CX08005, a Protein Tyrosine Phosphatase 1B Inhibitor, Attenuated Hepatic Lipid Accumulation and Microcirculation Dysfunction Associated with Nonalcoholic Fatty Liver Disease.
CX08005, a Protein Tyrosine Phosphatase 1B Inhibitor, Attenuated Hepatic Lipid Accumulation and Microcirculation Dysfunction Associated with Nonalcoholic Fatty Liver Disease.
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DOI：
10.3390/ph16010106
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发表时间：
2023-01-11
期刊：
影响因子：
--
通讯作者：
Ye F
中科院分区：
文献类型：
--
作者：
Li J;Zhang X;Tian J;Li J;Li X;Wu S;Liu Y;Han J;Ye F
非酒精性脂肪性肝病（NAFLD）是以肝脏脂质蓄积为特征的常见代谢性疾病之一。胰岛素抵抗和微循环障碍与NAFLD密切相关。CX 08005是一种PTP 1B抑制剂，IC 50为0.75 ± 0.07 μM，已被证明可直接增强胰岛素敏感性。本研究旨在研究CX 08005对KKAy小鼠和饮食诱导肥胖（DIO）小鼠肝脏脂质蓄积和微循环障碍的影响。在KKAy小鼠中通过肝脏甘油三酯测定和B超分析评估肝脏脂质蓄积。采用胰岛素耐量试验（ITT）和甘油三酯（TG）/总胆固醇（TC）测定评价胰岛素敏感性和血脂水平。此外，通过体内显微镜检查DIO小鼠的肝脏微循环。结果显示，CX 08005干预显著降低了KKAy小鼠肝脏中的TG和回声强度衰减系数。此外，我们发现CX 08005处理显著增强胰岛素敏感性，并分别降低KKAy和DIO小鼠的血浆TG和/或TC含量。此外，CX 08005治疗改善DIO小鼠的肝脏微循环功能障碍，如通过增加中央静脉和小叶间静脉中血流的RBC速度和剪切速率以及中央静脉区域中灌注的肝窦的速率增强所证明的。此外，CX 08005给药减少了中心静脉和肝窦区域中粘附的白细胞。综上所述，CX 08005对与NAFLD相关的肝脏脂质积聚和微循环功能障碍表现出有益作用，这涉及调节胰岛素敏感性和白细胞募集，以及恢复正常的微循环血流。
Nonalcoholic fatty liver disease (NAFLD) is one of the common metabolic diseases characterized by hepatic lipid accumulation. Insulin resistance and microcirculation dysfunction are strongly associated with NAFLD. CX08005, an inhibitor of PTP1B with the IC50 of 0.75 ± 0.07 μM, has been proven to directly enhance insulin sensitivity. The present study aimed to investigate the effects of CX08005 on hepatic lipid accumulation and microcirculation dysfunction in both KKAy mice and diet-induced obesity (DIO) mice. Hepatic lipid accumulation was evaluated by hepatic triglyceride determination and B-ultrasound analysis in KKAy mice. Insulin sensitivity and blood lipids were assessed by insulin tolerance test (ITT) and triglyceride (TG)/total cholesterol (TC) contents, respectively. In addition, the hepatic microcirculation was examined in DIO mice by in vivo microscopy. The results showed that CX08005 intervention significantly reduced the TG and echo-intensity attenuation coefficient in the livers of KKAy mice. Furthermore, we found that CX08005 treatment significantly enhanced insulin sensitivity, and decreased plasma TG and/or TC contents in KKAy and DIO mice, respectively. In addition, CX08005 treatment ameliorated hepatic microcirculation dysfunction in DIO mice, as evidenced by increased RBCs velocity and shear rate of the blood flow in central veins and in the interlobular veins, as well as enhanced rate of perfused hepatic sinusoids in central vein area. Additionally, CX08005 administration decreased the adhered leukocytes both in the center veins and in the hepatic sinusoids area. Taken together, CX08005 exhibited beneficial effects on hepatic lipid accumulation and microcirculation dysfunction associated with NAFLD, which was involved with modulating insulin sensitivity and leukocyte recruitment, as well as restoration of normal microcirculatory blood flow.
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影响因子：
29.4
作者：
Kanwal F;Kramer JR;Mapakshi S;Natarajan Y;Chayanupatkul M;Richardson PA;Li L;Desiderio R;Thrift AP;Asch SM;Chu J;El-Serag HB
通讯作者：
El-Serag HB
影响因子：
16.1
作者：
Higashi T;Friedman SL;Hoshida Y
通讯作者：
Hoshida Y
影响因子：
4.3
作者：
Chen, Wei-Xing;Wang, Fang;Han, Jing-Yan
通讯作者：
Han, Jing-Yan
影响因子：
2.7
作者：
Marušić M;Paić M;Knobloch M;Liberati Pršo AM
通讯作者：
Liberati Pršo AM
DOI：
10.1007/978-1-0716-0385-7_2
发表时间：
2020-01-01
期刊：
ANIMAL MODELS OF DIABETES
影响因子：
--
作者：
Lutz, Thomas A.
通讯作者：
Lutz, Thomas A.