Tmed10 deficiency results in impaired exocrine pancreatic differentiation in zebrafish larvae.

Transmembrane p24 trafficking protein 10 (TMED10) is a conserved vesicle trafficking protein. It is dysregulated in Alzheimer disease and plays a pivotal role in the pathogenesis of Alzheimer disease. In addition to the brain, TMED10 is highly expressed in the exocrine pancreas; however, its biological functions and underlying mechanisms remain largely unknown. We studied reduced Tmed10 in zebrafish embryos by morpholino oligonucleotide knockdown and CRISPR-Cas9 mutagenesis. Tmed10-deficient embryos showed extensive loss of acinar mass and impaired acinar differentiation. TMED10 has been reported to have an inhibitory effect on γ-secretase. As one of the substrates of γ-secretase, membrane-bound ß-catenin was significantly reduced in Tmed10-deficient embryos. Increased γ-secretase activity in wild-type embryos resulted in a phenotype similar to that of tmed10 mutants. And the mutant phenotype could be rescued by treatment with the γ-secretase inhibitor, N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-s-phenylglycinet-butyl ester (DAPT). In addition, the reduced membrane-bound ß-catenin was accompanied with up-regulated ß-catenin target genes in Tmed10-deficient embryos. Overexpression of ß-catenin signaling inhibitor Dickkopf-1 (DKK-1) could rescue the exocrine pancreas defects. Taken together, our study reveals that Tmed10 regulates exocrine pancreatic differentiation through γ-secretase. Reduced membrane-bound ß-catenin, accompanied with hyperactivation of ß-catenin signaling, is an important cause of exocrine pancreas defects in Tmed10-deficient embryos. Our study reaffirms the importance of appropriate ß-catenin signaling in exocrine pancreas development. These findings may provide a theoretical basis for the development of treatment strategies for TMED10-related diseases.

Diabetes of the Exocrine Pancreas: Implications for Pharmacological Management.

Post-pancreatitis diabetes mellitus, pancreatic cancer-related diabetes, and cystic fibrosis-related diabetes are often underappreciated. As a result, a substantial proportion of people with these sub-types of diabetes receive antidiabetic medications that may be suboptimal, if not harmful, in the context of their underlying disease of the exocrine pancreas. The present article delineates both classical (biguanides, insulin, sulfonylureas, α-glucosidase inhibitors, thiazolidinediones, and meglitinides) and newer (glucagon-like peptide-1 receptor agonists, amylin analogs, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors, D2 receptor agonists, bile acid sequestrants, and dual glucagon-like peptide-1 receptor and glucose-dependent insulinotropic polypeptide receptor co-agonists) therapies and provides recommendations for managing people with diabetes of the exocrine pancreas based on the most up-to-date clinical evidence. Also, several emerging directions (lipid-enriched pathways, Y4 receptor agonism, glucagon-like peptide-1 and glucagon receptor co-agonism) are presented with a view to informing the process of new drug discovery and development.

Observing exocrine pancreas metabolism using a novel pancreas perfusion technique in combination with hyperpolarized [1-13 C]pyruvate.

In a clinical setting, ex vivo perfusions are routinely used to maintain and assess organ viability prior to transplants. Organ perfusions are also a model system to examine metabolic flux while retaining the local physiological structure, with significant success using hyperpolarized (HP) 13 C NMR in this context. We use a novel exocrine pancreas perfusion technique via the common bile duct to assess acinar cell metabolism with HP [1-13 C]pyruvate. The exocrine component of the pancreas produces digestive enzymes through the ductal system and is often neglected in research on the pancreas. Real-time production of [1-13 C]lactate, [1-13 C]alanine, [1-13 C]malate, [4-13 C]malate, [1-13 C]aspartate, and H13 CO3 - was detected. The appearance of these resonances indicates flux through both pyruvate dehydrogenase and pyruvate carboxylase. We studied excised pancreata from C57BL/6J mice and NOD.Rag1-/- .AI4α/ß mice, a commonly used model of Type 1 Diabetes (T1D). Pancreata from the T1D mice displayed increased lactate to alanine ratio without changes in oxygen consumption, signifying increased cytosolic NADH levels. The mass isotopologue analysis of the extracted pancreas tissue using gas chromatography-mass spectrometry revealed confirmatory 13 C enrichment in multiple TCA cycle metabolites that are products of pyruvate carboxylation. The methodology presented here has the potential to provide insight into mechanisms underlying several pancreatic diseases, such as diabetes, pancreatitis, and pancreatic cancer.

