In the liver, insulin-mediated activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is at the core of metabolic control. Multiple PI3K and Akt isoenzymes are found in hepatocytes and whether isoform-selective interplays exist is currently unclear. Here we report that insulin signaling triggers the association of the liver specific class II PI3K isoform γ (PI3K-C2γ) with Rab5-GTP, and its recruitment to Rab5-positive early endosomes. In these vesicles, PI3K-C2γ produces a phosphatidylinositol-3,4-bisphosphate pool specifically required for delayed and sustained endosomal Akt2 stimulation. Accordingly, loss of PI3K-C2γ does not affect insulin-dependent Akt1 activation as well as S6K and FoxO1-3 phosphorylation, but selectively reduces Akt2 activation, which specifically inhibits glycogen synthase activity. As a consequence, PI3K-C2γ-deficient mice display severely reduced liver accumulation of glycogen and develop hyperlipidemia, adiposity as well as insulin resistance with age or after consumption of a high-fat diet. Our data indicate PI3K-C2γ supports an isoenzyme-specific forking of insulin-mediated signal transduction to an endosomal pool of Akt2, required for glucose homeostasis.

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DHT could positively regulate endothelial function through the control of the inflammatory response mediated by nuclear factor-kappaB in endothelial cells.

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Proprotein convertase subtilisin kexin type 9 (PCSK9) is a keyregulator of hepatic low-density lipoprotein-receptor (LDLR). PCSK9 is expressed in cultured smooth muscle cells (SMCs) and co-localizes with SMCs in human carotid atherosclerotic plaques. The present study aimed at comparing the neointimal lesions induced by periadventitial carotid placement of a non-occlusive collar in PCSK9 knock-out (PCSK9-/-) and wild type (WT) littermate (PCSK9+/+) mice. Collared carotids of the PCSK9-/-mice showed less intimal thickening compared to WT mice (p<0.05), a decreased intimal media ratio (p<0.02) and tendency to higher lumen area. When compared with PCSK9-/-, carotid lesions of WT mice had a higher content of SMCs (p<0.05) and collagen (p<0.05). No difference in macrophage content was detected between the two groups. SMCs freshly isolated from PCSK9-/-, when compared to PCSK9+/+ cells, showed higher levels of the contractile markers α-smooth muscle actin (α-SMA; 2.24±0.36 fold; p<0.01) and myosin heavy chain II (MHC-II; 8.65±1.55 fold; p<0.01), and decreased levels of synthetic markers caldesmon (-54±14%; p<0.01). PCSK9-/-cells also showed in response to platelet-derived growth factor-BB (PDGF-BB) a slower proliferation rate, and impaired migratory capacity and G1/S progression of the cell cycle. The reconstitution of PCSK9 expression, by retroviral infection of PCSK9-/-SMCs, led to a downregulation of α-SMA (-56±2%; p<0.01) and significant induction of caldesmon (1.46±0.3 fold; p<0.05). Proliferation rate of SMCs PCSK9-/-was significantly lower compared to PCSK9 reconstituted cells. Taken together, the present results suggest that by sustaining SMC synthetic phenotype, proliferation and migration PCSK9 may play a pro-atherogenic role in the arterial wall. HighlightsIn response to perivascular manipulation, the neointimal formation is reduced in PCSK9 -/-mice PCSK9 directly regulates smooth muscle cell differentiation, proliferation and migrationThe reconstitution of PCSK9 expression in SMCs PCSK9 -/-determines a switch towards a synthetic phenotype and rescue the impaired proliferation and migration capacities of SMCs PCSK9 -/-SMCs PCSK9 -/-respond less efficiently to the proliferative and chemotactic action of PDGF-BB 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 AbstractProprotein convertase subtilisin kexin type 9 (PCSK9) is a key-regulator of hepatic low-density lipoprotein-receptor (LDLR). PCSK9 is expressed in cultured smooth muscle cells (SMCs) and colocalizes with SMCs in human carotid atherosclerotic plaques. The present study aimed at comparing the neointimal lesions induced by periadventitial carotid placement of a non-occlusive collar in PCSK9 knock-out (PCSK9 -/-) and wild type (WT) littermate (PCSK9 +/+ ) mice. Collared carotids of the PCSK9 -/-mice showed less intimal thickening compared...

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