Berberine attenuates diabetic atherosclerosis via enhancing the interplay between KLF16 and PPARα in ApoE−/− mice

Cardiovascular disease caused by atherosclerosis is a leading cause of morbidity and mortality worldwide. Diabetes is a major independent risk factor for the development of atherosclerotic cardiovascular diseases. Diabetic atherosclerosis is characterized by hyperglycemia, hyperinsulinemia, and dyslipidemia. These multiple pathological factors can induce oxidative stress, inflammation, and vascular dysfunction, which can initiate and accelerate atherogenesis. Therefore, the strategy to control the development of diabetic atherosclerosis is beneficial to the patients. Berberine is one of the most promising natural products that feature significant beneficial properties on lipid and glucose metabolism, indicating the potential to improve diabetic atherosclerosis. However, the effect and underlying mechanism against diabetic atherosclerosis remain unclear. In this study, HFD and STZ were used to induce diabetic atherosclerosis in apoE−/− mice, which was followed by berberine administration. Subsequently, the degree of atherosclerotic plaque, plaque stability, and lipid and glucose metabolism were determined. In addition, the underlying mechanism was revealed by in vitro and in vivo experiments. We observed that berberine improved the dysfunction of lipid and glucose metabolism, and inhibited vascular inflammation, which reduced atherogenesis and plaque vulnerability. Mechanistically, berberine stimulated KLF16 and PPARα expression in vivo and in vitro, and activation of PPARα by berberine was through enhancing KLF16 expression and nuclear translocation. Collectively, berberine can attenuate diabetic atherosclerosis via enhancing the interplay between KLF16 and PPARα, suggesting that KLF16 is a new target of berberine and enhancing KLF16 by berberine is an efficient strategy for alleviating diabetic atherosclerosis.