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␤ 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.The number of adipocytes in an organism is determined by a tightly regulated differentiation process of fibroblast-like preadipocytes (1, 2). Fat cell differentiation (adipogenesis) is controlled by hormonal-induced coordinated expression and activation of two main groups of transcription factors, the CCAAT/enhancer-binding protein (C/EBP) family and peroxisome proliferator-activated receptor ␥ (PPAR␥) 4 (2). PPAR␥, a member of the nuclear hormone receptors superfamily, is a crucial component of this cascade, as adipogenesis is impaired in PPAR␥-deficient mesenchymal stem cells (3). Activation of PPAR␥ induces the expression of lipogenic genes, such as adipocyte fatty acid-binding protein (422/aP2) (4), CD36 and lipoprotein lipase (LPL) (5). Accumulation of intracellular triglyceride (TG) droplets ultimately gives rise to the morphologically distinct fat cell (2). During periods of caloric restriction, TGs stored in adipocytes are catabolized into glycerol and fatty acids, to provide energy. Mobilization of lipids involves the sequential activation of hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) (6), two lipolytic enzymes responsible for more than 95% of the TG hydrolase activity in the adipose tissues of mammals (7). The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional cell surface receptor. Two NPXY motifs in the intracellular domain (ICD) serve as docking sites for several cytoplasmic adaptor proteins including Shc, Disabled-1, JIP1, PSD-95, CED-6/GULP, ARH, and Fe65, which control intracellular trafficking, as well as signaling events (8). LRP1 interacts with and mediates endocytosis of more than 40 unrelated ligands ranging from viruses to protease/protease inhibitor complexes, cytokines, and growth factors (9). In the liver, LRP1 and the LDL receptor (LDLr) share the endocytosis and subsequent degradation of TG-rich very-low-density lipoproteins and chylomicron remnants. However, endocytosis and clearance of macromolecules is only one function of LRP1. There is now substantial evidence that LRP1 also serves ...

Psychological or physical stress induces an elevation of corticosteroids in the circulating system. We report here that corticosterone (CT) protects cardiomyocytes from apoptotic cell death induced by doxorubicin (Dox), an antineoplastic drug known to induce cardiomyopathy possibly through reactive oxygen species production. The cytoprotection induced by CT is within the range of physiologically relevant doses. The lowest dose tested, 0.1 M (or 3.5 g/dl), inhibited apoptosis by approximately 25% as determined by caspase activity. With 1 M CT, cardiomyocytes gain a cytoprotective effect after 8 h of incubation and remain protected for at least 72 h. Hydrocortisone, cortisone, dexamethasone, and aldosterone but not androstenedione or cholesterol also induced cytoprotection. Analyses of 20,000 gene expression sequences using Affymetrix high-density oligonucleotide array found that CT caused up-regulation of 140 genes and down-regulation of 108 genes over 1.5-fold. Among the up-regulated genes are bcl-xL, metallothioneins, glutathione peroxidase-3, and glutathione Stransferases. Western blot analyses revealed that CT induced an elevation of bcl-xL but not bcl-2 or proapoptotic factors bax, bak, and bad. Inhibiting the expression of bcl-xL reduced the cytoprotective effect of CT. Our data suggest that CT induces a cytoprotective effect on cardiomyocytes in association with reprogramming gene expression and induction of bcl-xL gene.

Caveolin-1 plays a checkpoint function in the regulation of processes often altered in cancer. Although increased expression of caveolin-1 seems to be the norm in the glioma family of malignancies, populations of caveolin-1 positive and negative cells coexist among glioblastoma specimens. As no data are available to date on the contribution of such cells to the phenotype of glioblastoma, we manipulated caveolin-1 in the glioblastoma cell line U87MG. We showed that caveolin-1 plays a critical role in the aggressiveness of glioblastoma. We identified integrins as the main set of genes affected by caveolin-1. We reported here that the phenotypic changes observed after caveolin-1 modulation were mediated by alpha(5)beta(1) integrins. As a consequence of the regulation of alpha(5)beta(1) levels by caveolin-1, the sensitivity of cells to the specific alpha(5)beta(1) integrin antagonist, SJ749, was affected. Mediator of caveolin-1 effects, alpha(5)beta(1) integrin, is also a marker for glioma aggressiveness and an efficient target for the treatment of glioma especially the ones exerting the highest aggressive phenotype.