PCSK9 Deficiency Modulates Glucose Homeostasis and Insulin Secretion Via Pancreatic Ldl Receptors And Cholesterol Accumulation |Biomedgrid
Journal: American Journal of Biomedical Science & Research (Vol.9, No. 5)Publication Date: 2020-07-15
Authors : Jing He; Yan Liu; Kai Li; Xin Fan; Rong Li; Michael A Hill; Jianbo Wu;
Page : 346-352
Keywords : PCSK9; Pancreatic Islet Lipid Handling; Cholesterol Accumulation; Insulin Secretion; High Fat Feeding;
Abstract
Intracellular lipid accumulation contributes to β-cell dysfunction in type 2 diabetes. How PCSK9 interacts with lipid metabolism to alter insulin availability/resistance is not well studied. Genetic deficiency of PCSK9 mice was fed a high fat (HFD; 45% Kcal from fat) for 14 weeks, and the metabolic phenotype including glucose, insulin, GTT, ITT, and cholesterol was examined. In addition, the expression of PCSK9 and LDLR was were examined by RT-qPCR, and immunohistochemistry. We provide data supporting a role for PCSK9 in pancreatic islets. In HFD mice, PCSK9 deletion led to impaired glucose tolerance and decreased insulin secretion. Pancreatic islets of HFD PCSK9-/ mice showed impaired insulin production and increased LDLR mRNA. Cholesterol was higher in islets of both HFD-fed WT and PCSK9 KO mice compared to low-fat diet controls. Glucose intolerance in PCSK9 deficiency was reversed when the LDLR was also lacking. Further, islets isolated from PCSK-/-LDR-/- mice showed improved insulin secretion. Our findings support a tissue-specific role for PCSK9 in pancreatic cholesterol homeostasis such that PCSK deficiency may accentuate LDLR-dependent β-cell dysfunction.
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