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Metabolic syndrome (MetS) is associated with abdominal obesity, hyperlipidemia, insulin resistance, and type 2 diabetes mellitus, and increases the risk of cardiovascular disease. Given the complex multifactorial pathogenesis of MetS, qualified animal models are currently seriously limited for researchers. The aim of our study was to develop a MetS model in juvenile rhesus monkeys (Macaca mulatta). Rhesus monkeys (1-year-old) fed a high-fat diet (15 % fat, 2 % cholesterol) were used as the HF group (n = 6), and those on a normal diet (5 % fat) were used as the control group (n = 4). After being fed a high-fat diet for approximately 12 months, 2 monkeys (HF + STZ group) were injected with low-dose streptozotocin (STZ, 25 mg/kg) twice, with a 7 days interval, and were then fed the same diet continuously for another 24 months. After 36 months of treatment, the high-fat diet monkeys, including the HF and HF + STZ groups, had acquired increased body weights, abnormal serum lipids, and impaired glucose tolerance compared to the control group. In addition, much more marked metabolic changes were observed in the two monkeys of the HF + STZ group, particularly in terms of high-blood glucose level and insulin resistance. Morphological observation of biopsies of liver and pancreatic tissues showed decreased islet number and mass and decreased insulin staining in the monkeys of the HF + STZ group. In addition, Oil red O staining suggested remarkable accumulation of lipid droplets in the hepatocytes. Our study suggested that a long-term high-fat diet followed with a low-dose STZ was able to induce MetS in juvenile rhesus monkeys with faster pathophysiological progress compared with high-fat diet induction alone. Our primary data showed that this method may have potentials to develop MetS animal model in non-human primates.

High levels of plasma free fatty acids (FFAs) lead to endothelial dysfunction (ED), which is involved in the pathogenesis of Metabolic Syndrome, diabetes as well as atherosclerosis. ER stress and Endothelial-to-mesenchymal transition (EndMT) are demonstrated mechanistically related to endothelial dysfunction. Mesenchymal stem cells (MSCs) have exhibited an extraordinary cytoprotective effect on cellular lipotoxicity and vasculopathy. However, the underlying mechanisms have not been clearly defined. In the present study, we investigated whether MSCs could ameliorate palmitic acid (PA) - induced endothelial lipotoxicity by reducing ER stress and EndMT. We observed that MSCs coculture substantially alleviated PA-induced lipotoxicity in human umbilical vein endothelial cells (HUVECs). MSCs were able to restore the cell viability, increase tubule formation and migration ability, and decrease inflammation response and lipid deposition. Furthermore, PA caused endothelial to mesenchymal transition in HUVECs, which was abrogated by MSCs possibly through inhibiting ER stress. In addition, PA stimulated MSCs to secrete more stanniocalcin 1 (STC1). Knocking down of STC1 in MSCs attenuated their effects on PA-induced lipotoxicity in HUVECs. In vivo, MSCs transplantation alleviated dyslipidemia and endothelial dysfunction in high fat diet-fed SD rats. MSCs treated rats showed reduced expressions of ER stress-related genes in aortas, as well as suppressed expressions of EndMT-related proteins in rat aortic endothelial cells (RAECs). Overall, our findings indicated that MSCs were able to attenuate endothelial lipotoxicity through inhibiting ER stress and EndMT, in which STC1 secreted from MSCs may play a critical role.

The aim of this study was to investigate how mesenchymal stromal cells (MSCs) modulate metabolic balance and attenuate hepatic lipotoxicity in the context of non‐alcoholic fatty liver disease (NAFLD). In vivo, male SD rats were fed with high‐fat diet (HFD) to develop NAFLD; then, they were treated twice by intravenous injections of rat bone marrow MSCs. In vitro, HepG2 cells were cocultured with MSCs by transwell and exposed to palmitic acid (PA) for 24 hours. The endoplasmic reticulum (ER) stressor thapsigargin and sarco/ER Ca2+‐ATPase (SERCA2)–specific siRNA were used to explore the regulation of ER stress by MSCs. We found that MSC administration improved hepatic steatosis, restored systemic hepatic lipid and glucose homeostasis, and inhibited hepatic ER stress in HFD‐fed rats. In hepatocytes, MSCs effectively alleviated the cellular lipotoxicity. Particularly, MSCs remarkably ameliorated the ER stress and intracellular calcium homeostasis induced by either PA or thapsigargin in HepG2 cells. Additionally, long‐term HFD or PA stimulation would activate pyroptosis in hepatocytes, which may contribute to the cell death and liver dysfunction during the process of NAFLD, and MSC treatment effectively ameliorates these deleterious effects. SERCA2 silencing obviously abolished the ability of MSCs against the PA‐induced lipotoxicity. Conclusively, our study demonstrated that MSCs were able to ameliorate liver lipotoxicity and metabolic disturbance in the context of NAFLD, in which the regulation of ER stress and the calcium homeostasis via SERCA has played a key role.

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