LRP1 controls intracellular cholesterol storage and fatty acid synthesis through modulation of wnt signaling

Jérome Terrand, Véronique Bruban, Li Zhou, Wanfeng Gong, Zeina El Asmar, Petra May, Kai Zurhove, Philipp Haffner, Claude Philippe, Estelle Woldt, Rachel L. Matz, Céline Gracia, Daniel Metzger, Johan Auwerx, Joachim Herz, Philippe Boucher

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

The low-density lipoprotein receptor-related protein LRP1 is a cell surface receptor with functions in diverse physiological pathways, including lipid metabolism. Here we show that LRP1- deficient fibroblasts accumulate high levels ofintracellular cholesterol and cholesteryl-ester when stimulated for adipocyte differentiation. We demonstrate that LRP1 stimulates a canonical Wnt5a signaling pathway that prevents cholesterol accumulation. Moreover, we show that LRP1 is required for lipolysis and stimulates fatty acid synthesis independently ofthe noradrener- gic pathway, through inhibition of GSK3β and its previously unknown target acetyl-CoA carboxylase (ACC). As a result of ACC inhibition, mature LRP1-deficient adipocytes of adult mice are hypotrophic, and lower uptake of fatty acids into adipose tissue leads to their redistribution to the liver. These results establish LRP1 as a novel integrator of adipogenic differentiation and fat storage signals.

Original languageEnglish (US)
Pages (from-to)381-388
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number1
DOIs
StatePublished - Jan 2 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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