Yandi Wu

BACKGROUND: Individuals with diabetes are susceptible to cardiac dysfunction and heart failure, potentially resulting in mortality. Metabolic disorders frequently occur in patients with diabetes, and diabetes usually leads to remodeling of heart structure and cardiac dysfunction. However, the contribution and underlying mechanisms of metabolic and structural coupling in diabetic cardiac dysfunction remain elusive. METHODS: Two mouse models of type 2 diabetes (T2DM) were used to assess alterations in glucose/lipid metabolism and cardiac structure. The potential metabolic-structural coupling molecule ACBP (acyl–coenzyme A–binding protein) was screened from 4 published datasets of T2DM-associated heart disease. In vivo loss-of-function and gain-of-function approaches were used to investigate the role of ACBP in diabetic cardiac dysfunction. The underlying mechanisms of metabolic and structural coupling were investigated by stable-isotope tracing metabolomics, coimmunoprecipitation coupled with mass spectrometry, and chromatin immunoprecipitation sequencing. RESULTS: Diabetic mouse hearts exhibit enhanced lipid metabolism and impaired ultrastructure with marked cardiac systolic and diastolic dysfunction. Analysis of 4 T2DM public datasets revealed that Acbp was a significant lipid metabolism gene whose expression was upregulated. Consistently, ACBP expression levels were markedly elevated in the hearts of patients with diabetes and diabetic mice. Moreover, we constructed cardiomyocyte-specific Acbp knockout mice that exhibited attenuation of T2DM-induced cardiac remodeling and cardiac dysfunction, including attenuation of cardiac hypertrophy, fibrosis, ultrastructural damage, and enhanced cardiomyocyte contractility and cardiac function. Conversely, cardiac-specific Acbp overexpression via adeno-associated virus type 9, which encodes Acbp under the cTnT (cardiac troponin T) promoter, recapitulated cardiac dysfunction. Mechanistically, cardiac-specific Acbp knockout enhances glucose utilization in diabetic cardiomyocytes, suggesting a potential compensatory mechanism for insufficient ATP levels, highlighting its metabolic role. In addition, combined with mass spectrometry analysis revealed that ACBP binds MyBPC3 (myosin-binding protein C3) in T2DM individuals, which potentially prevents MyBPC3 from assisting the formation of cross-bridge structures between myosin and actin, thereby impairing myocardial contraction. Importantly, chromatin immunoprecipitation sequencing revealed that peroxisome proliferator–activated receptor γ regulates the transcriptional activity of Acbp . CONCLUSIONS: Our findings demonstrated that ACBP mediates the bidirectional regulation of cardiomyocyte metabolic and structural associations and identified a promising therapeutic target for ameliorating cardiac dysfunction in patients with T2DM.

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.

Diabetic cardiomyopathy is a primary myocardial injury induced by diabetes with complex pathogenesis. In this study, we identify disordered cardiac retinol metabolism in type 2 diabetic male mice and patients characterized by retinol overload, all-trans retinoic acid deficiency. By supplementing type 2 diabetic male mice with retinol or all-trans retinoic acid, we demonstrate that both cardiac retinol overload and all-trans retinoic acid deficiency promote diabetic cardiomyopathy. Mechanistically, by constructing cardiomyocyte-specific conditional retinol dehydrogenase 10-knockout male mice and overexpressing retinol dehydrogenase 10 in male type 2 diabetic mice via adeno-associated virus, we verify that the reduction in cardiac retinol dehydrogenase 10 is the initiating factor for cardiac retinol metabolism disorder and results in diabetic cardiomyopathy through lipotoxicity and ferroptosis. Therefore, we suggest that the reduction of cardiac retinol dehydrogenase 10 and its mediated disorder of cardiac retinol metabolism is a new mechanism underlying diabetic cardiomyopathy.