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Assifi, Murwarid M., Gabriela Suchankova, Scarlet Constant, Marc Prentki, Asish K. Saha, and Neil B. Ruderman. AMP-activated protein kinase and coordination of hepatic fatty acid metabolism of starved/carbohydrate-refed rats. Am J Physiol Endocrinol Metab 289: E794-E800, 2005. First published June 14, 2005; doi:10.1152/ajpendo.00144.2005.-Acute increases in the concentration of malonyl-CoA play a pivotal role in mediating the decrease in fatty acid oxidation that occurs in many tissues during refeeding after a fast. In this study, we assess whether such increases in malonyl-CoA in liver could be mediated by malonyl-CoA decarboxylase (MCD), as well as acetyl-CoA carboxylase (ACC). In addition, we examine how changes in the activity of ACC, MCD, and other enzymes that govern fatty acid and glycerolipid synthesis relate temporally to alterations in the activities of the fuel-sensing enzyme AMP-activated protein kinase (AMPK). Rats starved for 48 h and refed a carbohydrate chow diet for 1, 3, 12, and 24 h were studied. Refeeding caused a 40% decrease in the activity of the ␣1-isoform of AMPK within 1 h, with additional decreases in AMPK␣1 activity and a decrease in AMPK␣2 occurring between 1 and 24 h. At 1 h, the decrease in AMPK activity was associated with an eightfold increase in the activity of the ␣1-isoform of ACC and a 30% decrease in the activity of MCD, two enzymes thought to be regulated by AMPK. Also, the concentration of malonyl-CoA was increased by 50%. Between 1 and 3 h of refeeding, additional increases in the activity of ACC and decreases in MCD were observed, as was a further twofold increase in malonyl-CoA. Increases in the activity (60%) and abundance (12-fold) of fatty acid synthase occurred predominantly between 3 and 24 h and increases in the activity of mitochondrial sn-glycerol-3-phosphate acyltransferase (GPAT) and acyl-CoA:diaclyglycerol acyltransferase (DGAT) at 12 and 24 h. The results strongly suggest that early changes in the activity of MCD, as well as ACC, contribute to the increase in hepatic malonyl-CoA in the starved-refed rat. They also suggest that the changes in these enzymes, and later occurring increases in enzymes regulating fatty acid and glycerolipid synthesis, could be coordinated by AMPK.acetyl-coenzyme A carboxylase; acyl-coenzyme A:diaclyglycerol acyltransferase; glycerol phosphate acyltransferase; malonyl-coenzyme A; malonyl-coenzyme A decarboxylase THE TRANSITION FROM THE FASTED TO THE FED STATE is associated with nutritional and hormonal changes that lead to increased hepatic glycerolipid and fatty acid synthesis and decreased fatty acid oxidation and ketogenesis (41). Many of the enzymes that mediate these events have been identified, as have the hormonal factors and molecular mechanism(s) by which their activity is altered (2,8,16,17,28, 45,53). We examine here the possibility that the changes in activity of these enzymes during refeeding are coordinated by AMP-activated protein kinase (AMPK). AMPK belongs to a family of highly conserved serine kinases that are reg...

Background Neoadjuvant treatment has proven beneficial for many GI malignancies, but no phase III trials have been completed examining this approach in pancreatic cancer. This meta-analysis examines the best available phase II trials using neoadjuvant treatment for resectable and borderline/unresectable pancreatic adenocarcinoma. Methods Phase II trials were identified using a MEDLINE search, and the Cochrane Central Register of Controlled Trials from 1960 to July 2010. Patients were divided into two groups: patients with initially resectable tumors (Group A), and patients with borderline/unresectable tumors (Group B). Primary outcome measures were rate of resection and survival. Pooled proportions and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies. Results A total of 14 phase II clinical trials including 536 patients were analyzed. Following treatment, resectability was 65.8% (95% CI 55.4%–75.6%) compared with 31.6% in Group B (95% CI 14.0%–52.5%). A significant partial response was observed in patients with borderline/unresectable tumors; 31.8 (95% CI 24.2%–39.8%) in Group B, and 9.5% (95% CI 2.9%–19.4%) in Group A (p=0.003). Progressive disease was seen in 17.0% (95% CI 11.9%–22.7) of patients in Group A versus 21.8% (95% CI 10.1%–36.5%) in Group B (p=0.006). Median survival in resected patients was 23 months for Group A, and 22.3 months for Group B. Conclusion Neoadjuvant treatment appears to have some activity in patients with borderline/unresectable pancreatic adenocarcinoma. Nearly one-third of tumors initially deemed marginal for operative intervention were ultimately able to be resected following treatment. Until more effective targeted chemotherapeutics are developed, the only group of patients with pancreatic cancer that may benefit from neoadjuvant treatment are those with locally advanced disease.