SnRNA-Seq of Pancreas Revealed the Dysfunction of Endocrine and Exocrine Cells in Transgenic Pigs with Prediabetes.

Diabetes poses a significant threat to human health. Exocrine pancreatic dysfunction is related to diabetes, but the exact mechanism is not fully understood. This study aimed to describe the pathological phenotype and pathological mechanisms of the pancreas of transgenic pigs (PIGinH11) that was constructed in our laboratory and to compare it with humans. We established diabetes-susceptible transgenic pigs and subjected them to high-fat and high-sucrose dietary interventions. The damage to the pancreatic endocrine and exocrine was evaluated using histopathology and the involved molecular mechanisms were analyzed using single-nucleus RNA-sequencing (SnRNA-seq). Compared to wild-type (WT) pigs, PIGinH11 pigs showed similar pathological manifestations to type 2 diabetes patients, such as insulin deficiency, fatty deposition, inflammatory infiltration, fibrosis tissue necrosis, double positive cells, endoplasmic reticulum (ER) and mitochondria damage. SnRNA-seq analysis revealed 16 clusters and cell-type-specific gene expression characterization in the pig pancreas. Notably, clusters of Ainar-M and Endocrine-U were observed at the intermediate state between the exocrine and endocrine pancreas. Beta cells of the PIGinH11 group demonstrated the dysfunction with insulin produced and secret decreased and ER stress. Moreover, like clinic patients, acinar cells expressed fewer digestive enzymes and showed organelle damage. We hypothesize that TXNIP that is upregulated by high glucose might play an important role in the dysfunction of endocrine to exocrine cells in PIGinH11 pigs.

Peroxisomes during postnatal development of mouse endocrine and exocrine pancreas display cell-type- and stage-specific protein composition.

Peroxisomal dysfunction unhinges cellular metabolism by causing the accumulation of toxic metabolic intermediates (e.g. reactive oxygen species, very -chain fatty acids, phytanic acid or eicosanoids) and the depletion of important lipid products (e.g. plasmalogens, polyunsaturated fatty acids), leading to various proinflammatory and devastating pathophysiological conditions like metabolic syndrome and age-related diseases including diabetes. Because the peroxisomal antioxidative marker enzyme catalase is low abundant in Langerhans islet cells, peroxisomes were considered scarcely present in the endocrine pancreas. Recently, studies demonstrated that the peroxisomal metabolism is relevant for pancreatic cell functionality. During the postnatal period, significant changes occur in the cell structure and the metabolism to trigger the final maturation of the pancreas, including cell proliferation, regulation of energy metabolism, and activation of signalling pathways. Our aim in this study was to (i) morphometrically analyse the density of peroxisomes in mouse endocrine versus exocrine pancreas and (ii) investigate how the distribution and the abundance of peroxisomal proteins involved in biogenesis, antioxidative defence and fatty acid metabolism change during pancreatic maturation in the postnatal period. Our results prove that endocrine and exocrine pancreatic cells contain high amounts of peroxisomes with heterogeneous protein content indicating that distinct endocrine and exocrine cell types require a specific set of peroxisomal proteins depending on their individual physiological functions. We further show that significant postnatal changes occur in the peroxisomal compartment of different pancreatic cells that are most probably relevant for the metabolic maturation and differentiation of the pancreas during the development from birth to adulthood.

The role of Ca2+ signalling in the pathology of exocrine pancreas.

Exocrine pancreas has been the field of many successful studies in pancreatic physiology and pathology. However, related disease - acute pancreatitis (AP) is still takes it toll with more than 100,000 related deaths worldwide per year. In spite of significant scientific progress and several human trials currently running for AP, there is still no specific treatment in the clinic. Studies of the mechanism of initiation of AP have identified two crucial conditions: sustained elevations of cytoplasmic calcium concentration (Ca2+ plateau) and significantly reduced intracellular energy (ATP depletion). These hallmarks are interdependent, i.e., Ca2+ plateau increase energy demand for its clearance while energy production is greatly affected by the pathology. Result of long standing Ca2+ plateau is destabilisation of the secretory granules and premature activation of the digestive enzymes leading to necrotic cell death. Main attempts so far to break the vicious circle of cell death have been concentrated on reduction of Ca2+ overload or reduction of ATP depletion. This review will summarise these approaches, including recent developments of potential therapies for AP.

