Sustained SREBP-1 Activation Mediates Cardiac Lipotoxicity to Statins Therapy in Diabetic Mice

Abstract

Abstract Under diabetes conditions, sterol regulatory element-binding protein 1 (SREBP1) activation could cause lipid dysfunction, leading to cardiac lipotoxicity. Here, we sought to investigate the effects of long-term statins use on cardiac lipid accumulation in diabetes and to elucidate whether the potential mechanism is related to SREBP1. Surprisingly, in three kinds of preclinical diabetic mouse model, long-term statins treatment induced cardiac dysfunction in diabetic mice, via accelerated fibrosis and inflammation. We confirmed that endogenous fatty acids (FA) synthesis in cardiomyocytes was increased by 13C-glucose metabolic flux analysis in vitro, and increased lipid deposition in the myocardium. Mechanistically, statins-induced increased cardiac glucose accumulation, further promoted N-glycosylation of SREBP1 cleavage-activating protein (SCAP). Glycosylation stabilized SCAP and reduced its association with insulin-induced gene 1(Insig1), allowing movement of SCAP/SREBP1 to the Golgi and consequent proteolytic activation of SREBP1. Genetic knockdown or L-carnitine inhibition of SREBP1 alleviated statins-induced cardiac dysfunction in diabetic mice. Collectively, these results suggest long-term statins therapy was associated with diabetes myocardial lipotoxicity. This effect was mediated through sustained SREBP-1 activation mediates cardiac endogenous fatty acid synthesis.