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Horng-Yih Ou, Hung-Tsung Wu, Feng-Hwa Lu, Yu-Chu Su, Hao-Chang Hung, Jin-Shang Wu, Yi-Ching Yang, Chao-Liang Wu and Chih-Jen Chang

Hepatic steatosis is highly correlated with insulin resistance and diabetes. Although, it has been demonstrated that activation of free fatty acid receptor 1 (FFAR1) by agonists showed benefits for the improvement of diabetes, the effects of FFAR1 agonists on hepatic steatosis were unknown. In this study, a high fat diet (HFD)-induced hepatic steatosis animal model was utilized to evaluate the effects of an FFAR1 agonist, GW9508, on hepatic lipid accumulation, and HepG2 hepatoma cells were also used to clarify the possible mechanisms. Administration of GW9508 significantly decreased the hepatic lipid accumulation with decreased expressions of lipogenesis-related proteins in HFD mice. Knockdown of hepatic Ffar1 by lentiviral vectors containing short hairpin RNA targeted to Ffar1 diminished the effect of GW9508 in HFD mice. In addition, GW9508 decreased oleic acid-induced lipid accumulation in HepG2 cells by decreases in the expression of lipogenesis-related proteins. Moreover, GW9508 downregulated the expression of sterol regulatory element-binding protein 1 (SREBP1) through a p38-dependent pathway, whereas knockdown of Ffar1 in HepG2 cells diminished the effect of GW9508 on the decrease in SREBP1. Considering all these results together, GW9508 exerts a therapeutic effect to improve hepatic steatosis through a p38-dependent pathway. Thus, investigation of chemicals that act on FFAR1 might be a new strategy for the treatment of hepatic steatosis.

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T Zhao, H Zhang, C Jin, F Qiu, Y Wu and L Shi

Melatonin, synthesized primarily by the pineal gland, is a neuroendocrine hormone with high membrane permeability. The vascular effects of melatonin, including vasoconstriction and vasodilation, have been demonstrated in numerous studies. However, the mechanisms underlying these effects are not fully understood. Large-conductance Ca2+-activated K+ (BKCa) channels are expressed broadly on smooth muscle cells and play an important role in vascular tone regulation. This study explored the mechanisms of myocyte BKCa channels and endothelial factors underlying the action of melatonin on the mesenteric arteries (MAs). Vascular contractility and patch-clamp studies were performed on myocytes of MAs from Wistar rats. Melatonin induced significant vasodilation on MAs. In the presence of N ω-nitro-l-arginine methyl ester (l-NAME), a potent endothelial oxide synthase (eNOS) inhibitor, melatonin elicited concentration-dependent relaxation, with lowered pIC50. The effect of melatonin was significantly attenuated in the presence of BKCa channel blocker iberiotoxin or MT1/MT2 receptor antagonist luzindole in both (+) l-NAME and (−) l-NAME groups. In the (+) l-NAME group, iberiotoxin caused a parallel rightward shift of the melatonin concentration–relaxation curve, with pIC50 lower than that of luzindole. Both inside-out and cell-attached patch-clamp recordings showed that melatonin significantly increased the open probability, mean open time and voltage sensitivity of BKCa channels. In a cell-attached patch-clamp configuration, the melatonin-induced enhancement of BKCa channel activity was significantly suppressed by luzindole. These findings indicate that in addition to the activation of eNOS, melatonin-induced vasorelaxation of MAs is partially attributable to its direct (passing through the cell membrane) and indirect (via MT1/MT2 receptors) activation of the BKCa channels on mesenteric arterial myocytes.

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Ray-Jade Chen, His-Chin Wu, Mu-Hsin Chang, Chao-Hung Lai, Yun-Chen Tien, Jin-Ming Hwang, Wu-Hsien Kuo, Fuu-Jen Tsai, Chang-Hai Tsai, Li-Mien Chen, Chih-Yang Huang and Chun-Hsien Chu

This study examines the role of IGF2/mannose 6-phosphate receptor (IGF2R) signaling in the signaling transduction regulation and cell apoptosis in H9c2 cardiomyoblast cells. However, it is difficult to recognize the distinct activation of IGF2 signaling without interfacing with IGFI receptor (IGF1R) after exposure to IGF2. Leu27IGF2, an analog of IGF2 that interacts selectively with the IGF2R, was used to specifically activate IGF2R signaling in this study. DNA fragmentation and TUNEL assay revealed that in contrast to IGF1 treatment preventing angiotensin II and AG1024-induced cell apoptosis, Leu27IGF2 appears to synergistically increase apoptosis in those cells. We further found cell apoptosis induction and an increase in the active form of caspase 3 in the treatment of cells with Leu27IGF2, but not IGF1. To detect the interaction between IGF2R and Gαq using the immunoprecipitation assay, we found that IGF2R could directly interact with Gαq and after treatment with Leu27IGF2 the binding ability of Gαq to IGF2R had increased. This sequentially resulted in the phosphorylation of phospholipase C-β, a key downstream modulator of Gαq, on serine 537. Moreover, disruption of the Gαq protein by small interferon RNA reduced the cell apoptosis induced by Leu27IGF2. Our findings demonstrate that IGF2R activation appears to induce cell apoptosis via Gαq-deriving signaling cascades and its effect is completely different from IGF1R survival signaling.

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Jie Sun, Yan Liu, Jinhui Yu, Jin Wu, Wenting Gao, Liyuan Ran, Rujiao Jiang, Meihua Guo, Dongyu Han, Bo Liu, Ning Wang, Youwei Li, He Huang, Li Zeng, Ying Gao, Xin Li and Yingjie Wu

Astragalus polysaccharide (APS) is the main component of Astragalus membranaceus, an anti-diabetic herb being used for thousands of years in Traditional Chinese medicine (TCM). In this study, we aimed to evaluate the impact of APS on hepatic insulin signaling, autophagy and ER stress response in high-fat-diet (HFD)-induced insulin resistance (IR) mice. APS was intra-gastrically administrated and metformin was used as a control medicine. Apart from monitoring the changes in the important parameters of IR progression, the gene and protein expression of the key factors marking the state of hepatic ER stress and autophagic flux were examined. We found that, largely comparable to the metformin regime, APS treatment resulted in an overall improvement of IR, as indicated by better control of body weight and blood glucose/lipid levels, recovery of liver functions and regained insulin sensitivity. In particular, the excessive and pro-apoptotic ER stress response and inhibition of autophagy, as a result of prolonged HFD exposure, were significantly corrected by APS administration, indicating a switch of the cellular fate in favor of cell survival. Using the HepG2/IR cell model, we demonstrated that APS modulated the insulin-initiated phosphorylation cascades in a similar manner to metformin. This study provides a rationale for exploiting the insulin-sensitizing potential of APS, which has a therapeutic performance almost equivalent to metformin, to enrich our options in the treatment of IR.