Bi-glandular and persistent enterovirus infection and distinct changes of the pancreas in slowly progressive type 1 diabetes mellitus.

In slowly progressive type 1 diabetes mellitus (SPIDDM), the pancreas shows sustained islet inflammation, pancreatitis, pancreatic acinar cell metaplasia/dysplasia (ADM), and intraepithelial neoplasia (PanIN), a precancerous lesion. The mechanisms underlying these changes remain unclear. The presence of enterovirus (EV) encoded-capsid protein 1 (VP1) and -2A protease (2Apro) and the innate immune responses of the pancreas were studied using immunohistochemistry and in situ hybridization in 12 SPIDDM and 19 non-diabetic control pancreases. VP1, 2Apro, and EV-RNA were detected in islets and the exocrine pancreas in all SPIDDM pancreases. Innate immune receptor, melanoma differentiation-associated gene 5 (MDA5), and interferon (IFN)-beta1 were intensified in the islets of SPIDDM patients with short disease duration. However, expressions of MDA5 and IFN-beta1were suppressed in those with longer disease duration. CD3+ T cell infiltration was observed in the VP1- and insulin-positive islets (insulitis) and exocrine acinar cells. CD11c+ dendritic cells (DCs) in islets were scarce in long-term SPIDDM. This study showed the consistent presence of EV, suggesting an association with inflammatory changes in the endocrine and exocrine pancreas in SPIDDM. Suppressed expressions of MDA5 and IFN-beta1, as well as decreased numbers of DCs in the host cells, may contribute to persistent EV infection and induction of ADM/PanIN lesions, which may potentially provide a scaffold for pancreatic neoplasms.

The Role of MicroRNAs in Pancreatitis Development and Progression.

Pancreatitis (acute and chronic) is an inflammatory disease associated with significant morbidity, including a high rate of hospitalization and mortality. MicroRNAs (miRs) are essential post-transcriptional modulators of gene expression. They are crucial in many diseases' development and progression. Recent studies have demonstrated aberrant miRs expression patterns in pancreatic tissues obtained from patients experiencing acute and chronic pancreatitis compared to tissues from unaffected individuals. Increasing evidence showed that miRs regulate multiple aspects of pancreatic acinar biology, such as autophagy, mitophagy, and migration, impact local and systemic inflammation and, thus, are involved in the disease development and progression. Notably, multiple miRs act on pancreatic acinar cells and regulate the transduction of signals between pancreatic acinar cells, pancreatic stellate cells, and immune cells, and provide a complex interaction network between these cells. Importantly, recent studies from various animal models and patients' data combined with advanced detection techniques support their importance in diagnosing and treating pancreatitis. In this review, we plan to provide an up-to-date summary of the role of miRs in the development and progression of pancreatitis.

Overexpression of Pdx1, reduction of p53, or deletion of CHOP attenuates pancreas hypoplasia in mice with pancreas-specific O-GlcNAc transferase deletion.

Deletion of O-GlcNAc transferase (Ogt) in pancreatic epithelial progenitor cells results in pancreatic hypoplasia at birth, partly due to increased apoptosis during embryonic development. Constitutive loss of Ogt in ß-cells results in increased ER stress and apoptosis, and in the Ogt-deficient pancreas, transcriptomic data previously revealed both tumor suppressor protein p53 and pancreatic duodenal homeobox 1 (Pdx1), key cell survival proteins in the developing pancreas, as upstream regulators of differentially expressed genes. However, the specific roles of these genes in pancreatic hypoplasia are unclear. In this study, we explored the independent roles of p53, ER stress protein CHOP, and Pdx1 in pancreas development and their use in the functional rescue of pancreatic hypoplasia in the context of Ogt loss. Using in vivo genetic manipulation and morphometric analysis, we show that Ogt plays a key regulatory role in pancreas development. Heterozygous, but not homozygous, loss of pancreatic p53 afforded a partial rescue of ß-cell, α-cell, and exocrine cell masses, while whole body loss of CHOP afforded a partial rescue in pancreas weight and a full rescue in exocrine cell mass. However, neither was sufficient to fully mitigate pancreatic hypoplasia at birth in the Ogt-deficient pancreas. Furthermore, overexpression of Pdx1 in the pancreatic epithelium resulted in partial rescues in pancreas weight and ß-cell mass in the Ogt loss background. These findings highlight the requirement of Ogt in pancreas development by targeting multiple proteins such as transcription factor Pdx1 and p53 in the developing pancreas.

