Lower plasma PCSK9 in normocholesterolemic subjects is associated with upregulated adipose tissue surface-expression of LDLR and CD36 and NLRP3 inflammasome

Background: LDL-cholesterol lowering variants that upregulate receptor uptake of LDL, such as in PCSK9 and HMGCR, are associated with diabetes via unclear mechanisms. Activation of the NLRP3 inflammasome/interleukin-1 beta (IL-1 beta) pathway promotes white adipose tissue (WAT) dysfunction and type 2 diabetes (T2D) and is regulated by LDL receptors (LDLR and CD36). We hypothesized that: (a) normocholesterolemic subjects with lower plasma PCSK9, identifying those with higher WAT surface-expression of LDLR and CD36, have higher activation of WAT NLRP3 inflammasome and T2D risk factors, and; (b) LDL upregulate adipocyte NLRP3 inflammasome and inhibit adipocyte function. Methodology: Post hoc analysis was conducted in 27 overweight/ obese subjects with normal plasma LDL-C and measures of disposition index (DI during Botnia clamps) and postprandial fat metabolism. WAT was assessed for surface-expression of LDLR and CD36 (immunohistochemistry), protein expression (immunoblot), IL-1 beta secretion (AlphaLISA), and function (H-3-triolein storage). Results: Compared to subjects with higher than median plasma PCSK9, subjects with lower PCSK9 had higher WAT surface-expression of LDLR (+81%) and CD36 (+36%), WAT IL-1 beta secretion (+284%), plasma IL-1 receptor-antagonist (+85%), and postprandial hypertriglyceridemia, and lower WAT pro-IL-1 beta protein (-66%), WAT function (-62%), and DI (-28%), without group-differences in body composition, energy intake or expenditure. Adjusting for WAT LDLR or CD36 eliminated group-differences in WAT function, DI, and postprandial hypertriglyceridemia. Native LDL inhibited Simpson-Golabi Behmel-syndrome (SGBS) adipocyte differentiation and function and increased inflammation. Conclusion: Normocholesterolemic subjects with lower plasma PCSK9 and higher WAT surface-expression of LDLR and CD36 have higher WAT NLRP3 inflammasome activation and T2D risk factors. This may be due to LDL-induced inhibition of adipocyte function.

Automated summary

This study found that normocholesterolemic subjects with lower plasma PCSK9 and higher WAT surface-expression of LDLR and CD36 have higher WAT NLRP3 inflammasome activation and T2D risk factors. This may be due to LDL-induced inhibition of adipocyte function.