| First Author | Peyot ML | Year | 2021 |
| Journal | Biochim Biophys Acta Mol Cell Biol Lipids | Volume | 1866 |
| Issue | 8 | Pages | 158968 |
| PubMed ID | 33992809 | Mgi Jnum | J:307091 |
| Mgi Id | MGI:6711873 | Doi | 10.1016/j.bbalip.2021.158968 |
| Citation | Peyot ML, et al. (2021) Substantial PCSK9 inactivation in beta-cells does not modify glucose homeostasis or insulin secretion in mice. Biochim Biophys Acta Mol Cell Biol Lipids 1866(8):158968 |
| abstractText | Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in cholesterol homeostasis by promoting the degradation of the LDL receptor (LDLR). PCSK9 loss-of-function mutations are associated with increased fasting plasma glucose levels and slightly elevated risk of type 2-diabetes. Considering the known detrimental effects of cholesterol accumulation in beta-cell, and the widespread use of PCSK9 inhibitors to treat hypercholesterolemia, it is important to gain insight into the role of pancreatic PCSK9 in glucose homeostasis and beta-cell function. We generated the first beta-cell-specific KO of PCSK9 (betaKO). PCSK9 mRNA and protein expression were reduced by 48% and 78% in betaKO islets, respectively, indicating that beta-cells constitute a major site of PCSK9 expression. In islets, loss of beta-cell PCSK9 resulted in unchanged LDLR protein levels, but reduced LDLR mRNA, indicating that cholesterol internalization is enhanced and that beta-cell PCSK9 promotes LDLR degradation. In contrast, whole body PCSK9 KO mice exhibited 2-fold higher LDLR protein levels in islets and a stable expression of cholesterogenic genes. Whole body KO and betaKO mice presented normal glucose tolerance, insulin release in response to glucose load and insulin sensitivity. Ex vivo glucose-stimulated insulin secretion in presence or absence of fatty acids was similar in WT and KO islets. Like KO mice, individuals carrying loss-of-function PCSK9 variants may be protected from cholesterol-induced toxicity due to reduced circulating cholesterol levels. Using both whole body KO or betaKO models, our data demonstrate that PCSK9 deletion in mouse does not have any toxic effect on beta-cell function and glucose homeostasis. |