Adar1 deletion causes degeneration of the exocrine pancreas via Mavs-dependent interferon signaling.

Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-binding protein that deaminates adenosine (A) to inosine (I). A-to-I editing alters post-transcriptional RNA processing, making ADAR1 a crucial regulator of gene expression. Consequently, Adar1 has been implicated in organogenesis. To determine the role of Adar1 in pancreatic development and homeostasis, we conditionally deleted Adar1 from the murine pancreas (Ptf1aCre/+; Adar1Fl/Fl). The resulting mice had stunted growth, likely due to malabsorption associated with exocrine pancreatic insufficiency. Analyses of pancreata revealed ductal cell expansion, heightened interferon-stimulated gene expression and an increased influx of immune cells. Concurrent deletion of Adar1 and Mavs, a signaling protein implicated in the innate immune pathway, rescued the degenerative phenotype and resulted in normal pancreatic development. Taken together, our work suggests that the primary function of Adar1 in the pancreas is to prevent aberrant activation of the Mavs-mediated innate immune pathway, thereby maintaining pancreatic homeostasis.

Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor.

Type 1 diabetes (T1D) is an autoimmune disease that selectively destroys insulin-producing ß-cells in the pancreas. An unmet need in diabetes management, current therapy is focussed on transplantation. While the reprogramming of progenitor cells into functional insulin-producing ß-cells has also been proposed this remains controversial and poorly understood. The challenge is determining why default transcriptional suppression is refractory to exocrine reactivation. After the death of a 13-year-old girl with established insulin-dependent T1D, pancreatic cells were harvested in an effort to restore and understand exocrine competence. The pancreas showed classic silencing of ß-cell progenitor genes with barely detectable insulin (Ins) transcript. GSK126, a highly selective inhibitor of EZH2 methyltransferase activity influenced H3K27me3 chromatin content and transcriptional control resulting in the expression of core ß-cell markers and ductal progenitor genes. GSK126 also reinstated Ins gene expression despite absolute ß-cell destruction. These studies show the refractory nature of chromatin characterises exocrine suppression influencing ß-cell plasticity. Additional regeneration studies are warranted to determine if the approach of this n-of-1 study generalises to a broader T1D population.

Misaligned feeding schedule elicits divergent circadian reorganizations in endo- and exocrine pancreas clocks.

Misaligned feeding may lead to pancreatic insufficiency, however, whether and how it affects circadian clock in the exocrine pancreas is not known. We exposed rats to a reversed restricted feeding regimen (rRF) for 10 or 20 days and analyzed locomotor activity, daily profiles of hormone levels (insulin, glucagon, and corticosterone) in plasma, and clock gene expression in the liver and endocrine and exocrine pancreas. In addition, we monitored responses of the exocrine pancreatic clock in organotypic explants of mPer2Luc mice in real time to acetylcholine, insulin, and glucocorticoids. rRF phase-reversed the clock in the endocrine pancreas, similar to the clock in the liver, but completely abolished clock gene rhythmicity and significantly downregulated the expression of Cpb1 and Cel in the exocrine pancreas. rRF desynchronized the rhythms of plasma insulin and corticosterone. Daily profiles of their receptor expression differed in the two parts of the pancreas and responded differently to rRF. Additionally, the pancreatic exocrine clock responded differently to treatments with insulin and the glucocorticoid analog dexamethasone in vitro. Mathematical simulation confirmed that the long-term misalignment between these two hormonal signals, as occurred under rRF, may lead to dampening of the exocrine pancreatic clock. In summary, our data suggest that misaligned meals impair the clock in the exocrine part of the pancreas by uncoupling insulin and corticosterone rhythms. These findings suggest a new mechanism by which adverse dietary habits, often associated with shift work in humans, may impair the clock in the exocrine pancreas and potentially contribute to exocrine pancreatic insufficiency.

