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- W72351112 abstract "Lecithin-cholesterol acyltransferase (LCAT) is an enzyme principally secreted by theliver into the circulation where it esterifies cholesterol and plays a key role in high-density lipoprotein (HDL) metabolism. In familial and acquired (liver disease) LCATdeficiency, the failure to esterify cholesterol causes many cellular and metabolicdisturbances. Here, I describe the purification of recombinant LCAT and assess twoapproaches to treat LCAT deficiency. Human LCAT cDNA was cloned into aselectable expression vector and used to generate a stably–transfected Chinesehamster ovary (CHO) cells secreting human LCAT tagged with 6 histidine residues.Productive clones were selected, monitoring LCAT activity by a modification of aradioactive enzymic assay for plasma, and the enzyme purified from culture mediumby immobilised cobalt affinity chromatography. The pure LCAT, as judged by SDS-PAGE, was used to raise monoclonal antibodies in LCAT knockout mice for futuredevelopment of a sensitive immunoassay. For therapy, I evaluated injection of pureLCAT into the peritoneal cavity of LCAT knockout mice using single and repeatdose regimes. LCAT activity was measurable in plasma post-injection and thepercentage of esterified cholesterol increased, while agarose gel electrophoresisconfirmed a rise in HDL levels. In a second approach, I encapsulated therecombinant CHO cells in biocompatible and semipermeable alginate-polylysinemicrocapsules using a syringe pump extrusion method. A study in vitro showed that,after an initial lag phase, LCAT was secreted for over 90 days with the capsulesremaining intact. These microencapsulated cells were implanted into peritonealcavities of LCAT-deficient mice. LCAT activity was detected in mice plasma oneweek post-implantation; the relative amount of esterified cholesterol was increasedand lipoprotein profile was improved. I conclude that injection of recombinantenzyme or of encapsulated LCAT-secreting cells are feasible therapies for familialand acquired LCAT deficiency." @default.
- W72351112 created "2016-06-24" @default.
- W72351112 creator A5030703730 @default.
- W72351112 date "2009-01-01" @default.
- W72351112 modified "2023-09-26" @default.
- W72351112 title "Protein and cell therapy for lecithin-cholesterol acyltransferase (LCAT) deficiency" @default.
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