This article reviews a study from Cell Metabolism, titled "Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity" [Tong L, Chen Z, Li Y, et al. Cell Metab. 2024, 36(5): 1013-1029.e5], and discusses its scientific implications. The study explores selective hepatic insulin resistance in metabolic dysfuction-associated fatty liver disease(MAFLD), where insulin stimulates lipid synthesis but not gluconeogenesis in resistant livers. It reveals the key role of transketolase(TKT) in MAFLD progression by disrupting pentose metabolism and nucleoside homeostasis, leading to inhibited mitochondrial activity. Targeting TKT with N-acetylgalactosamine-conjugated small interfering RNA(GalNAc-siTKT) improved metabolic dysfunction-associated steatohepatitis(MASH) and hepatic fibrosis.

This article reviews a study from Cell Metabolism, titled "Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity" [Tong L, Chen Z, Li Y, et al. Cell Metab. 2024, 36(5): 1013-1029.e5], and discusses its scientific implications. The study explores selective hepatic insulin resistance in metabolic dysfuction-associated fatty liver disease(MAFLD), where insulin stimulates lipid synthesis but not gluconeogenesis in resistant livers. It reveals the key role of transketolase(TKT) in MAFLD progression by disrupting pentose metabolism and nucleoside homeostasis, leading to inhibited mitochondrial activity. Targeting TKT with N-acetylgalactosamine-conjugated small interfering RNA(GalNAc-siTKT) improved metabolic dysfunction-associated steatohepatitis(MASH) and hepatic fibrosis.

Objective:To investigate the role of RNA m6A methylation in mediating cerebellar dysplasia through analyzing the phenotypes of the mouse cerebella and the expression of several key m6A regulators upon hypobaric hypoxia treatment.Methods:Five-day old C57/BL6 mice were exposed to hypobaric hypoxia for 9 days. The status of mouse cerebellar development was analyzed by comparing the body weights, brain weights and histological features. Immunostaining of cell-type-specific markers was performed to analyze the cerebellar morphology. Real-time PCR, Western blot and immunohistochemical staining were performed to detect the expression of key m6A regulators in the mouse cerebella.Results:Compared with the control, the body weights, brain weights and cerebellar volumes of hypobaric hypoxic mice were significantly reduced ( P<0.01). The expression of specific markers in different cells, including NeuN (mature neuron), Calbindin-D28K (Purkinje cell) and GFAP (astrocyte), was decreased in hypobaric hypoxic mouse cerebella ( P<0.01), accompanied with disorganized cellular structure. The expression of methyltransferase METTL3 was significantly down-regulated in the cerebella of hypobaric hypoxic mice ( P<0.05). Conclusions:Hypobaric hypoxia stimulation causes mouse cerebellar dysplasia, with structural abnormalities in mature granular neurons, Purkinje cells and astrocytes. Expression of METTL3 is decreased in hypobaric hypoxic mice cerebellum compared with that of normobaric normoxic mice, suggesting that its mediated RNA m6A methylation may play an important role in hypobaric hypoxia-induced mouse cerebellar dysplasia.

Objective Toinvestigatetheexpressionofsuppressorofcytokinesignaling1(SOCS1)inoverloaded ventricle papillary muscle, so as to understand its expression characteristics in structural remodeling after the overloading and the biomechanical properties of the muscle under cubic jellyfish toxin-1(CfTX-1) pretreatment that can affect cell signal transduction. Methods Abdominal aortic-venous fistula (AVF) were operated in Kunming mice (n=5), and the cardiac left ventricles were harvested after two weeks of fistulation. The mice in normal group were sham operated as a control (n=5). In vitro culture, the left ventricular papillary muscle of normal mice was used (n=20). In the stretching group, the isolated papillary muscles were double-ratio stretched and fixed on silicone plate. In the relaxation group, the muscles were not stretched. A separated subgroup that transfected with SOCS1 plasmids were set in each group of stretching and relaxation. The papillary muscle samples of each group were cultured in culture medium for 3 days at 37 ℃, and then homogenized for extracting total protein. The total protein was separated by 10％ sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The 23 ku band with SOCS1 was used as the target band, and the integrated optical density (IOD) value was measured by computer image analysis method. The expression of SOCS1 protein was detected by Western Blot and the imprinted IOD value was also measured. The papillary muscle in the stretching group was stretched by micro-positioned stretching method, and the initial load was 1 g. After stabilization, the papillary muscle was stretched by 15 mm for continuously 5 times, and the passive tension characteristic curves during the first and fifth stretching were observed and recorded. The peak passive tension (PTmax) and its deceleration velocity (DV) of the papillary muscle were calculated based on the curves. Results Comparing with the AVF group, the normal group had higher IOD values of 23 ku band and SOCS1 blot in total protein of the papillary muscle, and the differences were statistically significant (all P<0.01). The IOD value of 23 ku band in the SOCS1 transfected stretching group was significantly higher than those of the two relaxation groups, and the differences were statistically significant (all P<0.01). However, the difference of this value was not statistically significant between the two relaxation groups. The average IOD value of SOCS1 blot in the SOCS1 transfected stretching group was higher than those of the normal stretching group and the SOCS1 transfected relaxation group, and the differences were statistically significant (all P<0.01). Comparing with the normal group, the AVF group had higher PTmax and ultimate PTmax of the papillary muscles, and had a lower DV values, and the differences were statistically significant (all P<0.01). Conclusions The expression of SOCS1 is sensitive to tension load, and has a positive effect as an overload-sensitive signal in improving myocardial adaptability, protecting myocardial structure and maintaining systolic and diastolic function. CfTX-1 also has a positive effect on improving the compliance of ventricular papillary muscles.