Pancreatic PCSK9 controls the organization of the β-cell secretory pathway via LDLR-cholesterol axis

PCSK9 内科学 内分泌学 可欣 低密度脂蛋白受体 生物 胰岛素 前蛋白转化酶 胆固醇 下调和上调 细胞生物学 脂蛋白 医学 生物化学 基因
作者
A. Marku,Lorenzo Da Dalt,A. Galli,Nevia Dule,Paola Antonia Corsetto,Angela Maria Rizzo,Annalisa Moregola,Patrizia Uboldi,Fabrizia Bonacina,P. Marciani,Michela Castagna,Alberico L. Catapano,Giuseppe Danilo Norata,Carla Perego
出处
期刊:Metabolism-clinical and Experimental [Elsevier]
卷期号:136: 155291-155291 被引量:15
标识
DOI:10.1016/j.metabol.2022.155291
摘要

Cholesterol is central to pancreatic β-cell physiology and alterations of its homeostasis contribute to β-cell dysfunction and diabetes. Proper intracellular cholesterol levels are maintained by different mechanisms including uptake via the low-density lipoprotein receptor (LDLR). In the liver, the proprotein convertase subtilisin/kexin type 9 (PCSK9) routes the LDLR to lysosomes for degradation, thus limiting its recycling to the membrane. PCSK9 is also expressed in the pancreas and loss of function mutations of PCSK9 result in higher plasma glucose levels and increased risk of Type 2 diabetes mellitus. Aim of this study was to investigate whether PCSK9 also impacts β-cells function.Pancreas-specific Pcsk9 null mice (Pdx1Cre/Pcsk9 fl/fl) were generated and characterized for glucose tolerance, insulin release and islet morphology. Isolated Pcsk9-deficient islets and clonal β-cells (INS1E) were employed to characterize the molecular mechanisms of PCSK9 action.Pdx1Cre/Pcsk9 fl/fl mice exhibited normal blood PCSK9 and cholesterol levels but were glucose intolerant and had defective insulin secretion in vivo. Analysis of PCSK9-deficient islets revealed comparable β-cell mass and insulin content but impaired stimulated secretion. Increased proinsulin/insulin ratio, modifications of SNARE proteins expression and decreased stimulated‑calcium dynamics were detected in PCSK9-deficient β-cells. Mechanistically, pancreatic PCSK9 silencing impacts β-cell LDLR expression and cholesterol content, both in vivo and in vitro. The key role of LDLR is confirmed by the demonstration that LDLR downregulation rescued the phenotype.These findings establish pancreatic PCSK9 as a novel critical regulator of the functional maturation of the β-cell secretory pathway, via modulation of cholesterol homeostasis.
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