マウスにおける食事誘導性体重変化時の脂肪肝感知ヘパトカイン LECT2 の急速な反応

13301甲第4579号博士（工学）金沢大学博士論文要旨Abstract 以下に掲載：Biochemical and Biophysical Research Communications 478(3) pp.1310-1316 2016. ELSEVIER. 共著者：Keita Chikamoto, Hirofumi Misu, Hiroaki Takayama Akihiro Kikuchi, Kiyo-aki Ishii, Fei Lan, Noboru Takata, Natsumi Tajima-Shirasaki, Yumie Takeshita, Hirohiko Tsugane, Shuichi Kaneko, Seiichi Matsugo, Toshinari Takamur

Tumor Shrinkage in Response to Vitamin K2 in Hepatocellular Carcinoma with Multiple Lung Metastases: A Case Report

Introduction: Advanced or metastatic hepatocellular carcinoma (HCC) can be lethal because of the limited therapeutic approach such as sorafenib. Recently, Vitamin K2 (VK2) has been increasingly recognized to have anti-cancer effects for HCC in vitro and vivo. However, the direct anti-cancer effect of VK2 to HCC has not been established yet in human.Presentation of Case: We presented here a 88-year-HCC patient displayed a tumor shrinkage in response to VK2 in multiple lung metastases, indicating the possibility of VK2 as an anti-cancer agent in human. Menatetrenone, a VK2 analogue, was introduced for multiple lung metastases as a palliative treatment, and thereafter multiple lung metastases, except one lung lesion, displayed tumor shrinkage and disappeared within five months after VK2 intake. The residual one lesion continued to grow up during the intake of VK2, suggesting that the residual tumor was insensitive to VK2 represented by tumor heterogeneity. Consequently, after a radiation therapy for the residual lesion, the elevated tumor markers of all were finally decreased into normal levels, and he is still alive for 18 months after VK2 intake without elevated tumor marker levels and toxic adverse effects.Conclusion:VK2 may be a therapeutic option for advanced and metastatic HCCs without any toxic adverse

Time Course Effect of R-Alpha-Lipoic Acid on Cellular Metabolomics in Cultured Hepatoma Cells

Alpha-lipoic acid (LA) is a powerful antioxidant. LA has two enantiomers, R(+)-LA (R-LA) and S(-)-LA (S-LA). Of these, R-LA is naturally occurring and an essential cofactor in energy metabolism. R-LA treatment has been reported to affect glucose metabolism in rat hepatoma cells. This study analyzed the time course of metabolite levels in LA-treated cultured H4IIEC3 rat hepatoma cells, including a specific evaluation of the effect of R-LA and the enantioselectivity of LA. Principal component analysis showed that this experiment was well designed to observe enantioselectivity. R-LA treatment was found to inhibit the glycolysis and Thr-Gly-Ser pathways, as well as lactic acid production, leading to the inhibition of gluconeogenesis in starved H4IIEC3 cells. This study may provide mechanistic insight into how R-LA induces apoptosis in hepatoma cells. © Copyright 2017, Mary Ann Liebert, Inc. and Korean Society of Food Science and Nutrition 2017.Embargo Period 12 month

Plasma half-life and tissue distribution of leukocyte cell-derived chemotaxin 2 in mice

金沢大学疾患モデル総合研究センターLeukocyte cell-derived chemotaxin 2 (LECT2) is a hepatokine that causes skeletal muscle insulin resistance. The circulating levels of LECT2 are a possible biomarker that can predict weight cycling because they reflect liver fat and precede the onset of weight loss or gain. Herein, to clarify the dynamics of this rapid change in serum LECT2 levels, we investigated the in vivo kinetics of LECT2, including its plasma half-life and tissue distribution, by injecting 125I-labelled LECT2 into ICR mice and radioactivity tracing. The injected LECT2 was eliminated from the bloodstream within 10 min (approximate half-life, 5 min). In the kidneys, the radioactivity accumulated within 10 min after injection and declined thereafter. Conversely, the radioactivity in urine increased after 30 min of injection, indicating that LECT2 is mainly excreted by the kidneys into the urine. Finally, LECT2 accumulated in the skeletal muscle and liver until 30 min and 2 min after injection, respectively. LECT2 accumulation was not observed in the adipose tissue. These findings are in agreement with LECT2 action on the skeletal muscle. The present study indicates that LECT2 is a rapid-turnover protein, which renders the circulating level of LECT2 a useful rapid-response biomarker to predict body weight alterations. © 2020, The Author(s).CC-BY 4.

Selenoprotein P as a diabetes-associated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells

Aims/hypothesis Impaired angiogenesis induced by vascular endothelial growth factor (VEGF) resistance is a hallmark of vascular complications in type 2 diabetes; however, its molecular mechanism is not fully understood. We have previously identified selenoprotein P (SeP, encoded by the SEPP1 gene in humans) as a liver-derived secretory protein that induces insulin resistance. Levels of serum SeP and hepatic expression of SEPP1 are elevated in type 2 diabetes. Here, we investigated the effects of SeP on VEGF signalling and angiogenesis. Methods We assessed the action of glucose on Sepp1 expression in cultured hepatocytes. We examined the actions of SeP on VEGF signalling and VEGF-induced angiogenesis in HUVECs. We assessed wound healing in mice with hepatic SeP overexpression or SeP deletion. The blood flow recovery after ischaemia was also examined by using hindlimb ischaemia model with Sepp1-heterozygous-knockout mice. Results Treatment with glucose increased gene expression and transcriptional activity for Sepp1 in H4IIEC hepatocytes. Physiological concentrations of SeP inhibited VEGF-stimulated cell proliferation, tubule formation and migration in HUVECs. SeP suppressed VEGF-induced reactive oxygen species (ROS) generation and phosphorylation of VEGF receptor 2 (VEGFR2) and extracellular signal-regulated kinase 1/2 (ERK1/2) in HUVECs. Wound closure was impaired in the mice overexpressing Sepp1, whereas it was improved in SeP-/-mice. SeP+/-mice showed an increase in blood flow recovery and vascular endothelial cells after hindlimb ischaemia. Conclusions/interpretation The hepatokine SeP may be a novel therapeutic target for impaired angiogenesis in type 2 diabetes. © 2014 Springer-Verlag Berlin Heidelberg

LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance

Recent articles have reported an association between fatty liver disease and systemic insulin resistance in humans, but the causal relationship remains unclear. The liver may contribute to muscle insulin resistance by releasing secretory proteins called hepatokines. Here we demonstrate that leukocyte cell-derived chemotaxin 2 (LECT2), an energy-sensing hepatokine, is a link between obesity and skeletal muscle insulin resistance. Circulating LECT2 positively correlated with the severity of both obesity and insulin resistance in humans. LECT2 expression was negatively regulated by starvation-sensing kinase adenosine monophosphate-activated protein kinase in H4IIEC hepatocytes. Genetic deletion of LECT2 in mice increased insulin sensitivity in the skeletal muscle. Treatment with recombinant LECT2 protein impaired insulin signaling via phosphorylation of Jun NH2-terminal kinase in C2C12 myocytes. These results demonstrate the involvement of LECT2 in glucose metabolism and suggest that LECT2 may be a therapeutic target for obesity-associated insulin resistance. © 2014 by the American Diabetes Association