Mutations in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) cause congenital generalized lipodystrophy. To understand the molecular mechanisms underlying the metabolic complications associated with AGPAT2 deficiency, Agpat2 null mice were generated. Agpat2(-/-) mice develop severe lipodystrophy affecting both white and brown adipose tissue, extreme insulin resistance, diabetes, and hepatic steatosis. The expression of lipogenic genes and rates of de novo fatty acid biosynthesis were increased approximately 4-fold in Agpat2(-/-) mouse livers. The mRNA and protein levels of monoacylglycerol acyltransferase isoform 1 were markedly increased in the livers of Agpat2(-/-) mice, suggesting that the alternative monoacylglycerol pathway for triglyceride biosynthesis is activated in the absence of AGPAT2. Feeding a fat-free diet reduced liver triglycerides by approximately 50% in Agpat2(-/-) mice. These observations suggest that both dietary fat and hepatic triglyceride biosynthesis via a monoacylglycerol pathway may contribute to hepatic steatosis in Agpat2(-/-) mice.

Background The surgical management of periampullary lesions, status post-Roux-en-Y gastric bypass procedure (RYGBP), poses a challenge. The strategy should focus on managing the gastric remnant. Methods We propose a technique of managing the gastric remnant while doing a pancreaticoduodenectomy (PD) in a patient with a previous RYGBP. From September 2005 to June 2008, two patients with a previous RYGBP underwent PD with a modified technique. The records were reviewed with respect to preoperative, intraoperative, and postoperative data. Results Both patients were operated for a carcinoma of the head of pancreas. Neither patient underwent a preoperative endoscopic ultrasound. The operating times were 315 and 218 min. There was no mortality or morbidity seen. Neither patient was re-operated. The mean length of stay was 6 days. Conclusions The technique suggests an approach of managing the gastric remnant and preventing delayed gastric emptying which resulted in a decreased length of hospital stay.

outcomes.Although larger spleens are associated with a higher conversion rate, splenic weight is not an independent risk factor for complications, and not a contraindication to the laparoscopic approach.Patient Demographics T1541 Further Advances in the Alternative EUS-Guided Translumenal Drainage of Bile and Pancreatic Duct Obstructions -A Progression Report Uwe Will, Frank Meyer ERCP-guided stent implantation into the bile or pancreatic duct is considered an established treatment for obstructions.However, there are cases with not introducible catheter into the papilla or not reachable papilla because of both pyloric/duodenal stenosis or previous GI surgery.The aim of the study was to investigate feasibility & outcome of the EUS-guided translumenal drainage of the i) bile duct in cases with failure of PTCD or in patients who decline it & ii) pancreatic duct.Methods: All consecutive patients were enrolled in this ongoing prospective observational unicenter study (case series) through a 6-year time period.Patient-& intervention-related specifics were documented.Feasibility was characterized by success rate (e.g., regressive cholestasis, improval of clinical symptoms) & outcome by complication rate (frequency of bleeding or perforation), mortality & short-term followup.Results: From 2002-2008, 67 patients underwent endoscopic interventions (n=78) for translumenal drainage into the i) bile duct (main indication, cholestasis because of advanced tumor growth), n=32 (47.8%; interventions, n=33); ii) pancreatic duct (chronic pancreatitis), n=35 (52.2%; interventions, n=45).After translumenal ductal puncture, cholangio-& pancreaticography were successful in each case (100%).While cholangiodrainage was achieved in 25/32 subjects (technical success rate, 78%; plastic prosthesis, n=6; metallic stent, n=19), drain into the pancreatic duct was placed in 21/35 individuals (60%; not required, n=1) using this novel translumenal route: Transgastric drainage, n=7/35 (20%); transpapillary drainage with ERCP-based rendesvouz, n=14/35 (40%).Though slight postinterventional pain was observed in each case, only cholangitis (n=3/33; 9.1%) & hemobilia (n=1/33; 3%) occurred after cholangiodrainage (major complication, n=1 resulting in mortality of 3%) whereas after translumenal drainage of the pancreatic duct, bleeding (n=3/45; 6.7%), perforation (n=1/45; 2.2%), pancreatitis (n=2/45; 4.4%) & pseudocysts (n=4/45; 8.9% -no deaths but following surgery, n=9) were documented resulting in a periinterventional morbidity of 15.2% (n=5/33) & 22.2% (n=10/45), resp.Endoscopic reintervention rate was 21.2% (n= 7/33) & 17.8% (n=8/45), resp.(main cause, stent dislocation).Conclusion: In selected patients, EUS-guided translumenal drainage of the bile & pancreatic duct is a reasonable, feasible & promizing endoscopic approach, with an acceptable periinterventional risk.It broadens the spectrum of therapeutic options but still needs further evaluation on the indication & the advantageous impact as well as long-term follow-up investigation.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the proteinase K subfamily of subtilases that reduces the number of LDL receptors (LDLRs) in liver through an undefined posttranscriptional mechanism. We show that purified PCSK9 added to the medium of HepG2 cells reduces the number of cell-surface LDLRs in a dose- and time-dependent manner. This activity was approximately 10-fold greater for a gain-of-function mutant, PCSK9(D374Y), that causes hypercholesterolemia. Binding and uptake of PCSK9 were largely dependent on the presence of LDLRs. Coimmunoprecipitation and ligand blotting studies indicated that PCSK9 and LDLR directly associate; both proteins colocalized to late endocytic compartments. Purified PCSK9 had no effect on cell-surface LDLRs in hepatocytes lacking autosomal recessive hypercholesterolemia (ARH), an adaptor protein required for endocytosis of the receptor. Transgenic mice overexpressing human PCSK9 in liver secreted large amounts of the protein into plasma, which increased plasma LDL cholesterol concentrations to levels similar to those of LDLR-knockout mice. To determine whether PCSK9 was active in plasma, transgenic PCSK9 mice were parabiosed with wild-type littermates. After parabiosis, secreted PCSK9 was transferred to the circulation of wild-type mice and reduced the number of hepatic LDLRs to nearly undetectable levels. We conclude that secreted PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels.