LRP1 controls intracellular cholesterol storage and fatty acid synthesis through modulation of Wnt signaling
- PMID: 18990694
- PMCID: PMC2610522
- DOI: 10.1074/jbc.M806538200
LRP1 controls intracellular cholesterol storage and fatty acid synthesis through modulation of Wnt signaling
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 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.
Figures
Similar articles
-
Convergent Signaling Pathways Controlled by LRP1 (Receptor-related Protein 1) Cytoplasmic and Extracellular Domains Limit Cellular Cholesterol Accumulation.J Biol Chem. 2016 Mar 4;291(10):5116-27. doi: 10.1074/jbc.M116.714485. Epub 2016 Jan 19. J Biol Chem. 2016. PMID: 26792864 Free PMC article.
-
Low-density lipoprotein receptor-related protein 1 mediates hypoxia-induced very low density lipoprotein-cholesteryl ester uptake and accumulation in cardiomyocytes.Cardiovasc Res. 2012 Jun 1;94(3):469-79. doi: 10.1093/cvr/cvs136. Epub 2012 Mar 27. Cardiovasc Res. 2012. PMID: 22454363
-
LRP1 integrates murine macrophage cholesterol homeostasis and inflammatory responses in atherosclerosis.Elife. 2017 Nov 16;6:e29292. doi: 10.7554/eLife.29292. Elife. 2017. PMID: 29144234 Free PMC article.
-
Low-density lipoprotein receptor-related protein 1 is a novel modulator of radial glia stem cell proliferation, survival, and differentiation.Glia. 2016 Aug;64(8):1363-80. doi: 10.1002/glia.23009. Epub 2016 Jun 3. Glia. 2016. PMID: 27258849 Free PMC article.
-
LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies.Physiol Rev. 2008 Jul;88(3):887-918. doi: 10.1152/physrev.00033.2007. Physiol Rev. 2008. PMID: 18626063 Free PMC article. Review.
Cited by
-
Altered Adipose Tissue DNA Methylation Status in Metabolic Syndrome: Relationships Between Global DNA Methylation and Specific Methylation at Adipogenic, Lipid Metabolism and Inflammatory Candidate Genes and Metabolic Variables.J Clin Med. 2019 Jan 13;8(1):87. doi: 10.3390/jcm8010087. J Clin Med. 2019. PMID: 30642114 Free PMC article.
-
KIF13B establishes a CAV1-enriched microdomain at the ciliary transition zone to promote Sonic hedgehog signalling.Nat Commun. 2017 Jan 30;8:14177. doi: 10.1038/ncomms14177. Nat Commun. 2017. PMID: 28134340 Free PMC article.
-
Assessment of inbreeding coefficients and inbreeding depression on complex traits from genomic and pedigree data in Nelore cattle.BMC Genomics. 2024 Oct 8;25(1):944. doi: 10.1186/s12864-024-10842-w. BMC Genomics. 2024. PMID: 39379819 Free PMC article.
-
Genome-wide scans for candidate genes involved in the aquatic adaptation of dolphins.Genome Biol Evol. 2013;5(1):130-9. doi: 10.1093/gbe/evs123. Genome Biol Evol. 2013. PMID: 23246795 Free PMC article.
-
LDL Receptor-Related Protein-1 (LRP1) Regulates Cholesterol Accumulation in Macrophages.PLoS One. 2015 Jun 10;10(6):e0128903. doi: 10.1371/journal.pone.0128903. eCollection 2015. PLoS One. 2015. PMID: 26061292 Free PMC article.
References
-
- Rosen, E. D., and MacDougald, O. A. (2006) Nat. Rev. Mol. Cell. Biol. 7 885-896 - PubMed
-
- Rosen, E. D., Walkey, C. J., Puigserver, P., and Spiegelman, B. M. (2000) Genes Dev. 14 1293-1307 - PubMed
-
- Rosen, E. D., Sarraf, P., Troy, A. E., Bradwin, G., Moore, K., Milstone, D. S., Spiegelman, B. M., and Mortensen, R. M. (1999) Mol. Cell 4 611-617 - PubMed
-
- Tontonoz, P., Hu, E., Graves, R. A., Budavari, A. I., and Spiegelman, B. M. (1994) Genes Dev. 8 1224-1234 - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials
Miscellaneous