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 mannose-6-phosphate (M6P) pathway of hydrolase delivery to lysosomes critically regulates pancreatic acinar cell cholesterol metabolism. Ablation of the Gnptab gene coding for a key enzyme in M6P pathway disrupted acinar cell cholesterol turnover, causing accumulation of non-esterified 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 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 M6P pathway in maintaining exocrine pancreas homeostasis and function, and implicate cholesterol disordering in the pathogenesis of pancreatitis.

ATF3 induces RAB7 to govern autodegradation in paligenosis, a conserved cell plasticity program

“…We saw dramatic structural changes in mitochondria during paligenosis, which likely reflect changes in metabolism. The metabolic profile of cells as they transition from their normal state to a metaplastic state is not well characterized, though a recent study demonstrated disrupted acinar cell cholesterol metabolism underlies pancreatitis in mouse models (Mareninova et al , 2021). We showed a dependency on dynamic mTORC1 activity during metaplasia (Willet et al , 2018) and recent studies show acetyl‐CoA metabolism contributes to cell plasticity in the pancreas and potentially tumorigenesis via epigenetic regulation (Carrer et al , 2019).…”

Genetic Analysis of the ATG16L1 c.898A>G (p.T300A) Variant in Acute and Chronic Pancreatitis

“…23 Moreover, ablation of Gnptab in mice resulted in impaired cholesterol transport through lysosomes and blockage of autophagic flux. 24 Remarkably, Gnptab −/− mice spontaneously develop pancreatitis.…”

“…Furthermore, acinar cell–specific Tfeb -deficient mice developed alcohol-induced pancreatic damage, whereas Tfeb overexpression diminished alcohol-induced injury 23 . Moreover, ablation of Gnptab in mice resulted in impaired cholesterol transport through lysosomes and blockage of autophagic flux 24 . Remarkably, Gnptab −/− mice spontaneously develop pancreatitis.…”

Association between autophagy and acute pancreatitis

“…Recent study indicates that dysregulation of mannose-6-phosphate (M6P) pathway mediates disorder of lysosome and autophagy and affects cholesterol metabolism ( Mareninova et al, 2021 ). GNPTAB gene that code the key enzyme of M6P pathway regulates the lysosomal system and autophagy in exocrine pancreas.…”

“…In addition, Gnptab deficiency increases total and free cholesterol in acinar cell and result in unbalanced distribution of cholesterol in mitochondria and lysosomes. More interestingly, Gnptab ablation also causes increased levels of serum amylase and lipase, inflammation, as well as parenchymal necrosis of mice pancreas ( Mareninova et al, 2021 ).…”