LRP1 controls intracellular cholesterol storage and fatty acid synthesis through modulation of Wnt signaling.
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 GSK3beta 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.
Terrand
Járome
J
CNRS, UMR7175, Universitá de Strasbourg, Illkirch, F-67401 France, the Zentrum fu¨r Neurowissenschaften, Universita¨t Freiburg, 79104 Freiburg Germany, the Department of Functional Genomics, IGBMC (Institut de Gánátique et de Biologie Moláculaire et Cellulaire), Illkirch, F-67400 France, the Institut Clinique de la souris, Universitá Louis Pasteur, Illkirch, F-67000 France, and the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
Bruban
Váronique
V
CNRS, UMR7175, Universitá de Strasbourg, Illkirch, F-67401 France, the Zentrum fu¨r Neurowissenschaften, Universita¨t Freiburg, 79104 Freiburg Germany, the Department of Functional Genomics, IGBMC (Institut de Gánátique et de Biologie Moláculaire et Cellulaire), Illkirch, F-67400 France, the Institut Clinique de la souris, Universitá Louis Pasteur, Illkirch, F-67000 France, and the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
Zhou
Li
L
CNRS, UMR7175, Universitá de Strasbourg, Illkirch, F-67401 France, the Zentrum fu¨r Neurowissenschaften, Universita¨t Freiburg, 79104 Freiburg Germany, the Department of Functional Genomics, IGBMC (Institut de Gánátique et de Biologie Moláculaire et Cellulaire), Illkirch, F-67400 France, the Institut Clinique de la souris, Universitá Louis Pasteur, Illkirch, F-67000 France, and the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
Gong
Wanfeng
W
CNRS, UMR7175, Universitá de Strasbourg, Illkirch, F-67401 France, the Zentrum fu¨r Neurowissenschaften, Universita¨t Freiburg, 79104 Freiburg Germany, the Department of Functional Genomics, IGBMC (Institut de Gánátique et de Biologie Moláculaire et Cellulaire), Illkirch, F-67400 France, the Institut Clinique de la souris, Universitá Louis Pasteur, Illkirch, F-67000 France, and the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
El Asmar
Zeina
Z
CNRS, UMR7175, Universitá de Strasbourg, Illkirch, F-67401 France, the Zentrum fu¨r Neurowissenschaften, Universita¨t Freiburg, 79104 Freiburg Germany, the Department of Functional Genomics, IGBMC (Institut de Gánátique et de Biologie Moláculaire et Cellulaire), Illkirch, F-67400 France, the Institut Clinique de la souris, Universitá Louis Pasteur, Illkirch, F-67000 France, and the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
May
Petra
P
CNRS, UMR7175, Universitá de Strasbourg, Illkirch, F-67401 France, the Zentrum fu¨r Neurowissenschaften, Universita¨t Freiburg, 79104 Freiburg Germany, the Department of Functional Genomics, IGBMC (Institut de Gánátique et de Biologie Moláculaire et Cellulaire), Illkirch, F-67400 France, the Institut Clinique de la souris, Universitá Louis Pasteur, Illkirch, F-67000 France, and the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
Zurhove
Kai
K
CNRS, UMR7175, Universitá de Strasbourg, Illkirch, F-67401 France, the Zentrum fu¨r Neurowissenschaften, Universita¨t Freiburg, 79104 Freiburg Germany, the Department of Functional Genomics, IGBMC (Institut de Gánátique et de Biologie Moláculaire et Cellulaire), Illkirch, F-67400 France, the Institut Clinique de la souris, Universitá Louis Pasteur, Illkirch, F-67000 France, and the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
Haffner
Philipp
P
CNRS, UMR7175, Universitá de Strasbourg, Illkirch, F-67401 France, the Zentrum fu¨r Neurowissenschaften, Universita¨t Freiburg, 79104 Freiburg Germany, the Department of Functional Genomics, IGBMC (Institut de Gánátique et de Biologie Moláculaire et Cellulaire), Illkirch, F-67400 France, the Institut Clinique de la souris, Universitá Louis Pasteur, Illkirch, F-67000 France, and the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
Philippe
Claude
C
