期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 131, 期 15, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI146870
关键词
-
资金
- NIH Program Project [P01DK098108]
- US Veterans Administration Merit Review award [BX004306]
- NIH Southern California Research Center for ALPD and Cirrhosis [P50AA11999]
- US Department of Defense Focused Program Award [W81XWH1910888]
- NIH [DK119437, P30DK052574]
- Rosztoczy Foundation
- U.S. Department of Defense (DOD) [W81XWH1910888] Funding Source: U.S. Department of Defense (DOD)
The study reveals the essential role of the M6P pathway in maintaining exocrine pancreas homeostasis and function, with Gnptab(-/-) mice developing spontaneous pancreatitis. Normalization of cholesterol metabolism by pharmacologic means alleviated responses of experimental pancreatitis.
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据