White Adipose Tissue Lipolysis Induced By Protein Arginine Methyltransferase 4 Regulates The Development Of Diabetic Cardiomyopathy

PartⅠ: Protein Arginine Methyltransferase 4 Regulates White Adipose Tissue Lipolysis in Type 1 Diabetic Mice【Objective】 Hypertriglyceridemia is considered to be driven by increased lipolysis in type 1 diabetes mellitus(T1DM).However,information regarding the transcriptional circuitry that governs lipolysis remains incomplete in T1 DM.Protein arginine methyltransferase 4(PRMT4),a transcriptional coactivation factor,promotes autophagy and may play an important role in lipolysis.We wonder whether activated white adipose tissue lipolysis in T1 DM is regulated by PRMT4.【Methods】 Recombinant adeno-associated virus was adopted to overexpress PRMT4 in white adipose tissue of mice.Streptozotocin(150?mg/kg)was injected intraperitoneally into mice to induce T1 DM.Plasma insulin,triglycerides,free fatty acids levels were determined using commercial assay kits.Western blotting and quantitative RT-PCR was used to detect the expression of Adipose Triglyceride Lipase(ATGL),Hormone-Sensitive Lipase(HSL)and Monoacylglycerol Lipase(MAGL)as well as the phosphorylation of HSL.In vitro,PRMT4 was overexpressed or knocked down in adipocytes with adenovirus,and then the release of free fatty acids and HSL phosphorylation were measured.【Results】 PRMT4 was upregulated in the white adipose tissue of TIDM mice.Elevated serum triglycerides and free fatty acids were observed in PRMT4 overexpressed T1 DM mice.We also observed that PRMT4 overexpression induced the decrease of fat pads weights and adipocyte sizes.Moreover,the expression levels of ATGL,HSL,and MAGL m RNA were increased,and the phosphorylation of HSL was activated in PRMT4 overexpressed mice when compared to these of control mice.In vitro,overexpression of PRMT4 promoted CL316,423-induced adipocyte free fatty acid release and HSL phosphorylation activation.Whileas,adipocyte PRMT4 knockdown in adipocyte blocked the inhibitory effect of insulin on lipolysis.【Conclusion】PRMT4 promotes white adipose tissue lipolysis and increases serum triglyceride in T1 DM.PartⅡ: PRMT4 Overexpression in White Adipose Tissue Promotes the Development of Diabetic Cardiomyopathy and Its Mechanisms【Objective】 Dysfunction of white adipose tissue leads to cardiac hypertrophy and cardiac function damages.Previously,we have found that PRMT4 activate white adipose tissue lipolysis in type 1 diabetic mice,results to the increase of serum triglycerides and free fatty acids.However,whether it results to further myocardial damages is unclear.In this study,we will explore the effects of white adipose tissue PRMT4 overexpression on diabetic cardiomyopathy and the possible mechanisms.【Methods】 White adipose tissue PRMT4 overexpressed mice and its control mice were injected streptozotocin intraperitoneally to establish a diabetic cardiomyopathy model for 12 weeks.The cardiac function of mice was evaluated with an ultrasonic diagnostic instrument.Western blotting and quantitative RT-PCR were used to detect the molecules expression about cardiac fatty acid oxidation,apoptosis,and inflammation.Tissue immunofluorescence was used to detect the infiltration of inflammatory cells in cardiac tissue.【Results】 Heart weight increase and deteriorate cardiac function was observed in adipose tissue PRMT4 overexpressed mice.What is more,the expression of molecules related to fatty acid uptake and oxidation were upregulated.In addition,overexpression of PRMT4 in white adipose tissue also activated apoptosis related pathways and promoted infiltration of inflammatory cells in cardiac tissue.【Conclusion】 In type 1 diabetes,overexpression of PRMT4 in white adipose tissue results to heart myocardium damages by activating fatty acid oxidation,apoptosis and inflammation.