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

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, 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

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.

Keywords: adipose tissue and systemic inflammation; apoB-lipoproteins; cardiometabolic risk; plasma apoB-to-PCSK9.

Conflict of interest statement

The authors declare no conflict of interest associated with this manuscript.

© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.

Figures

FIGURE 1
FIGURE 1
Representative plasma membrane localization of CD36 and LDLR by immunohistofluorescence staining in WAT. Specificity of LDLR and CD36 detection in WAT was verified by secondary antibody‐only staining for CD36 (Alexa Fluor 555 anti‐rabbit IgG) (a), and LDLR (Alexa Fluor 647 anti‐rabbit IgG) (b), used as negative control; Positive staining (primary and secondary antibodies) of WAT section for CD36 (c) and LDLR (d) All samples counterstained with nuclear stain DAPI. A‐B represent the same WAT section, C‐D represent the same WAT section, all from the same subject
FIGURE 2
FIGURE 2
Subjects with lower PCSK9 have higher WAT surface LDLR and CD36 expression with upregulated NLRP3 inflammasome activity. Group difference in WAT surface LDLR (a) and CD36 (b), total WAT NLRP3 expression (c), pro‐IL‐1β expression (d), IL‐1β medium accumulation (e), and plasma IL‐1Ra (f). Data presented for N = 13 in the lower and N = 14 in the higher PCSK9 groups except for panel C where N = 11 in the higher PCSK9 group, panel D where N = 12 in the higher PCSK9 group, panel E where N = 12 in the lower and N = 9 in the higher PCSK9 group, and panel F where N = 12 in the higher PCSK9 group due to missing data. Women are presented as closed circles and men as open circles. Significant findings hold when performing non‐parametric sensitivity analysis
FIGURE 3
FIGURE 3
Subjects with lower PCSK9 have lower disposition index, impaired WAT function, and delayed postprandial TG clearance. Group differences in ex vivo WAT function (a), and postprandial plasma clearance of TGs (b), glucose‐induced total C‐peptide secretion (c), insulin sensitivity index M/I (d), first phase disposition index (E), and total disposition index (F). Data presented for N = 13 in the lower and N = 14 in the higher PCSK9 group in both groups except for panel A where N = 12 in the higher PCSK9 group due to insufficient WAT samples. Women are presented as closed circles and men as open circles. Significant findings hold when performing non‐parametric sensitivity analysis except for WAT function (p = 0.054)
FIGURE 4
FIGURE 4
Native human LDL impairs differentiation and function of SGBS preadipocytes. The effect of differentiation of SGBS preadipocytes for 7 days on proliferation (a) and lipid‐droplet accumulation per cell (b). A representative experiment using laser‐scanning confocal microscopy (10×) to visualize cell number and lipid‐droplet accumulation in preadipocytes, 7d‐normally differentiated adipocytes (CTL), and 7d‐differentiated adipocytes in the presence of native human LDL (0.2 g apoB/L) (c). The effect of 7d‐differentiation of SGBS preadipocytes in the presence of LDL (0–1.0 g apoB/L) on cell number (d), lipid‐droplet accumulation per cell (e), and adipocyte function per cell (f). N = 3 different experiments measured in triplicates
FIGURE 5
FIGURE 5
Native human LDL downregulate genes related to differentiation and function and upregulate MCP‐1 expression during SGBS preadipocyte differentiation. Expression of genes related to differentiation (a), lipid metabolism (b), glucose uptake/utilization and insulin sensitivity (c), and inflammation (d) in SGBS preadipocytes and 7d‐differentiation of SGBS preadipocytes in the presence of native human LDL (0.05 or 0.20 g apoB/L) compared to normally differentiated adipocytes. mRNA are normalized to beta‐2‐microglobulin (B2M) and expressed relative to control adipocytes. Data were analyzed by 2‐way ANOVA with interaction and Dunnett correction for multiple comparisons. N = 4 experiments in duplicates. *p < 0.05, **p < 0.01, ***p < 0.001; compared to control adipocytes

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