| First Author | Marku A | Year | 2022 |
| Journal | Metabolism | Volume | 136 |
| Pages | 155291 | PubMed ID | 35981632 |
| Mgi Jnum | J:328547 | Mgi Id | MGI:7336610 |
| Doi | 10.1016/j.metabol.2022.155291 | Citation | Marku A, et al. (2022) Pancreatic PCSK9 controls the organization of the beta-cell secretory pathway via LDLR-cholesterol axis. Metabolism 136:155291 |
| abstractText | BACKGROUND: Cholesterol is central to pancreatic beta-cell physiology and alterations of its homeostasis contribute to beta-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 beta-cells function. METHODS: 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 beta-cells (INS1E) were employed to characterize the molecular mechanisms of PCSK9 action. RESULTS: 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 beta-cell mass and insulin content but impaired stimulated secretion. Increased proinsulin/insulin ratio, modifications of SNARE proteins expression and decreased stimulatedcalcium dynamics were detected in PCSK9-deficient beta-cells. Mechanistically, pancreatic PCSK9 silencing impacts beta-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. CONCLUSIONS: These findings establish pancreatic PCSK9 as a novel critical regulator of the functional maturation of the beta-cell secretory pathway, via modulation of cholesterol homeostasis. |
