Combined lipase deficiency (cld/cld) in mice affects differently post-translational processing of lipoprotein lipase, hepatic lipase and pancreatic lipase.
Lipoprotein lipase (LPL) and hepatic lipase (HL), which act on plasma lipoproteins, belong to the same gene family as pancreatic lipase. LPL is synthesized in heart, muscle and adipose tissue, while HL is synthesized primarily in liver. LPL is also synthesized in liver of newborn rodents. The active form of LPL is a dimer, whereas that of HL has not been established. Combined lipase deficiency (CLD) is an autosomal recessive mutation (cld) in mice which impairs post-translational processing of LPL and HL. Cld/cld mice have very low LPL and HL activities (< 5% of normal), yet normal pancreatic lipase activity. They develop massive hypertriglyceridemia and die within 3 days after birth. The CLD mutation allows synthesis, glycosylation and dimerization of LPL, but blocks activation and secretion of the lipase. Thus, dimerization per se does not result in production of active LPL. Immunofluorescence studies showed that LPL is retained in endoplasmic reticulum (ER) in cld/cld cells. Translocation of Golgi components to ER by treatment with brefeldin A (BFA) enabled synthesis of active LPL in cultured cld/cld brown adipocytes. Thus, production of inactive LPL in cld/cld cells results from inability of the cells to transport LPL from ER. The CLD mutation allows synthesis and glycosylation of HL, but blocks activation of the lipase. Immunofluorescence studies located HL mostly outside of cells in liver, liver cell cultures and incubated adrenal tissue of normal and cld/cld mice and mostly inside of cells in liver cell cultures and adrenal tissues treated with monensin (to block secretion of protein). These findings demonstrate synthesis and secretion of HL by both liver and adrenal cells of normal and cld/cld mice. Thus, the CLD mutation allows secretion of inactive HL by liver and adrenals. However, it does not block synthesis or secretion of active pancreatic lipase. Our findings indicate that LPL, HL and pancreatic lipase, although closely related, are processed differently.
Scow
R O
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Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA. rs1j@nih.gov
Schultz
C J
CJ
Park
J W
JW
Blanchette-Mackie
E J
EJ
D000818:Animals; D008049:Lipase / Q000172:deficiency* / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D051379:Mice; D010179:Pancreas / Q000201:enzymology*; D011499:Protein Processing, Post-Translational
D008049:Lipase; D008071:Lipoprotein Lipase