The liver may regulate glucose homeostasis by modulating the sensitivity/resistance of peripheral tissues to insulin, by way of the production of secretory proteins, termed hepatokines. Here, we demonstrate that selenoprotein P (SeP), a liver-derived secretory protein, causes insulin resistance. Using serial analysis of gene expression (SAGE) and DNA chip methods, we found that hepatic SeP mRNA levels correlated with insulin resistance in humans. Administration of purified SeP impaired insulin signaling and dysregulated glucose metabolism in both hepatocytes and myocytes. Conversely, both genetic deletion and RNA interference-mediated knockdown of SeP improved systemic insulin sensitivity and glucose tolerance in mice. The metabolic actions of SeP were mediated, at least partly, by inactivation of adenosine monophosphate-activated protein kinase (AMPK). In summary, these results demonstrate a role of SeP in the regulation of glucose metabolism and insulin sensitivity and suggest that SeP may be a therapeutic target for type 2 diabetes.

The activation protein-1 (AP-1) 1 transcription factors are immediate early response genes involved in a diverse set of transcriptional regulatory processes (1). The AP-1 complex consists of a heterodimer of a Fos family member and a Jun family member. This complex binds the consensus DNA sequence (TGAGTCA) (termed AP-1) sites found in a variety of promoters (2, 3). The Fos family contains four proteins (c-Fos, Fos-B, Fra-1, and Fra-2) (4 -6), whereas the Jun family is composed of three (c-Jun, Jun-B, and Jun-D) (7-10). Fos and Jun are members of the bZIP family of sequence-specific dimeric DNA-binding proteins (11). The C-terminal half of the bZIP domain is amphipathic, containing a heptad repeat of leucines that is critical for the dimerization of bZIP proteins (12,13). The N-terminal half of the long bipartite helix is the basic region that is critical for sequence-specific DNA binding (14 -16).Transcription coactivators bridge transcription factors and the components of the basal transcriptional apparatus (17). Functionally conserved proteins CREB-binding protein (CBP) and p300 have been shown to be essential for the activation of transcription by a large number of regulated transcription factors, including nuclear receptors (18 -21), , NFB (25,26), basic helix-loop-helix factors (27), STATs (28,29), and AP-1 (30, 31). In particular, the nuclear receptor superfamily is a group of ligand-dependent transcriptional regulatory proteins that function by binding to specific DNA sequences named hormone response elements in promoters of target genes (reviewed in Ref. 32). Transcriptional regulation by nuclear receptors depends primarily upon a ligand-dependent activation function, AF-2, located in the C terminus and predicted to undergo an allosteric change upon ligand binding (32). Consistent with this, CBP and p300 have been found to interact directly with nuclear receptors in a ligand-and AF-2-dependent manner (18 -21). In addition, a series of factors that exhibit ligand-and AF-2-dependent binding to nuclear receptors have been identified both biochemically and by expression cloning. Among these, a group of highly related proteins have been shown to form a complex with CBP and p300 and enhance transcriptional activation by several nuclear receptors, i.e. steroid receptor coactivator-1 (SRC-1) (20, 33), xSRC-3 (34), AIB1 (35), TIF2 (36), RAC3 (37), ACTR (38), TRAM-1 (39), and p/CIP (40). Interestingly, SRC-1 (41) and its homologue ACTR (38), along with CBP and p300 (42,43), were recently shown to contain potent histone acetyltransferase activities themselves and associate with yet another histone acetyltransferase protein p/CAF (44). In contrast, it was shown that SMRT (45) and N-CoR (46), nuclear receptor corepressors, form complexes with Sin3 and histone deacetylase proteins (47,48). From these results, it was suggested that chromatin remodeling by cofactors may contribute, through histone acetylation-deacetylation, to transcription factor-mediated transcriptional regulation.In light of the fact that SRC-1 is ...

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Vascular calcification is prevalent in patients with chronic kidney disease and leads to increased cardiovascular morbidity and mortality. Although several reports have implicated mitochondrial dysfunction in cardiovascular disease and chronic kidney disease, little is known about the potential role of mitochondrial dysfunction in the process of vascular calcification. This study investigated the effect of α-lipoic acid (ALA), a naturally occurring antioxidant that improves mitochondrial function, on vascular calcification in vitro and in vivo. Calcifying vascular smooth muscle cells (VSMCs) treated with inorganic phosphate (Pi) exhibited mitochondrial dysfunction, as demonstrated by decreased mitochondrial membrane potential and ATP production, the disruption of mitochondrial structural integrity and concurrently increased production of reactive oxygen species. These Pi-induced functional and structural mitochondrial defects were accompanied by mitochondria-dependent apoptotic events, including release of cytochrome c from the mitochondria into the cytosol, subsequent activation of caspase-9 and -3, and chromosomal DNA fragmentation. Intriguingly, ALA blocked the Pi-induced VSMC apoptosis and calcification by recovery of mitochondrial function and intracellular redox status. Moreover, ALA inhibited Pi-induced down-regulation of cell survival signals through the binding of growth arrest-specific gene 6 (Gas6) to its cognate receptor Axl and subsequent Akt activation, resulting in increased survival and decreased apoptosis. Finally, ALA significantly ameliorated vitamin D3-induced aortic calcification and mitochondrial damage in mice. Collectively, the findings suggest ALA attenuates vascular calcification by inhibiting VSMC apoptosis through two distinct mechanisms; preservation of mitochondrial function via its antioxidant potential and restoration of the Gas6/Axl/Akt survival pathway.