SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells.

SIRT4, a member of the sirtuin family, has been implicated in the regulation of insulin secretion by modulation of glutamate dehydrogenase. However, the role of this enzyme in the regulation of metabolism in other tissues is unknown. In this study we investigated whether depletion of SIRT4 would enhance liver and muscle metabolic functions. To do this SIRT4 was knocked down using an adenoviral shRNA in mouse primary hepatocytes and myotubes. We observed a significant increase in gene expression of mitochondrial and fatty acid metabolism enzymes in hepatocytes with reduced SIRT4 levels. SIRT4 knockdown also increased SIRT1 mRNA and protein levels both in vitro and in vivo. In agreement with the increased fatty acid oxidation (FAO) gene expression, we showed a significant increase in FAO in SIRT4 knockdown primary hepatocytes compared with control, and this effect was dependent on SIRT1. In primary myotubes, knockdown of SIRT4 resulted in increased FAO, cellular respiration, and pAMPK levels. When SIRT4 was knocked down in vivo by tail vein injection of a shRNA adenovirus, we observed a significant increase in hepatic mitochondrial and FAO gene expression consistent with the findings in primary hepatocytes. Taken together these findings demonstrate that SIRT4 inhibition increases fat oxidative capacity in liver and mitochondrial function in muscle, which might provide therapeutic benefits for diseases associated with ectopic lipid storage such as type 2 diabetes.

[Value of multi-slice spiral CT in the diagnosis of closed thyroid cartilage injury].

OBJECTIVE: To explore the clinical application and to evaluate the value of multi-slice spiral computed tomography (MSCT) in closed thyroid cartilage injury. METHODS: MSCT scan was performed in 5 patients with closed thyroid cartilage injury, and 2D and 3D images reconstructions were achieved after volume data was transferred to workstation. RESULTS: In 5 cases, the thyroid cartilage fracture was found in left board in 4 patients, in right board in 1 patient. In addition, one patient had concurrent cricoid cartilage fracture and another patient had laryngotracheal stenosis. These fractures and changes were all visualized by 2D and 3D images. Lower window level and window width were helpful to reveal the structures of thyroid cartilage. Multi-planar reconstruction (MPR) was superior in displaying alignment and displacement of fracture in 4 cases. 3D-volume reconstruction (3D-VR) was accurate in displaying space change of cartilage structures. In 3 cases, the evaluation of 3D-VR was accurate in assessing the length, width and shape of fracture, providing helpful data for the clinician to adopt the optimal management Computed tomography virtual laryngoscope (CTVL) helped to offer the criterions to the diagnosis of upper airway stricture and the location of laryngotracheal stenosis in one case. CONCLUSIONS: MSCT was useful in the diagnosis and management of closed thyroid cartilage injury and the laryngotracheal stenosis. It was believed that the reasonable use of the reprocessing technique plays an important role in the diagnosis, treatment and evaluation of the effect of closed thyroid cartilage injury.

Identification of ortho-amino benzamides and nicotinamides as MCHr1 antagonists.

Several potent and efficacious MCHr1 antagonists containing an ortho-amino benzamide or nicotinamide chemotype have been identified, exemplified by 28 and 50.