SLC25A28 Overexpression Promotes Adipogenesis by Reducing ATGL.

Adipose tissue dysfunction is seen among obese and type 2 diabetic individuals. Adipocyte proliferation and hypertrophy are the root causes of adipose tissue expansion. Solute carrier family 25 member 28 (SLC25A28) is an iron transporter in the inner mitochondrial membrane. This study is aimed at validating the involvement of SLC25A28 in adipose accumulation by tail vein injection of adenovirus (Ad)-SLC25A28 and Ad-green fluorescent protein viral particles into C57BL/6J mice. After 16 weeks, the body weight of the mice was measured. Subsequently, morphological analysis was performed to establish a high-fat diet (HFD)-induced model. SLC25A28 overexpression accelerated lipid accumulation in white and brown adipose tissue (BAT), enhanced body weight, reduced serum triglyceride (TG), and impaired serum glucose tolerance. The protein expression level of lipogenesis, lipolysis, and serum adipose secretion hormone was evaluated by western blotting. The results showed that adipose TG lipase (ATGL) protein expression was reduced significantly in white and BAT after overexpression SLC25A28 compared to the control group. Moreover, SLC25A28 overexpression inhibited the BAT formation by downregulating UCP-1 and the mitochondrial biosynthesis marker PGC-1α. Serum adiponectin protein expression was unregulated, which was consistent with the expression in inguinal white adipose tissue (iWAT). Remarkably, serum fibroblast growth factor (FGF21) protein expression was negatively related to the expansion of adipose tissue after administrated by Ad-SLC25A28. Data from the current study indicate that SLC25A28 overexpression promotes diet-induced obesity and accelerates lipid accumulation by regulating hormone secretion and inhibiting lipolysis in adipose tissue.

Exercise alleviates cardiac remodelling in diabetic cardiomyopathy via the miR-486a-5p-Mst1 pathway.

OBJECTIVES: Physical exercise has emerged as an effective therapy to mitigate cardiac remodelling in diabetic cardiomyopathy (DCM). The results of our previous studies revealed mammalian sterile 20-like kinase 1 (Mst1) is a key regulator of the progression of DCM. However, the precise molecular mechanism of physical exercise-induced cardiac protection and its association with Mst1 inhibition remain unclear. MATERIALS AND METHODS: Wildtype and Mst1 transgenic mice were challenged with streptozotocin (STZ) to induce experimental diabetes and were divided into sedentary and exercise groups. The DCM phenotype was evaluated by echocardiography, Masson's trichrome staining, TUNEL and immunoblotting analyses. The exercise-regulated miRNAs targeting Mst1 were predicted by bioinformatic analysis and later confirmed by RT-qPCR, immunoblotting, and dual-luciferase reporter assays. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulate diabetes to elucidate the underlying mechanisms. RESULTS: Compared to the sedentary diabetic control, physical exercise inhibited Mst1 and alleviated cardiac remodelling in mice with DCM, as evidenced by decreases in the left ventricular end-systolic internal dimension (LVESD) and left ventricular end-diastolic internal dimension (LVEDD), increases in the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), attenuation of collagen deposition, and the suppression of apoptosis. Bioinformatic analysis and apoptosis assessments revealed exercise exerted protective effects against DCM through miR-486a-5p release. Moreover, luciferase reporter assays confirmed miR-486a-5p directly suppressed the expression of Mst1, thereby inhibiting the apoptosis of cardiomyocytes subjected to high glucose treatment. CONCLUSION: Physical exercise inhibits cardiac remodelling in DCM, and the mechanism is associated with miR-486a-5p release-induced Mst1 inhibition.

SHANK3 Co-ordinately Regulates Autophagy and Apoptosis in Myocardial Infarction.

Cardiac remodeling and dysfunction are responsible for the high mortality after myocardial infarction (MI). We assessed the potential for Shank3 to alleviate the post-infarction cardiac dysfunction. The experimental MI mice model was constructed by left anterior descending coronary artery ligation. Shank3 knockout aggravated cardiac dysfunction after MI, while Shank3 overexpression alleviated it. The histological examination showed that the infarct size was significantly increased in the acute phase of MI in the Shank3 knockout group, and the cardiac dysfunction of the Shank3 knockout group was even more severe than the Shank3 overexpression group, revealed by echocardiography analyses. In vitro, cultured neonatal cardiomyocytes were subjected to simulated MI. Shank3 downregulation curbed LC3 expression and autophagosome-lysosome fusion. Furthermore, Shank3 downregulation increased cardiomyocyte apoptosis. In contrast, Shank3 upregulation induced autophagy, and inhibited apoptosis under hypoxia. In vivo, western blot analysis showed decreased levels of Atg7, Beclin1, LC3-II, and Bcl-2 as well as increased expression of p62, cleaved caspase-3, and cleaved caspase-9 in the Shank3 knockout group which suffered from MI. On the other hand, it also revealed that Shank3 overexpression induced autophagy and inhibited apoptosis after MI. Shank3 may serve as a new target for improving cardiac function after MI by inducing autophagy while inhibiting apoptosis.