PCSK9 (PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9)AND GLUCOSE METABOLISM: WHICH CONNECTION?

PCSK9 (proprotein convertase subtilisin/kexin type 9) and glucose metabolism: which connection? Background: PCSK9 (proprotein convertase subtilisin/kexin type 9), is a protein, mainly synthesized and secreted by the liver, which binds to specific target proteins and escorts them towards lysosomes for degradation. The best defined activity of PCSK9 is its ability to modulate the hepatic uptake of LDL cholesterol (LDL-C), by enhancing the intracellular degradation of the LDL receptor (LDLR). In humans, several mutations in PCSK9 gene were described, both “gain-of-function” mutations associated to hypercholesterolemia and “loss of function” mutations linked to low LDL-C levels [1]. These findings suggest PCSK9 inhibitors as a promising class of drugs for the treatment of patients with severe hypercholesterolemia or at very high cardiovascular risk. However, some gaps regarding the potential role of PCSK9 in targeting the LDLR in organs other than the liver are still open. Indeed, the LDLR is abundantly expressed in pancreatic β-cells, where it plays a key role in the uptake of plasma LDL particles [2]. Therefore, further investigations are needed to better clarify the physiological role of PCSK9, also in light of its pharmacological targeting. Methods: WT, PCSK9 KO, LDLR KO, PCSK9/LDLR DKO, albumin (Alb)Cre+/PCSK9LoxP/LoxP (liver selective PCSK9 KO mice) and AlbCre-/PCSK9LoxP/LoxP mice were fed a HFD (High Fat Diet – 45% Kcal fat) or SFD (Standard Fat Diet – 10% Kcal fat) for 12 or 20 weeks. GTT, ITT, insulin and C-peptide plasma levels, pancreas morphology and cholesterol accumulation in pancreatic islets were studied in the different animal models. Results: Glucose clearance was significantly impaired in PCSK9 KO mice fed a SFD or a HFD for 20 weeks compared to WT animals, with both diet. On the contrary, insulin sensitivity was not affected as both animals showed a similar decrease in plasma glucose levels following insulin injection (ITT). Plasma insulin and C-peptide levels were reduced in PCSK9 KO mice compared to WT and accordingly fasting and refeeding experiments showed increased plasma glucose but reduced insulin levels in PCSK9 KO compared to controls. A detailed analysis of pancreas morphology of PCSK9 KO mice vs WT littermates revealed larger islets with increased accumulation of cholesteryl esters, paralleled by increased insulin intracellular levels. This phenotype was completely reverted in PCSK9/LDLR DKO mice implying the LDLR as the PCSK9 target responsible for the phenotype observed. Further studies in AlbCre+/PCSK9LoxP/LoxP, which lack detectable circulating PCSK9, also showed a complete recovery of the phenotype, thus indicating that circulating, liver-derived PCSK9 does not impact β-cells function and insulin secretion. Conclusion:The PCSK9/LDLR axis affects β-cells function and control insulin secretion. Our data indicate that this effect is independent of circulating PCSK9, and is probably related to local effects of PCSK9 suggesting the possibility that anti-PCSK9 antibodies or liver specific therapies, such as siRNAs, might have a limited impact on LDLR expression in pancreas and β-cells dysfunction.