An ANGPTL4-ceramide-protein kinase Cζ axis mediates chronic glucocorticoid exposure-induced hepatic steatosis and hypertriglyceridemia in mice.

Chronic or excess glucocorticoid exposure causes lipid disorders such as hypertriglyceridemia and hepatic steatosis. Angptl4 (angiopoietin-like 4), a primary target gene of the glucocorticoid receptor in hepatocytes and adipocytes, is required for hypertriglyceridemia and hepatic steatosis induced by the synthetic glucocorticoid dexamethasone. Angptl4 has also been shown to be required for dexamethasone-induced hepatic ceramide production. Here, we further examined the role of ceramide-mediated signaling in hepatic dyslipidemia caused by chronic glucocorticoid exposure. Using a stable isotope-labeling technique, we found that dexamethasone treatment induced the rate of hepatic de novo lipogenesis and triglyceride synthesis. These dexamethasone responses were compromised in Angptl4-null mice (Angptl4-/-). Treating mice with myriocin, an inhibitor of the rate-controlling enzyme of de novo ceramide synthesis, serine palmitoyltransferase long-chain base subunit 1 (SPTLC1)/SPTLC2, decreased dexamethasone-induced plasma and liver triglyceride levels in WT but not Angptl4-/- mice. We noted similar results in mice infected with adeno-associated virus-expressing small hairpin RNAs targeting Sptlc2. Protein phosphatase 2 phosphatase activator (PP2A) and protein kinase Cζ (PKCζ) are two known downstream effectors of ceramides. We found here that mice treated with an inhibitor of PKCζ, 2-acetyl-1,3-cyclopentanedione (ACPD), had lower levels of dexamethasone-induced triglyceride accumulation in plasma and liver. However, small hairpin RNA-mediated targeting of the catalytic PP2A subunit (Ppp2ca) had no effect on dexamethasone responses on plasma and liver triglyceride levels. Overall, our results indicate that chronic dexamethasone treatment induces an ANGPTL4-ceramide-PKCζ axis that activates hepatic de novo lipogenesis and triglyceride synthesis, resulting in lipid disorders.

Initial Experience with a Novel Pericardiocentesis Training Simulator Incorporating a Three-dimensional Printed Cardiac Model.

Pericardial effusion is a rare but serious complication in cardiac electrophysiology procedures. To avoid progression to acute tamponade and reduce the risk of adverse patient outcomes, emergent pericardiocentesis is often necessary. The conduct of more pericardiocentesis training may further mitigate this risk. However, teaching and practice opportunities are rare, creating the need for pericardiocentesis simulators. While various pericardiocentesis simulators exist, their applications have been limited; further, commercial simulators are anatomically realistic but can be expensive. As such, cheaper homemade simulators have been developed, yet these may lack the cardiac anatomical features for a high-fidelity simulation or may be overly complex to assemble. The purpose of this study is to report initial findings from a pericardiocentesis simulator that incorporates a three-dimensional (3D) cardiac model that is economical, simple to assemble, and anatomically accurate. A 3D-printed cardiac model was printed from a computed tomography file. The model was fitted with a latex balloon-in-a-balloon pericardium filled with colored saline and placed in an ultrasound-compatible gelatin mold to create a pericardiocentesis simulator. The simulator was then tested with experienced and novice trainees at an academic hospital. A total of 10 participants (four interventional cardiology faculty members and six cardiology fellows) performed simulated pericardiocentesis using the simulator and completed a questionnaire to evaluate the model's features and usefulness. The overall feedback regarding this novel simulation approach was positive and the model exhibited important anatomical features to accurately simulate ultrasound-guided pericardiocentesis. All participants were able to successfully insert the needle into the pericardial space and all but one successfully placed the pericardial drain. Survey results indicated that the model was largely perceived as useful for training. This work suggests incorporating a 3D-printed cardiac model into a gelatin mold results in a simple and inexpensive yet high-fidelity pericardiocentesis simulation experience. This novel approach may be useful for teaching pericardiocentesis in an academic hospital.