Ablation of DGKα facilitates α-smooth muscle actin expression via the Smad and PKCδ signaling pathways during the acute phase of CCl4 -induced hepatic injury.

Expression of α-smooth muscle actin (αSMA) is constitutive in vascular smooth muscle cells, but is induced in nonmuscle cells such as hepatic stellate cells (HSCs). HSCs play important roles in both physiological homeostasis and pathological response. HSC activation is characterized by αSMA expression, which is regulated by the TGFß-induced Smad pathway. Recently, protein kinase C (PKC) was identified to regulate αSMA expression. Diacylglycerol kinase (DGK) metabolizes a second-messenger DG, thereby controlling components of DG-mediated signaling, such as PKC. In the present study we aimed to investigate the putative role of DGKα in αSMA expression. Use of a cellular model indicated that the DGK inhibitor R59949 promotes αSMA expression and PKCδ phosphorylation. It also facilitates Smad2 phosphorylation after 30 min of TGFß stimulation. Furthermore, immunocytochemical analysis revealed that DGK inhibitor pretreatment without TGFß stimulation engenders αSMA expression in a granular pattern, whereas DGK inhibitor pretreatment plus TGFß stimulation significantly induces αSMA incorporation in stress fibers. Through animal model experiments, we observed that DGKα-knockout mice exhibit increased expression of αSMA in the liver after 48 h of carbon tetrachloride injection, together with enhanced phosphorylation levels of Smad2 and PKCδ. Together, these findings suggest that DGKα negatively regulates αSMA expression by acting on the Smad and PKCδ signaling pathways, which differentially regulate stress fiber incorporation and protein expression of αSMA, respectively.

Deletion of diacylglycerol kinase ε confers susceptibility to obesity via reduced lipolytic activity in murine adipocytes.

Lipid metabolism is closely involved with signal transduction and energy homeostasis. Excess calorie intake causes abnormal lipid metabolism, promoting obesity and insulin resistance. Diacylglycerol (DG) represents not only a lipidic second messenger but also an intermediate metabolite for triglyceride metabolism in the endoplasmic reticulum (ER). However, it remains undetermined how the roles of DG in signaling and energy homeostasis is regulated within the cell. Of DG kinases (DGKs), which are enzymes that phosphorylate DG, DGKε resides in the ER. This study examined how DGKε is implicated in signal transduction and lipid homeostasis. DGKε-deficient mice were fed a high-fat diet (HFD) for 40 d. We observed that DGKε deficiency promotes fat accumulation in adipocytes and subsequently promotes insulin resistance in mice fed an HFD. This abnormal fat metabolism is mediated by down-regulation of lipolytic activities, such as adipose triglyceride lipase and hormone-sensitive lipase. In addition, activation of DG-sensitive PKC leads to insulin resistance in adipose tissue, which may be caused by delayed metabolism of DG. Our data suggest that DGKε links the second messenger signaling system to energy homeostasis in adipocytes and that its deficiency results in abnormal lipid metabolism such as obesity and insulin resistance.-Nakano, T., Seino, K., Wakabayashi, I., Stafforini, D. M., Topham, M. K., Goto, K. Deletion of diacylglycerol kinase ε confers susceptibility to obesity via reduced lipolytic activity in murine adipocytes.

[Acute respiratory failures caused by post-tracheotomy tracheomalacia].

A 77-year-old man underwent thoracic surgery. He had a history of two previous operations: parapharyngeal tumor removal with temporal tracheotomy 14 years ago and, two years later, a sinus surgery when, according to our anesthesia registry, intubation was extremely difficult due to stricture of the trachea underneath the tracheotomy scar. Pathology was not fully elucidated. Preoperative examinations including chest x-ray, spirogram and CT were not remarkable. The scar above the suprasternal notch was visibly sunken and retracted with respiration. Stridor was auscultated but breathing was not labored. The patient was anesthetized with propofol and intubation was smooth. During surgery anesthesia was maintained with sevoflurane, remifentanil and rocuronium. However, extubation was followed by desperate gasping and severe respiratory distress. The tracheotomy scar caved in and the airway collapsed. Continuous airway pressure via a facemask restored airway patency and improved breathing. After overnight respiratory support with non-invasive positive pressure ventilation (NPPV), patient was weaned from ventilator. Airway collapse and the two episodes of respiratory failures while under general anesthesia were attributed to post-tracheotomy tracheomalacia.

[Case of carbon monoxide poisoning with delayed encephalopathy assessed by magnetic resonance imaging].

A 21-year-old man attempted suicide by burning charcoal in a car for more than one day and was admitted to a regional hospital. On admission, his blood carboxyhemoglobin concentration was 4.4%. The patient was transferred to our emergency department because of suspected carbon monoxide poisoning. Hyperbaric oxygen therapy (HBO) was performed 5 times over 3 days. Fluid-attenuation inversion recovery (FLAIR) and diffusion-weighted (DWI) magnetic resonance imaging (MRI) performed on day 3 showed high signal-intensity lesions in the cerebral white matter. Additional HBO was performed once per day until day 16. Wecheler Memory Scale-Reviced (WMS-R) and Mini-Mental State Examination (MMSE) performed on day 17 showed his cognitive impairment. He gradually recovered the cognitive function and was discharged from the hospital without neurological sequelae on day 49. Delayed encephalopathy after acute carbon monoxide poisoning with dementia, mental impairment, and psychosis is a serious complication. Hyperintensity in FLAIR and DWI MRI predicts delayed encephalopathy and indicates cellular edema and demyelination of the white matter. One of the risk factors is prolonged carbon monoxide exposure. This case suggests that the patient, who was exposed to carbon monoxide for many hours, was at a high risk of delayed encephalopathy despite the low blood carboxyhemoglobin concentration and therefore must be monitored using MRI.