Scow R O, Schultz C J, Park J W, Blanchette-Mackie E J
Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA.
Chem Phys Lipids. 1998 Jun;93(1-2):149-55. doi: 10.1016/s0009-3084(98)00039-5.
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.
作用于血浆脂蛋白的脂蛋白脂肪酶（LPL）和肝脂肪酶（HL）与胰脂肪酶属于同一基因家族。LPL在心脏、肌肉和脂肪组织中合成，而HL主要在肝脏中合成。新生啮齿动物的肝脏中也能合成LPL。LPL的活性形式是二聚体，而HL的活性形式尚未明确。联合脂肪酶缺乏症（CLD）是小鼠中的一种常染色体隐性突变（cld），它会损害LPL和HL的翻译后加工过程。Cld/cld小鼠的LPL和HL活性极低（<正常水平的5%），但胰脂肪酶活性正常。它们会出现严重的高甘油三酯血症，并在出生后3天内死亡。CLD突变允许LPL的合成、糖基化和二聚化，但会阻断脂肪酶的激活和分泌。因此，二聚化本身并不会导致活性LPL的产生。免疫荧光研究表明，LPL在cld/cld细胞中保留在内质网（ER）中。用布雷菲德菌素A（BFA）处理使高尔基体成分转运至ER，从而在培养的cld/cld棕色脂肪细胞中合成活性LPL。因此，cld/cld细胞中无活性LPL的产生是由于细胞无法将LPL从ER转运出去。CLD突变允许HL的合成和糖基化，但会阻断脂肪酶的激活。免疫荧光研究发现，在正常和cld/cld小鼠的肝脏、肝细胞培养物以及孵育的肾上腺组织中，HL大多位于细胞外，而在用莫能菌素处理（以阻断蛋白质分泌）的肝细胞培养物和肾上腺组织中，HL大多位于细胞内。这些发现表明正常和cld/cld小鼠的肝脏和肾上腺细胞均可合成和分泌HL。因此，CLD突变允许肝脏和肾上腺分泌无活性的HL。然而，它并不阻断活性胰脂肪酶的合成或分泌。我们的研究结果表明，LPL、HL和胰脂肪酶虽然密切相关，但加工方式不同。