Estrogen-Related Receptor γ Maintains Pancreatic Acinar Cell Function and Identity by Regulating Cellular Metabolism.

BACKGROUND & AIMS: Mitochondrial dysfunction disrupts the synthesis and secretion of digestive enzymes in pancreatic acinar cells and plays a primary role in the etiology of exocrine pancreas disorders. However, the transcriptional mechanisms that regulate mitochondrial function to support acinar cell physiology are poorly understood. Here, we aim to elucidate the function of estrogen-related receptor γ (ERRγ) in pancreatic acinar cell mitochondrial homeostasis and energy production. METHODS: Two models of ERRγ inhibition, GSK5182-treated wild-type mice and ERRγ conditional knock-out (cKO) mice, were established to investigate ERRγ function in the exocrine pancreas. To identify the functional role of ERRγ in pancreatic acinar cells, we performed histologic and transcriptome analysis with the pancreas isolated from ERRγ cKO mice. To determine the relevance of these findings for human disease, we analyzed transcriptome data from multiple independent human cohorts and conducted genetic association studies for ESRRG variants in 2 distinct human pancreatitis cohorts. RESULTS: Blocking ERRγ function in mice by genetic deletion or inverse agonist treatment results in striking pancreatitis-like phenotypes accompanied by inflammation, fibrosis, and cell death. Mechanistically, loss of ERRγ in primary acini abrogates messenger RNA expression and protein levels of mitochondrial oxidative phosphorylation complex genes, resulting in defective acinar cell energetics. Mitochondrial dysfunction due to ERRγ deletion further triggers autophagy dysfunction, endoplasmic reticulum stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRγ-deficient acinar cells that escape cell death acquire ductal cell characteristics, indicating a role for ERRγ in acinar-to-ductal metaplasia. Consistent with our findings in ERRγ cKO mice, ERRγ expression was significantly reduced in patients with chronic pancreatitis compared with normal subjects. Furthermore, candidate locus region genetic association studies revealed multiple single nucleotide variants for ERRγ that are associated with chronic pancreatitis. CONCLUSIONS: Collectively, our findings highlight an essential role for ERRγ in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRγ and exocrine pancreas disorders.

Abnormal exocrine-endocrine cell cross-talk promotes ß-cell dysfunction and loss in MODY8.

MODY8 (maturity-onset diabetes of the young, type 8) is a dominantly inherited monogenic form of diabetes associated with mutations in the carboxyl ester lipase (CEL) gene expressed by pancreatic acinar cells. MODY8 patients develop childhood-onset exocrine pancreas dysfunction followed by diabetes during adulthood. However, it is unclear how CEL mutations cause diabetes. In the present study, we report the transfer of CEL proteins from acinar cells to ß-cells as a form of cross-talk between exocrine and endocrine cells. Human ß-cells show a relatively higher propensity for internalizing the mutant versus the wild-type CEL protein. After internalization, the mutant protein forms stable intracellular aggregates leading to ß-cell secretory dysfunction. Analysis of pancreas sections from a MODY8 patient reveals the presence of CEL protein in the few extant ß-cells. The present study provides compelling evidence for the mechanism by which a mutant gene expressed specifically in acinar cells promotes dysfunction and loss of ß-cells to cause diabetes.

Lack of CFTR alters the ferret pancreatic ductal epithelial secretome and cellular proteome: Implications for exocrine/endocrine signaling.

