White Adipose Tissue Surface Expression of LDLR and CD36 is Associated with Risk Factors for Type 2 Diabetes in Adults with Obesity

Abstract

Objective: Human conditions with upregulated receptor uptake of low-density lipoproteins (LDL) are associated with diabetes risk, the reasons for which remain unexplored. LDL induce metabolic dysfunction in murine adipocytes. Thus, it was hypothesized that white adipose tissue (WAT) surface expression of LDL receptor (LDLR) and/or CD36 is associated with WAT and systemic metabolic dysfunction. Whether WAT LDLR and CD36 expression is predicted by plasma lipoprotein-related parameters was also explored. Methods: This was a cross-sectional analysis of 31 nondiabetic adults (BMI > 25 kg/m 2) assessed for WAT surface expression of LDLR and CD36 (immunohistochemistry), WAT function, WAT and systemic inflammation, postprandial fat metabolism, and insulin resistance (IR; hyperinsulinemic-euglycemic clamp). Results: Fasting WAT surface expression of LDLR and CD36 was negatively associated with WAT function (3 H-triglyceride storage, r = −0.45 and −0.66, respectively) and positively associated with plasma IL-1 receptor antagonist (r = 0.64 and 0.43, respectively). Their expression was suppressed 4 hours postprandially, and reduced LDLR was further associated with IR (M/I clamp , r = 0.61 women, r = 0.80 men). Plasma apolipoprotein B (apoB)-to-PCSK9 ratio predicted WAT surface expression of LDLR and CD36, WAT dysfunction, WAT NLRP3 inflammasome priming and disrupted cholesterol-sensing genes, and systemic IR independent of sex and body composition. Conclusions: Higher fasting and lower postprandial WAT surface expression of LDLR and CD36 is associated with WAT dysfunction, systemic inflammation, and IR in adults with overweight/obesity, anomalies that are predicted by higher plasma apoB-to-PCSK9 ratio.

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

“…This suggests that the source of increased WAT IL-1β secretion in subjects with lower plasma PCSK9 and upregulate WAT LDLR and CD36 pathways, and after the incubation of human WAT with native LDL , may not be adipocytes but resident macrophage within WAT. In line with this hypothesis, we recently reported macrophage infiltration of WAT in the fasting and 4-hour postprandial states in a similar population of subjects with overweight and obesity (Cyr et al, 2020). Lower fasting plasma PCSK9 also predicted the increase in WAT macrophage infiltration in the postprandial state in this population (Cyr et al, 2020).…”

“…The DI, which assesses insulin sensitivity and secretion concomitantly, was calculated as the 1 st phase or total glucose‐induced C‐peptide secretion multiplied by M/I (Lorenzo et al, 2010). Fasting index of insulin resistance was calculated as the Homeostatic Model Assessment of Insulin Resistance (HOMA‐IR) (Bissonnette et al, 2015; Bissonnette, Saint‐Pierre, et al, 2018; Cyr et al, 2020; Lamantia et al, 2017; Wassef et al, 2015).…”

“…Protein samples were separated by SDS‐PAGE with equal loading verified by 1.0% TCE (Sigma T54801) stain‐free total protein visualization. Proteins were transferred onto 0.45 µm polyvinylidene difluoride membrane (PVDF; Millipore), blocked in 5% non‐fat dry milk in 0.1% Tween‐Tris buffer, and probed overnight with required antibodies as previously published (Cyr et al, 2020). Protein bands were revealed by chemiluminescence (SuperSignal West Femto Substrate, Thermo Fisher) in the ChemiDoc XRS+imaging system (Bio‐Rad).…”

“…Postprandial plasma clearance of fat was measured over 6 hours. In both clinical trials, when sufficient WAT samples were collected, one portion was immediately snap-frozen in liquid nitrogen for mRNA and protein expression, a second portion was fixed overnight at 4°C in 4% paraformaldehyde, embedded in paraffin and cut into 5 µm sections, and a third portion was used fresh to measure WAT function ex vivo and collect WAT-conditioned medium over 4 hours (Bissonnette et al, 2013;Cyr et al, 2016Cyr et al, , 2020Lamantia et al, 2017;Wassef et al, 2012).…”

Coming Back to Physiology: Extra Hepatic Functions of Proprotein Convertase Subtilisin/Kexin Type 9

“…This mechanism has been linked to type 2 diabetes (Faraj, 2020). Similarly, fasting reduces plasma PCSK9 and thereby increases LDL-R expression in adipocytes leading to NLRP-3 activation (Cry et al, 2020).…”