Inducible inactivation of hepatic LRP gene by Cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants

Astrid Rohlmann, Michael Gotthardt, Robert E Hammer, Joachim Herz

Research output: Contribution to journalArticlepeer-review

365 Scopus citations

Abstract

The multifunctional low density lipoprotein (LDL) receptor-related protein (LRP) has been postulated to participate in a number of diverse physiological and pathological processes ranging from the homeostasis of plasma lipoproteins, atherosclerosis, and fibrinolysis to neuronal regeneration and survival. It has not been possible to demonstrate in vivo the physiological significance of LRP for each of these complex processes by a conventional gene knockout approach because LRP is essential for embryonic development. Here we have used the Cre/loxP recombination system to achieve inducible, tissue-specific and quantitative disruption of the LRP gene in adult mice. Inactivation of LRP in the livers of LDL receptor-deficient mice resulted in the accumulation of cholesterol-rich remnant lipoproteins in the circulation. In normal animals, this caused a compensatory upregulation of the LDL receptor in the liver. Conditional gene targeting has thus allowed us to isolate a specific physiological function of LRP for in vivo analysis and has provided unequivocal evidence for another LDL receptor-independent cholesterol clearance pathway in liver.

Original languageEnglish (US)
Pages (from-to)689-695
Number of pages7
JournalJournal of Clinical Investigation
Volume101
Issue number3
DOIs
StatePublished - Feb 1 1998

Keywords

  • Cholesterol metabolism
  • Chylomicron remnant
  • Cre recombinase
  • Homologous recombination
  • Low density lipoprotein

ASJC Scopus subject areas

  • Medicine(all)

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