BACKGROUND: Cystic fibrosis (CF) related diabetes is the most common comorbidity for CF patients and associated with islet dysfunction. Exocrine pancreas remodeling in CF alters the microenvironment in which islets reside. Since CFTR is mainly expressed in pancreatic ductal epithelium, we hypothesized altered CF ductal secretions could impact islet function through paracrine signals. METHOD: We evaluated the secretome and cellular proteome of polarized WT and CF ferret ductal epithelia using quantitative ratiometric mass spectrometry. Differentially secreted proteins (DSPs) or expressed cellular proteins were used to mine pathways, upstream regulators and the CFTR interactome to map candidate CF-associated alterations in ductal signaling and phenotype. Candidate DSPs were evaluated for their in vivo pancreatic expression patterns and their functional impact on islet hormone secretion. RESULTS: The secretome and cellular proteome of CF ductal epithelia was significantly altered relative to WT and implicated dysregulated TGFß, WNT, and BMP signaling pathways. Cognate receptors of DSPs from CF epithelia were equally distributed among endocrine, exocrine, and stromal pancreatic cell types. IGFBP7 was a downregulated DSP in CF ductal epithelia in vitro and exhibited reduced CF ductal expression in vivo. IGFBP7 also altered WT islet insulin secretion in response to glucose. Many CFTR-associated proteins, including SLC9A3R1, were differentially expressed in the CF cellular proteome. Upstream regulators of the differential CF ductal proteome included TGFß, PDX1, AKT/PTEN, and INSR signaling. Data is available via ProteomeXchange with identifier PXD025126. CONCLUSION: These findings provide a proteomic roadmap for elucidating disturbances in autocrine and paracrine signals from CF pancreatic ducts and how they may alter islet function and maintenance.

Exocrine pancreas function is impaired in adult relatives of patients with type 1 diabetes.

AIMS: Alterations of the exocrine pancreas have been reported in type 1 diabetes, but their contribution to the pathogenesis of the disease is poorly understood. Here, we investigated markers of exocrine pancreas dysfunction in individuals at-risk of developing type 1 diabetes. METHODS: Serum P-amylase and lipase levels were assessed in samples obtained from healthy controls, patients with new onset type 1 diabetes, relatives participating to the TrialNet Pathway to Prevention who were, at blood collection, autoantibody negative or positive for a single autoantibody (low-risk individuals), and positive for multiple autoantibodies (high-risk individuals). Linear mixed models were adopted to estimate variation of pancreatic enzymes among the groups and to evaluate the influence of high-risk HLA genotypes and residual beta cell function on exocrine pancreas function. RESULTS: In adults, but not children, reduced levels of P-amylase and lipase were shown in at-risk individuals, including (for P-amylase levels only) those at low-risk, and in T1Dnew. Furthermore, while high-risk HLA genotypes negatively affected P-amylase levels in autoantibody negative adult individuals, fasting C-peptide levels did not correlate with pancreatic enzyme levels. CONCLUSIONS: Exocrine pancreas dysfunction precedes the onset of type 1 diabetes in adult at-risk individuals and may be unrelated to fasting C-peptide levels.

ELAPOR1 is a secretory granule maturation-promoting factor that is lost during paligenosis.

A single transcription factor, MIST1 (BHLHA15), maximizes secretory function in diverse secretory cells (like pancreatic acinar cells) by transcriptionally upregulating genes that elaborate secretory architecture. Here, we show that the scantly studied MIST1 target, ELAPOR1 (endosome/lysosome-associated apoptosis and autophagy regulator 1), is an evolutionarily conserved, novel mannose-6-phosphate receptor (M6PR) domain-containing protein. ELAPOR1 expression was specific to zymogenic cells (ZCs, the MIST1-expressing population in the stomach). ELAPOR1 expression was lost as tissue injury caused ZCs to undergo paligenosis (i.e., to become metaplastic and reenter the cell cycle). In cultured cells, ELAPOR1 trafficked with cis-Golgi resident proteins and with the trans-Golgi and late endosome protein: cation-independent M6PR. Secretory vesicle trafficking was disrupted by expression of ELAPOR1 truncation mutants. Mass spectrometric analysis of co-immunoprecipitated proteins showed ELAPOR1 and CI-M6PR shared many binding partners. However, CI-M6PR and ELAPOR1 must function differently, as CI-M6PR co-immunoprecipitated more lysosomal proteins and was not decreased during paligenosis in vivo. We generated Elapor1-/- mice to determine ELAPOR1 function in vivo. Consistent with in vitro findings, secretory granule maturation was defective in Elapor1-/- ZCs. Our results identify a role for ELAPOR1 in secretory granule maturation and help clarify how a single transcription factor maintains mature exocrine cell architecture in homeostasis and helps dismantle it during paligenosis.NEW & NOTEWORTHY Here, we find the MIST1 (BHLHA15) transcriptional target ELAPOR1 is an evolutionarily conserved, trans-Golgi/late endosome M6PR domain-containing protein that is specific to gastric zymogenic cells and required for normal secretory granule maturation in human cell lines and in mouse stomach.

Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases: Workshop Proceedings.

ABSTRACT: The "Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases" Workshop was a 1.5-day scientific conference at the National Institutes of Health (Bethesda, MD) that engaged clinical and basic science investigators interested in diseases of the pancreas. This report summarizes the workshop proceedings. The goal of the workshop was to forge connections and identify gaps in knowledge that could guide future research directions. Presentations were segregated into 6 major themes, including (a) Pancreas Anatomy and Physiology; (b) Diabetes in the Setting of Exocrine Disease; (c) Metabolic Influences on the Exocrine Pancreas; (d) Genetic Drivers of Pancreatic Diseases; (e) Tools for Integrated Pancreatic Analysis; and (f) Implications of Exocrine-Endocrine Crosstalk. For each theme, there were multiple presentations followed by panel discussions on specific topics relevant to each area of research; these are summarized herein. Significantly, the discussions resulted in the identification of research gaps and opportunities for the field to address. In general, it was concluded that as a pancreas research community, we must more thoughtfully integrate our current knowledge of the normal physiology as well as the disease mechanisms that underlie endocrine and exocrine disorders so that there is a better understanding of the interplay between these compartments.

IRAG2 Interacts with IP3-Receptor Types 1, 2, and 3 and Regulates Intracellular Ca2+ in Murine Pancreatic Acinar Cells.

The inositol 1,4,5-triphosphate receptor-associated 2 (IRAG2) is also known as Jaw1 or lymphoid-restricted membrane protein (LRMP) and shares homology with the inositol 1,4,5-triphosphate receptor-associated cGMP kinase substrate 1 (IRAG1). IRAG1 interacts with inositol trisphosphate receptors (IP3 receptors /IP3R) via its coiled-coil domain and modulates Ca2+ release from intracellular stores. Due to the homology of IRAG1 and IRAG2, especially in its coiled-coil domain, it is possible that IRAG2 has similar interaction partners like IRAG1 and that IRAG2 also modulates intracellular Ca2+ signaling. In our study, we localized IRAG2 in pancreatic acinar cells of the exocrine pancreas, and we investigated the interaction of IRAG2 with IP3 receptors and its impact on intracellular Ca2+ signaling and exocrine pancreatic function, like amylase secretion. We detected the interaction of IRAG2 with different subtypes of IP3R and altered Ca2+ release in pancreatic acinar cells from mice lacking IRAG2. IRAG2 deficiency decreased basal levels of intracellular Ca2+, suggesting that IRAG2 leads to activation of IP3R under unstimulated basal conditions. Moreover, we observed that loss of IRAG2 impacts the secretion of amylase. Our data, therefore, suggest that IRAG2 modulates intracellular Ca2+ signaling, which regulates exocrine pancreatic function.

Loss of the ciliary protein Chibby1 in mice leads to exocrine pancreatic degeneration and pancreatitis.

Primary cilia protrude from the apical surface of many cell types and act as a sensory organelle that regulates diverse biological processes ranging from chemo- and mechanosensation to signaling. Ciliary dysfunction is associated with a wide array of genetic disorders, known as ciliopathies. Polycystic lesions are commonly found in the kidney, liver, and pancreas of ciliopathy patients and mouse models. However, the pathogenesis of the pancreatic phenotype remains poorly understood. Chibby1 (Cby1), a small conserved coiled-coil protein, localizes to the ciliary base and plays a crucial role in ciliogenesis. Here, we report that Cby1-knockout (KO) mice develop severe exocrine pancreatic atrophy with dilated ducts during early postnatal development. A significant reduction in the number and length of cilia was observed in Cby1-KO pancreta. In the adult Cby1-KO pancreas, inflammatory cell infiltration and fibrosis were noticeable. Intriguingly, Cby1-KO acinar cells showed an accumulation of zymogen granules (ZGs) with altered polarity. Moreover, isolated acini from Cby1-KO pancreas exhibited defective ZG secretion in vitro. Collectively, our results suggest that, upon loss of Cby1, concomitant with ciliary defects, acinar cells accumulate ZGs due to defective exocytosis, leading to cell death and progressive exocrine pancreatic degeneration after birth.