Upregulated monocyte expression of PLIN2 is associated with early arterial injury in children with overweight/obesity

Abstract

Background and aims: Perilipin 2 (PLIN2) regulates intracellular lipid metabolism in macrophages, and thus, plays a role in atherosclerosis. Aim of the study was to evaluate whether PLIN2 dysregulation is involved in the onset of preclinical atherosclerosis in children with overweight/obesity and to explore dysregulation mechanisms.

Methods: Sixty-three children with overweight/obesity and 21 normal weight children (controls) of the same age and sex were enrolled. Carotid intima media thickness (cIMT) was evaluated; mRNA expression of PLIN2 and proteasome subunits (PSMD3, PSMC4) was determined by Real Time PCR, and protein expression of PLIN2, LAMP2A and Hsc70 by Western blot analysis; fluorimetric assay was used to measure proteasome chymotrypsin like activity. We performed transient LAMP2A downregulation by siRNA and quantified intracellular lipids in monocytes by Nile Red staining and flow cytometry analysis.

Results: PLIN2 protein levels were significantly higher in children with overweight/obesity and correlated with cIMT after adjusting for confounders. Accordingly, monocytes of children with overweight/obesity showed a higher intracellular amount of lipids compared with controls. mRNA expression of the regulatory subunits PSMC4 and PSMD3 and proteasome activity were lower in children with overweight/obesity, while expression of LAMP2A and Hsc70 proteins, which belong to the chaperone-mediated autophagy (CMA) pathway, was not different, suggesting that PLIN2 dysregulation in monocytes was due to an impairment of proteasome efficiency and was not CMA related.

Conclusion: PLIN2 was overexpressed in monocytes of children with overweight/obesity and could contribute to the onset of arteropathy. Our data suggest that proteasome impairment could contribute to PLIN2 overexpression.

Keywords: Atherosclerosis; Cardiovascular disease; Chaperone-mediated autophagy; Children obesity; Perilipin 2; Personalized medicine; Proteasome.