INDUCIBLE INACTIVATION OF HEPATIC LRP GENE BY CRE-MEDIATED RECOMBINATION CONFIRMS ROLE OF LRP IN CLEARANCE OF CHYLOMICRON REMNANTS

The multifunctional low density lipoprotein (LDL) receptor-related pro tein (LRP) has been postulated to participate in a number of diverse p hysiological and pathological processes ranging from the homeostasis o f plasma lipoproteins, atherosclerosis, and fibrinolysis to neuronal r egeneration and survival. It has not been possible to demonstrate in v ivo the physiological significance of LRP for each of these complex pr ocesses by a conventional gene knockout approach because LRP is essent ial for embryonic development. Here we have used the Cre/loxP recombin ation system to achieve inducible, tissue-specific and quantitative di sruption of the LRP gene in adult mice, Inactivation of LRP in the liv ers of LDL receptor-deficient mice resulted in the accumulation of cho lesterol-rich remnant lipoproteins in the circulation. In normal anima ls, this caused a compensatory upregulation of the LDL receptor in the liver, Conditional gene targeting has thus allowed us to isolate a sp ecific physiological function of LRP for in vivo analysis and has prov ided unequivocal evidence for another LDL receptor-independent cholest erol clearance pathway in liver.