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Visceral adipose tissue plays a critical role in numerous diseases. Although imaging studies often show adipose involvement in abdominal diseases, their outcomes may vary from being a mild self-limited illness to one with systemic inflammation and organ failure. We therefore compared the pattern of visceral adipose injury during acute pancreatitis and acute diverticulitis to determine its role in organ failure. Acute pancreatitis-associated adipose tissue had ongoing lipolysis in the absence of adipocyte triglyceride lipase (ATGL). Pancreatic lipase injected into mouse visceral adipose tissue hydrolyzed adipose triglyceride and generated excess nonesterified fatty acids (NEFAs), which caused organ failure in the absence of acute pancreatitis. Pancreatic triglyceride lipase (PNLIP) increased in adipose tissue during pancreatitis and entered adipocytes by multiple mechanisms, hydrolyzing adipose triglyceride and generating excess NEFAs. During pancreatitis, obese PNLIP-knockout mice, unlike obese adipocyte-specific ATGL knockouts, had lower visceral adipose tissue lipolysis, milder inflammation, less severe organ failure, and improved survival. PNLIP-knockout mice, unlike ATGL knockouts, were protected from adipocyte-induced pancreatic acinar injury without affecting NEFA signaling or acute pancreatitis induction. Therefore, during pancreatitis, unlike diverticulitis, PNLIP leaking into visceral adipose tissue can cause excessive visceral adipose tissue lipolysis independently of adipocyte-autonomous ATGL, and thereby worsen organ failure., Introduction In humans, visceral adipose tissue is commonly involved in acute diseases like acute diverticulitis (1, 2), appendicitis (3, 4), and acute pancreatitis (5-7), but the extent of visceral adipose [...]

Typical mammalian mitogen-activated protein kinase (MAPK) pathways consist of a cascade of three consecutive phosphorylation events exerted by a MAPK kinase kinase (MAPKKK), a MAPK kinase (MAPKK), and finally a MAPK. MAPKs not only target non-protein kinase substrates, they can also phosphorylate other protein kinases designated as MAPK-activated protein kinases (MAPKAPK). The MAPKAPK family includes the ribosomal-S6-kinases (RSK1-4), the MAPK-interacting kinases (MNK1 and 2), the mitogen-and stress-activated kinases (MSK1 and 2), and the MAPKAPK (MK2, 3, and 5) subfamilies. Although several reports indicate extensive cross-talk between the MAPK and protein kinase A (PKA) pathways, evidence of a direct interaction at the level of the MAPKAPK only appeared recently. The MAPKAPKs RSK1 and MK5 can bind to PKA, but the features of these interactions are distinct. This review discusses the different characteristics of regulating the activity and subcellular localization of MK5 and RSK1 by PKA and the functional implications of these interactions. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) is a common disease with no targeted therapy and has varied outcomes ranging from spontaneous resolution to being lethal. Although typically painful, AP can also be painless. Various agents, including opioids, are used for pain control in AP; the risks and benefits of which are often debated. As experimental AP in mice is used to study the efficacy of potential therapies, we studied the effect of a commonly used opioid, buprenorphine, on the initiation and progression of AP. For this, we administered extended-release buprenorphine subcutaneously before inducing the previously established severe AP model that uses interleukins 12 and 18 (IL12,18) in genetically obese (ob/ob) mice and compared this to mice with AP but without the drug. Mice were monitored over 3 days, and parameters of AP induction and progression were compared. Buprenorphine significantly reduced serum amylase, lipase, pancreatic necrosis, and AP-associated fat necrosis, which is ubiquitous in obese mice and humans. Buprenorphine delayed the AP-associated reduction of carotid artery pulse distention and the development of hypothermia, hastened renal injury, and muted the early increase in respiratory rate versus IL12,18 alone. The site of buprenorphine injection appeared erythematous, inflamed, and microscopically showed thinning, loss of epidermal layers that had increased apoptosis. In summary, subcutaneous extended-release buprenorphine interfered with the induction of AP by reducing serum amylase, lipase, pancreatic and fat necrosis, the worsening of AP by delaying hypotension, hypothermia, while hastening renal injury, respiratory depression, and causing cutaneous injury at the site of injection. NEW & NOTEWORTHY Extended-release buprenorphine interferes with the initiation and progression of acute pancreatitis at multiple levels.

Aim: To identify novel substrates for the mitogen-activated protein kinase-activated protein kinase 5 (MK5)., Methods: Yeast two-hybrid screening with MK5 as bait was used to identify novel possible interaction partners. The binding of putative partner was further examined by glutathione S-transferase (GST) pull-down, co-immunoprecipitation and fluorescence resonance energy transfer (FRET) analysis. In vitro kinase and peptide array assays were used to map MK5 phosphoacceptor sites on the new partner. Confocal microscopy was performed to study the subcellular localization of MK5 and its partners., Results: Septin 8 was identified as a novel interaction partner for MK5 by yeast two-hybrid screening. This interaction was confirmed by GST pull-down, co-immunoprecipitation and FRET analysis. Septin 5, which can form a complex with septin 8, did not interact with MK5. Serine residues 242 and 271 on septin 8 were identified as in vitro MK5 phosphorylation sites. MK5 and septin 8 co-localized in the perinuclear area and in cell protrusions. Moreover, both proteins co-localized with vesicle marker synaptophysin., Conclusion: Septin 8 is a bona fide interaction partner and in vitro substrate for MK5. This interaction may be implicated in vesicle trafficking.