Dysregulation of mannose-6-phosphate-dependent cholesterol homeostasis in acinar cells mediates pancreatitis.

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.

• Authors: Olga A Mareninova, Eszter T Vegh, Natalia Shalbueva, Carli Jm Wightman, Dustin L Dillon, Sudarshan Malla, Yan Xie, Toshimasa Takahashi, Zoltan Rakonczay Jr, Samuel W French, Herbert Y Gaisano, Fred S Gorelick, Stephen J Pandol, Steven J Bensinger, Nicholas O Davidson, David W Dawson, Ilya Gukovsky, Anna S Gukovskaya
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 131 Issue 15 (08 02 2021) ISSN: 1558-8238 [Electronic] United States
• PMID: 34128834 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Mannosephosphates
• mannose-6-phosphate
• Cholesterol
• Transferases (Other Substituted Phosphate Groups)
• GNPTAB protein, mouse

Topics

• Acinar Cells (metabolism, pathology)
• Animals
• Cholesterol (genetics, metabolism)
• Disease Models, Animal
• Humans
• Mannosephosphates (genetics, metabolism)
• Mice
• Mice, Knockout
• Pancreas, Exocrine (metabolism, pathology)
• Pancreatitis (metabolism, pathology)
• Transferases (Other Substituted Phosphate Groups) (deficiency, metabolism)