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Purpose Of Review: In this article, we discuss recent studies that advance our understanding of molecular and cellular factors initiating and driving pancreatitis, with the emphasis on the role of acinar cell organelle disorders.
Recent Findings: The central physiologic function of the pancreatic acinar cell - to synthesize, store, and secrete digestive enzymes - critically relies on coordinated actions of the endoplasmic reticulum (ER), the endolysosomal system, mitochondria, and autophagy. Recent studies begin to unravel the roles of these organelles' disordering in the mechanism of pancreatitis. Mice deficient in key autophagy mediators Atg5 or Atg7, or lysosome-associated membrane protein-2, exhibit dysregulation of multiple signaling and metabolic pathways in pancreatic acinar cells and develop spontaneous pancreatitis. Mitochondrial dysfunction caused by sustained opening of the permeability transition pore is shown to mediate pancreatitis in several clinically relevant experimental models, and its inhibition by pharmacologic or genetic means greatly reduces local and systemic pathologic responses. Experimental pancreatitis is also alleviated with inhibitors of ORAI1, a key component of the plasma membrane channel mediating pathologic rise in acinar cell cytosolic Ca2+. Pancreatitis-promoting mutations are increasingly associated with the ER stress. These findings suggest novel pathways and drug targets for pancreatitis treatment. In addition, the recent studies identify new mediators (e.g., neutrophil extracellular traps) of the inflammatory and other responses of pancreatitis.
Summary: The recent findings illuminate a critical role of organelles regulating the autophagic, endolysosomal, mitochondrial, and ER pathways in maintaining pancreatic acinar cell homeostasis and secretory function; provide compelling evidence that organelle disordering is a key pathogenic mechanism initiating and driving pancreatitis; and identify molecular and cellular factors that could be targeted to restore organellar functions and thus alleviate or treat pancreatitis.
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http://dx.doi.org/10.1097/MOG.0000000000000301 | DOI Listing |
iScience
December 2024
Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, USA.
Increased blood amino acid levels (hyperaminoacidemia) stimulate pancreas expansion by unclear mechanisms. Here, by genetic and pharmacological disruption of glucagon receptor (GCGR) in mice and zebrafish, we found that the ensuing hyperaminoacidemia promotes pancreatic acinar cell proliferation and cell hypertrophy, which can be mitigated by a low protein diet in mice. In addition to mammalian target of rapamycin complex 1 (mTORC1) signaling, acinar cell proliferation required , the most highly expressed amino acid transporter gene in both species.
View Article and Find Full Text PDFCommun Biol
December 2024
CAS Key Laboratory for Agro-Ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, Hunan, 410125, China.
Unlike monogastric animals, ruminants exhibit significantly lower starch digestibility in the small intestine. A better understanding of the physiological mechanisms that regulate digestion patterns in ruminants could lead to an increased use of starch concentrates. Here we show more robust pancreatic exocrine function in adult goats (AG) than in neonatal goats (NG) by combining scRNA-seq and proteomic analysis.
View Article and Find Full Text PDFDev Cell
December 2024
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:
The coordinated movement of cell collectives is essential for normal epithelial tissue development, maintenance, and cancer progression. Here, we report on a minimal 3D extracellular matrix (ECM) system wherein both invasive collective migration (ICM) and rotational collective migration (RCM) arise spontaneously from individually seeded epithelial cells of mammary and hepatic origin, regardless of whether they express adherens junctions, and lead to ductal-like and acinar-like structures, respectively. Quantitative microscopy and cellular Potts modeling reveal that initial differences in cell protrusion dynamics and matrix-remodeling localization generate RCM and ICM behavior in confining 3D ECM.
View Article and Find Full Text PDFCell Mol Gastroenterol Hepatol
December 2024
Divison of Digestive and Liver Diseases, Department of Medicine, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York 10032; USA. Electronic address:
Inflammation
December 2024
Department of Emergency Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China.
Acute pancreatitis (AP) is a common acute inflammatory abdominal condition. Severe acute pancreatitis (SAP) can provoke a systemic inflammatory response and lead to multiple organ failure. The S100A9 protein, recognized as a major inflammatory biomarker, plays a significant role in both infection and inflammatory responses.
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