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Dysregulation of mannose-6-phosphate–dependent cholesterol homeostasis in acinar cells mediates pancreatitis
- Source :
- J Clin Invest, The Journal of clinical investigation, vol 131, iss 15
- Publication Year :
- 2021
- Publisher :
- American Society for Clinical Investigation, 2021.
-
Abstract
- Disordered lysosomal/autophagy pathways initiate and drive pancreatitis, but the underlying mechanisms and links to disease pathology are poorly understood. Here, we show that the mannose-6-phosphate (M6P) pathway of hydrolase delivery to lysosomes critically regulates pancreatic acinar cell cholesterol metabolism. Ablation of the Gnptab gene encoding a key enzyme in the M6P pathway disrupted acinar cell cholesterol turnover, causing accumulation of nonesterified cholesterol in lysosomes/autolysosomes, its depletion in the plasma membrane, and upregulation of cholesterol synthesis and uptake. We found similar dysregulation of acinar cell cholesterol, and a decrease in GNPTAB levels, in both WT experimental pancreatitis and human disease. The mechanisms mediating pancreatic cholesterol dyshomeostasis in Gnptab(–/–) and experimental models involve a disordered endolysosomal system, resulting in impaired cholesterol transport through lysosomes and blockage of autophagic flux. By contrast, in Gnptab(–/–) liver the endolysosomal system and cholesterol homeostasis were largely unaffected. Gnptab(–/–) mice developed spontaneous pancreatitis. Normalization of cholesterol metabolism by pharmacologic means alleviated responses of experimental pancreatitis, particularly trypsinogen activation, the disease hallmark. The results reveal the essential role of the M6P pathway in maintaining exocrine pancreas homeostasis and function, and implicate cholesterol disordering in the pathogenesis of pancreatitis.
- Subjects :
- Knockout
Immunology
Transferases (Other Substituted Phosphate Groups)
Mannose 6-phosphate
Acinar Cells
Medical and Health Sciences
Oral and gastrointestinal
chemistry.chemical_compound
Mice
Rare Diseases
Downregulation and upregulation
03.01.07. Fiziológia (benne citológia)
Autophagy
Acinar cell
medicine
2.1 Biological and endogenous factors
Animals
Humans
Aetiology
Trypsinogen activation
Pancreas
Mice, Knockout
Mannosephosphates
Animal
Cholesterol
Gastroenterology
Cell Biology
General Medicine
medicine.disease
Pancreas, Exocrine
Mitochondria
Cell biology
Disease Models, Animal
chemistry
Pancreatitis
Disease Models
Lysosomes
Digestive Diseases
Exocrine
Homeostasis
Research Article
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- J Clin Invest, The Journal of clinical investigation, vol 131, iss 15
- Accession number :
- edsair.doi.dedup.....51296d66f09bb85e129d2fbc9e461ec8