Mesenchymal stem cells ameliorate palmitic acid induced lipotoxicity of human umbilical vein endothelial cells and high‐fat induced obese rats by suppression of endoplasmic reticulum stress

Abstract

BackgroundEndothelial dysfunction caused by the high levels of plasma free fatty acids is involved in the pathogenesis of metabolic syndrome (MS). Mesenchymal stem cells (MSCs) were reported able to ameliorate MS. Here we explored the effects of MSCs on palmitic acid (PA) induced endothelial lipotoxicity and disclose the mechanism in human umbilical vein endothelial cells (HUVECs).MethodsThe primary HUVECs were treated by PA (50 μM) with or without human bone marrow derived MSCs (BMSCs) for 24 h in Transwell system at a ratio of 5:1. Cell viability and functions of HUVECs were determined. Cell apoptosis, oxidative stress, inflammation and endoplasmic reticulum (ER) stress was evaluated by qPCR, western blot or flow cytometry. Then glucose and lipid metabolism was detected by glucose uptake test, oil red O stain and relative genes expression.In vivo, Male Sprague Dawley rats were fed a normal diet or high fat diet (HFD) for 16 weeks. 2×106 MSCs were transplanted to rats via tail vein injection weekly for 2 weeks. At the 19th weeks, the rats were sacrificed and abdominal and thoracic aortas were collected for further detection.Result The cell viability of HUVECs declined to 68.7% of control after PA stimulation. However, apoptosis and ROS production was not elevated by PA, and ROS scavenger MitoTempo failed to reverse PA induced cell dysfunction. Coculture with BMSCs restored the cell viability to 99.4%, and the endothelial functions (tube formation and cell migration capacity) were obviously improved by BMSCs as well. Additionally, BMSCs robustly inhibited either mRNA or protein expression of the inflammatroy factors such as IL‐1β and IL‐8. In respect of nutrients metabolism, PA induced accumulation of cellular triglyceride and PA impaired glucose uptake ability was significantly reversed in BMSCs. qPCR found that mRNA expression of multiple genes essential for glucose, lipid and cholesterol metabolism was modulated by MSCs including Fdps, Cpt1, PPARγ, PDK4, et al. Next we found BMSCs substantially attenuated PA‐triggered ER stress, evidenced by decreased genes expression of UPR genes and protein levels of CHOP, ATF6, SREBP1, and ATF4. Furthermore, ER stressor thapsigargin (Thp) specifically induced ER stress in HUVECs and interestingly, BMSCs also reduced Thp induced ER stress. In vivo, serum levels of TG, LDL‐c and TC were reduced by 54%, 43% and 31% respectively, and HDL‐c was slightly increased by MSCs injection compared with HFD group. Glucose intolerance and hyperinsulinemia was improved as well. mRNA expression of multiple genes essential for glucose, lipid and cholesterol metabolism in thoraco‐abdominal aorta was modulated by BMSCs transplantation. Western blot showed that several ER stress related protein levels (ATF4, ATF6, SREBP, CHOP) were reduced in BMSCs groups. ConclusionBMSCs were able to ameliorate PA induced lipotoxicity and metabolic disorder in both HUVECs and HFD rats. BMSCs attenuated PA‐ or Thp‐triggered ER stress, which may contribute to the protective effects of BMSCs on lipotoxicity.Support or Funding InformationThis work was supported by the Program of National Natural Science Foundation of China (31571474) and the National Key Clinical Project.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.