70% of controls, LPL mass in cld postheparin plasma was markedly reduced to only 7% of control values, suggesting that the majority of LPL is not secreted but remains intracellular. Consistent with a lipase secretory defect, neither the LPL nor HL oligomannosyl forms were converted to their respective complex forms in cld tissues, indicating that the lipases had failed to move from the endoplasmic reticulum/cis-Golgi to the medial/trans-Golgi network. In addition, the majority of intracellular LPL was catalytically inactive, since LPL specific activity (units/mg LPL protein) in cld heart, kidney, and brain was reduced 80-97%. In contrast to the severe impairment of lipase posttranslational processing and secretion, cld mouse plasma contained normal levels of another secretory N-linked glycoprotein, adipsin, with its oligosaccharide chains fully processed to the complex form. Thus, the cld mutation appears not to globally disrupt the secretion of all N-linked glycoproteins, but rather selectively impairs LPL and HL at points essential to their normal intracellular transport and secretion.