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

Abstract

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-1β) 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-1β secretion (AlphaLISA), and function (3 H-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-1β secretion (+284%), plasma IL-1 receptor-antagonist (+85%), and postprandial hypertriglyceridemia, and lower WAT pro-IL-1β 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.

• Authors: Yannick Cyr, Valérie Lamantia, Simon Bissonnette, Melanie Burnette, Aurèle Besse-Patin, Annie Demers, Martin Wabitsch, Michel Chrétien, Gaétan Mayer, Jennifer L Estall, Maya Saleh, May Faraj
• Journal: Physiological reports (Physiol Rep) Vol. 9 Issue 3 Pg. e14721 (02 2021) ISSN: 2051-817X [Electronic] United States
• PMID: 33527668 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.

Chemical References

• Biomarkers
• CD36 Antigens
• CD36 protein, human
• IL1B protein, human
• Inflammasomes
• Interleukin-1beta
• LDLR protein, human
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• Receptors, LDL
• Cholesterol
• PCSK9 protein, human
• Proprotein Convertase 9

Topics

• Adipocytes, White (immunology, metabolism)
• Adipogenesis
• Adipose Tissue, White (immunology, metabolism)
• Aged
• Biomarkers (blood)
• CD36 Antigens (metabolism)
• Cells, Cultured
• Cholesterol (blood)
• Diabetes Mellitus, Type 2 (etiology)
• Down-Regulation
• Female
• Humans
• Inflammasomes (metabolism)
• Interleukin-1beta (metabolism)
• Male
• Middle Aged
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Obesity (blood, complications, enzymology, immunology)
• Proprotein Convertase 9 (blood)
• Receptors, LDL (metabolism)
• Risk Assessment
• Risk Factors