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Differential expression of Lp-PLA2 in obesity, type 2 diabetes and the influence of lipids
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Jackisch, Laura, Kumsaiyai, W., Moore, Jonathan D., Al-Daghri, N. M., Kyrou, Ioannis, Barber, T. M., Randeva, Harpal S., Kumar, Sudhesh, Tripathi, Gyanendra and McTernan, P. G. (2018) Differential expression of Lp-PLA2 in obesity, type 2 diabetes and the influence of lipids. Diabetologia, 61 . pp. 1155-1166. doi:10.1007/s00125-018-4558-6 ISSN 0012-186X.
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Official URL: https://doi.org/10.1007/s00125-018-4558-6
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/m2, n = 23), overweight (age 45.4 ± 12.3 years; BMI 26.99 ± 1.5 kg/m2, n = 24), obese (age 49.0 ± 9.1 years; BMI 33.74 ± 3.3 kg/m2, n = 32) and type 2 diabetic women (age 53.0 ± 6.13 years; BMI 35.08 ± 8.6 kg/m2, 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 HDL-cholesterol 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).
Conclusions/interpretation
Our study suggests adipose tissue and adipocytes are active sources of Lp-PLA2, with differential regulation by fat depot and metabolic state. Moreover, levels of circulating Lp-PLA2 appear to be influenced by unfavourable lipid profiles in type 2 diabetes, which may occur in part through regulation of LDL-cholesterol and oxLDL metabolism in adipocytes
| Item Type: | Journal Article | |||||||||||||||
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| Subjects: | R Medicine > RC Internal medicine | |||||||||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Dean's Office & Professional Support Services Faculty of Science, Engineering and Medicine > Research Centres > Warwick Systems Biology Centre Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Obesity -- Physiological aspects, Non-insulin-dependent diabetes -- Physiological aspects, Lipoproteins, Cardiovascular system -- Diseases, Adipose tissues, Lipids | |||||||||||||||
| Journal or Publication Title: | Diabetologia | |||||||||||||||
| Publisher: | Springer | |||||||||||||||
| ISSN: | 0012-186X | |||||||||||||||
| Official Date: | May 2018 | |||||||||||||||
| Dates: |
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| Volume: | 61 | |||||||||||||||
| Page Range: | pp. 1155-1166 | |||||||||||||||
| DOI: | 10.1007/s00125-018-4558-6 | |||||||||||||||
| Status: | Peer Reviewed | |||||||||||||||
| Publication Status: | Published | |||||||||||||||
| Access rights to Published version: | Open Access (Creative Commons) | |||||||||||||||
| Date of first compliant deposit: | 26 January 2018 | |||||||||||||||
| Date of first compliant Open Access: | 2 March 2018 | |||||||||||||||
| RIOXX Funder/Project Grant: |
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