Disease relevance of cld

• Here we briefly describe the phenotypes and genetics of several mutants with blood and tissue lipid abnormalities, and then provide a more in-depth discussion of two mutations, fatty liver dystrophy (fld) and combined lipase deficiency (cld) [1].

High impact information on cld

• A single recessive mutation, cld, on mouse chromosome 17 causes an apparent deficiency of both lipoprotein lipase and hepatic triglyceride lipase activities [2].
• Combined lipase deficiency (cld): a lethal mutation on chromosome 17 of the mouse [2].
• 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 [3].
• The findings demonstrate that brown adipocytes cultured from cld/cld mice synthesize lipoprotein lipase with two high mannose oligosaccharide chains, but it is inactive and retained in endoplasmic reticulum [4].
• Whether the cld mutation affects primarily processing of oligosaccharide chains of lipoprotein lipase in endoplasmic reticulum, transport of the lipase from the reticulum, or some other process, is to be resolved [4].

Biological context of cld

• After transient transfection with lipase expression constructs, secretion of hLPL activity from cld cells was only 12% of that from het cells [5].
• The CLD mutation allows synthesis and glycosylation of HL, but blocks activation of the lipase [6].
• The CLD mutation allows synthesis, glycosylation and dimerization of LPL, but blocks activation and secretion of the lipase [6].
• Combined lipase deficiency, cld, is a recessive mutation within the T/t complex of mouse chromosome 17 [7].
• An alteration of LPL gene expression in cld mice may affect the amount and/or the distribution of LPL mRNA in different cell types [8].

Anatomical context of cld

• LPL is synthesized in cld tissues but is retained in the endoplasmic reticulum (ER), whereas mouse HL (mHL) is secreted but inactive [5].
• Differentiated liver cell lines were derived from cld mice and their normal heterozygous (het) littermates by transformation of hepatocytes with SV40 large T antigen [5].
• Translocation of Golgi components to ER by treatment with brefeldin A (BFA) enabled synthesis of active LPL in cultured cld/cld brown adipocytes [6].
• LPL mRNA had the same pattern of distribution in both cld and normal newborn mice; the probe hybridized strongly to pyramidal neurons of the hippocampus, heart myocytes, and hepatocytes [8].
• Immunofluorescence studies showed HL was present in extracellular space, but not in cells, in liver and adrenal of both normal and cld/cld mice [9].

Associations of cld with chemical compounds

• 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) [6].
• Heparin injection increased plasma lipoprotein lipase activity in cld/cld mice, but the increment was less than 10% of that in unaffected mice [10].
• Cells cultured from cld/cld mice replicated, accumulated triacylglycerol, and differentiated into adipocytes at normal rates [4].
• Synthesis of inactive nonsecretable high mannose-type lipoprotein lipase by cultured brown adipocytes of combined lipase-deficient cld/cld mice [4].
• Brefeldin A enables synthesis of active lipoprotein lipase in cld/cld and castanospermine-treated mouse brown adipocytes via translocation of Golgi components to endoplasmic reticulum [11].

Other interactions of cld

• Thus, the CLD mutation allows secretion of inactive HL by liver and adrenals [6].

Analytical, diagnostic and therapeutic context of cld

• Immunofluorescence studies showed that LPL is retained in endoplasmic reticulum (ER) in cld/cld cells [6].
• Therefore, we performed in situ hybridization for LPL mRNA in tissues from normal and cld pups and adult mice using an antisense 35S-labeled cRNA probe [8].
• We also studied the LPL gene mutation in cld mice by Southern blot analysis [12].
• Molecular cloning of mouse hepatic triacylglycerol lipase: gene expression in combined lipase-deficient (cld/cld) mice [13].
• Northern blot analysis of total cellular RNA from livers of cld/cld and normal mice showed that there are two mRNA species for HL with the sizes of 1.8 and 1.9 kilobases in both groups [13].

References