Key result
Ablation of the Gnptab gene disrupted acinar cell cholesterol turnover, causing accumulation of nonesterified cholesterol in lysosomes and spontaneous pancreatitis in mice.
Why the study?
Disordered lysosomal/autophagy pathways initiate and drive pancreatitis, but the underlying mechanisms and links to disease pathology are poorly understood.
The mannose-6-phosphate pathway is essential for maintaining exocrine pancreas cholesterol homeostasis, and its disruption leads to spontaneous pancreatitis.
May inform pancreatitis therapies targeting lysosomal cholesterol handling; leaves open clinical translation from preclinical models.
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.
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Mareninova et al. (2021) studied Pancreatitis. Gnptab ablation vs. Wild-type (WT) was evaluated on Cholesterol homeostasis and pancreatitis development. Ablation of the Gnptab gene disrupted acinar cell cholesterol turnover, causing accumulation of nonesterified cholesterol in lysosomes and spontaneous pancreatitis in mice.