CNRS, UMR7175, Universitá de Strasbourg, Illkirch, F-67401 France, the Zentrum fu¨r Neurowissenschaften, Universita¨t Freiburg, 79104 Freiburg Germany, the Department of Functional Genomics, IGBMC (Institut de Gánátique et de Biologie Moláculaire et Cellulaire), Illkirch, F-67400 France, the Institut Clinique de la souris, Universitá Louis Pasteur, Illkirch, F-67000 France, and the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
Woldt
Estelle
E
CNRS, UMR7175, Universitá de Strasbourg, Illkirch, F-67401 France, the Zentrum fu¨r Neurowissenschaften, Universita¨t Freiburg, 79104 Freiburg Germany, the Department of Functional Genomics, IGBMC (Institut de Gánátique et de Biologie Moláculaire et Cellulaire), Illkirch, F-67400 France, the Institut Clinique de la souris, Universitá Louis Pasteur, Illkirch, F-67000 France, and the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
Matz
Rachel L
RL
CNRS, UMR7175, Universitá de Strasbourg, Illkirch, F-67401 France, the Zentrum fu¨r Neurowissenschaften, Universita¨t Freiburg, 79104 Freiburg Germany, the Department of Functional Genomics, IGBMC (Institut de Gánátique et de Biologie Moláculaire et Cellulaire), Illkirch, F-67400 France, the Institut Clinique de la souris, Universitá Louis Pasteur, Illkirch, F-67000 France, and the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
Gracia
Cáline
C
CNRS, UMR7175, Universitá de Strasbourg, Illkirch, F-67401 France, the Zentrum fu¨r Neurowissenschaften, Universita¨t Freiburg, 79104 Freiburg Germany, the Department of Functional Genomics, IGBMC (Institut de Gánátique et de Biologie Moláculaire et Cellulaire), Illkirch, F-67400 France, the Institut Clinique de la souris, Universitá Louis Pasteur, Illkirch, F-67000 France, and the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
Metzger
Daniel
D
CNRS, UMR7175, Universitá de Strasbourg, Illkirch, F-67401 France, the Zentrum fu¨r Neurowissenschaften, Universita¨t Freiburg, 79104 Freiburg Germany, the Department of Functional Genomics, IGBMC (Institut de Gánátique et de Biologie Moláculaire et Cellulaire), Illkirch, F-67400 France, the Institut Clinique de la souris, Universitá Louis Pasteur, Illkirch, F-67000 France, and the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
Auwerx
Johan
J
CNRS, UMR7175, Universitá de Strasbourg, Illkirch, F-67401 France, the Zentrum fu¨r Neurowissenschaften, Universita¨t Freiburg, 79104 Freiburg Germany, the Department of Functional Genomics, IGBMC (Institut de Gánátique et de Biologie Moláculaire et Cellulaire), Illkirch, F-67400 France, the Institut Clinique de la souris, Universitá Louis Pasteur, Illkirch, F-67000 France, and the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
Herz
Joachim
J
CNRS, UMR7175, Universitá de Strasbourg, Illkirch, F-67401 France, the Zentrum fu¨r Neurowissenschaften, Universita¨t Freiburg, 79104 Freiburg Germany, the Department of Functional Genomics, IGBMC (Institut de Gánátique et de Biologie Moláculaire et Cellulaire), Illkirch, F-67400 France, the Institut Clinique de la souris, Universitá Louis Pasteur, Illkirch, F-67000 France, and the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046. Electronic address: joachim.herz@utsouthwestern.edu.
Boucher
Philippe
P
CNRS, UMR7175, Universitá de Strasbourg, Illkirch, F-67401 France, the Zentrum fu¨r Neurowissenschaften, Universita¨t Freiburg, 79104 Freiburg Germany, the Department of Functional Genomics, IGBMC (Institut de Gánátique et de Biologie Moláculaire et Cellulaire), Illkirch, F-67400 France, the Institut Clinique de la souris, Universitá Louis Pasteur, Illkirch, F-67000 France, and the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046. Electronic address: philippe.boucher@pharma.u-strasbg.fr.
D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein
D005227:Fatty Acids; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011518:Proto-Oncogene Proteins; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D002784:Cholesterol; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D000103:Acetyl-CoA Carboxylase