Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 284, Issue 1, Pages 381-388Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M806538200
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Funding
- National Institutes of Health [HL20948, HL63762, NS43408, DK067320]
- center national pour la recherche scientifique (CNRS)
- Fondation pour la Recherche Medicale (FRM)
- Fondation de France
- Universite Louis Pasteur de Strasbourg
- agence nationale de la recherche [ANR-05-PCOD-020]
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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 of intracellular 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 of the noradrenergic pathway, through inhibition of GSK3 beta 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.
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