Differential expression of Lp-PLA2 in obesity and type 2 diabetes and the influence of lipids

Abstract

Aims/hypothesis Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a circulatory macrophage-derived factor that increases with obesity and leads to a higher risk of cardiovascular disease (CVD). Despite this, its role in adipose tissue and the adipocyte is unknown. Therefore, the aims of this study were to clarify the expression of Lp-PLA2 in relation to different adipose tissue depots and type 2 diabetes, and ascertain whether markers of obesity and type 2 diabetes correlate with circulating Lp-PLA2. A final aim was to evaluate the effect of cholesterol on cellular Lp-PLA2 in an in vitro adipocyte model. Methods Analysis of anthropometric and biochemical variables from a cohort of lean (age 44.4 ± 6.2 years; BMI 22.15 ± 1.8 kg/ m 2 , n = 23), overweight (age 45.4 ± 12.3 years; BMI 26.99 ± 1.5 kg/m 2 , n = 24), obese (age 49.0 ± 9.1 years; BMI 33.74 ± 3.3 kg/ m 2 , n = 32) and type 2 diabetic women (age 53.0 ± 6.13 years; BMI 35.08 ± 8.6 kg/m 2 , n = 35), as part of an ethically approved study. Gene and protein expression of PLA2 and its isoforms were assessed in adipose tissue samples, with serum analysis undertaken to assess circulating Lp-PLA2 and its association with cardiometabolic risk markers. A human adipocyte cell model, Chub-S7, was used to address the intracellular change in Lp-PLA2 in adipocytes. Results Lp-PLA2 and calcium-independent PLA2 (iPLA2) isoforms were altered by adiposity, as shown by microarray analysis (p < 0.05). Type 2 diabetes status was also observed to significantly alter gene and protein levels of Lp-PLA2 in abdominal subcutaneous (AbdSc) (p < 0.01), but not omental, adipose tissue. Furthermore, multivariate stepwise regression analysis of circulating Lp-PLA2 and metabolic markers revealed that the greatest predictor of Lp-PLA2 in non-diabetic individuals was LDL-cholesterol (p = 0.004). Additionally, in people with type 2 diabetes, oxidised LDL (oxLDL), triacylglycerols and HDLcholesterol appeared important predictors, accounting for 59.7% of the variance (p < 0.001). Subsequent in vitro studies determined human adipocytes to be a source of Lp-PLA2, as confirmed by mRNA expression, protein levels and immunochemistry. Further in vitro experiments revealed that treatment with LDL-cholesterol or oxLDL resulted in significant upregulation of Lp-PLA2, while inhibition of Lp-PLA2 reduced oxLDL production by 19.8% (p < 0.05).

Energy Intake and Plasma Adiponectin as Potential Determinants of Lipoprotein‐Associated Phospholipase A2 Activity: A Cross‐Sectional Study

“…No significant differences were observed across Lp‐PLA 2 activity quartiles with reference to history of dyslipidemia or hypertension. Our results are in agreement with previous studies among overweight and obese subjects (Jackisch et al, ; Steffen et al, ), subjects with dyslipidemia (Tellis et al, ) and apparently healthy subjects with prehypertension (Kim et al, ). Higher Lp‐PLA 2 activity could be explained by higher Lp‐PLA 2 mass concurrently with higher levels of total and LDL‐cholesterol, triacylglycerols, and apolipoprotein B in obese compared to nonobese subjects and in subjects with dyslipidemia compared to subjects with normal lipid levels (Barakat et al, ; Jackisch et al, ; Tellis et al, ).…”

“…No significant differences were observed across Lp-PLA 2 activity quartiles with reference to history of dyslipidemia or hypertension. Our results are in agreement with previous studies among overweight and obese subjects (Jackisch et al, 2018;Steffen et al, 2013), subjects with dyslipidemia (Tellis et al, 2013) and apparently healthy subjects with prehypertension (Kim et al, 2014a). Higher Lp- 6.3 (5.3-8.4) 6.2 (5.4-7.5) 6.4 (5.7-6.9) 6.5 (5.7-7.7) 0.555 MUFA-to-SFA ratio 1.7 (1.5-2.1) 1.7 (1.5-1.9) 1.7 (1.4-1.9) 1.…”

“…Higher Lp- 6.3 (5.3-8.4) 6.2 (5.4-7.5) 6.4 (5.7-6.9) 6.5 (5.7-7.7) 0.555 MUFA-to-SFA ratio 1.7 (1.5-2.1) 1.7 (1.5-1.9) 1.7 (1.4-1.9) 1. PLA 2 activity could be explained by higher Lp-PLA 2 mass concurrently with higher levels of total and LDL-cholesterol, triacylglycerols, and apolipoprotein B in obese compared to nonobese subjects and in subjects with dyslipidemia compared to subjects with normal lipid levels (Barakat et al, 2017;Jackisch et al, 2018;Tellis et al, 2013).…”

Lipoprotein‐associated phospholipase A2: The story continues

“…For example, the abdominal subcutaneous but not the omental, adipose tissue displayed enhanced Lp‐PLA2 expression, and type 2 diabetes status contributed to the upregulation of Lp‐PLA2 in adipose tissue. Owing to its association with inflammation and atherosclerotic risk, Lp‐PLA2 action within adipocytes may represent a potential therapeutic target to prevent the development of cardiometabolic complications in type 2 diabetes . On the basis of this study, the perivascular adipose tissue (PVAT), which surrounds most large blood vessels, is probably a potential source of Lp‐PLA2 as well.…”

“…Consequently, Lp‐PLA2 exhibits characteristics of both PLA2s and neutral lipases. Even though hematopoietic cells might be chiefly responsible for the circulating Lp‐PLA2 levels, a number of tissues, such as liver cells, aorta cells, and adipocytes, seem to be additional sources. After secretion, Lp‐PLA2 circulates by binding to lipoproteins in plasma, whereby LDL and HDL carry 70% to 80% and 20% to 30% of the total plasma activity, respectively .…”