CX08005, a Protein Tyrosine Phosphatase 1B Inhibitor, Attenuated Hepatic Lipid Accumulation and Microcirculation Dysfunction Associated with Nonalcoholic Fatty Liver Disease
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 IC<sub>50</sub> of 0.75 ± 0.07 μM,...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-01-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/16/1/106 |
| _version_ | 1827622615013916672 |
|---|---|
| author | Jiang Li Xiaolin Zhang Jinying Tian Juan Li Xuechen Li Song Wu Yuying Liu Jingyan Han Fei Ye |
| author_facet | Jiang Li Xiaolin Zhang Jinying Tian Juan Li Xuechen Li Song Wu Yuying Liu Jingyan Han Fei Ye |
| author_sort | Jiang Li |
| collection | DOAJ |
| description | 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 IC<sub>50</sub> 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. |
| first_indexed | 2024-03-09T11:28:11Z |
| format | Article |
| id | doaj.art-12735e52cdf3442180cff7015566befc |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T11:28:11Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-12735e52cdf3442180cff7015566befc2023-11-30T23:55:53ZengMDPI AGPharmaceuticals1424-82472023-01-0116110610.3390/ph16010106CX08005, a Protein Tyrosine Phosphatase 1B Inhibitor, Attenuated Hepatic Lipid Accumulation and Microcirculation Dysfunction Associated with Nonalcoholic Fatty Liver DiseaseJiang Li0Xiaolin Zhang1Jinying Tian2Juan Li3Xuechen Li4Song Wu5Yuying Liu6Jingyan Han7Fei Ye8Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, 1 Xiannongtan St., Beijing 100050, ChinaBeijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, 1 Xiannongtan St., Beijing 100050, ChinaBeijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, 1 Xiannongtan St., Beijing 100050, ChinaBeijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, 1 Xiannongtan St., Beijing 100050, ChinaBeijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, 1 Xiannongtan St., Beijing 100050, ChinaBeijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, 1 Xiannongtan St., Beijing 100050, ChinaKey Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People’s Republic of China, Beijing 100191, ChinaKey Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People’s Republic of China, Beijing 100191, ChinaBeijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, 1 Xiannongtan St., Beijing 100050, ChinaNonalcoholic 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 IC<sub>50</sub> 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.https://www.mdpi.com/1424-8247/16/1/106CX08005PTP1B inhibitorinsulin sensitivitymicrocirculationNAFLD |
| spellingShingle | Jiang Li Xiaolin Zhang Jinying Tian Juan Li Xuechen Li Song Wu Yuying Liu Jingyan Han Fei Ye CX08005, a Protein Tyrosine Phosphatase 1B Inhibitor, Attenuated Hepatic Lipid Accumulation and Microcirculation Dysfunction Associated with Nonalcoholic Fatty Liver Disease Pharmaceuticals CX08005 PTP1B inhibitor insulin sensitivity microcirculation NAFLD |
| title | CX08005, a Protein Tyrosine Phosphatase 1B Inhibitor, Attenuated Hepatic Lipid Accumulation and Microcirculation Dysfunction Associated with Nonalcoholic Fatty Liver Disease |
| title_full | CX08005, a Protein Tyrosine Phosphatase 1B Inhibitor, Attenuated Hepatic Lipid Accumulation and Microcirculation Dysfunction Associated with Nonalcoholic Fatty Liver Disease |
| title_fullStr | CX08005, a Protein Tyrosine Phosphatase 1B Inhibitor, Attenuated Hepatic Lipid Accumulation and Microcirculation Dysfunction Associated with Nonalcoholic Fatty Liver Disease |
| title_full_unstemmed | CX08005, a Protein Tyrosine Phosphatase 1B Inhibitor, Attenuated Hepatic Lipid Accumulation and Microcirculation Dysfunction Associated with Nonalcoholic Fatty Liver Disease |
| title_short | CX08005, a Protein Tyrosine Phosphatase 1B Inhibitor, Attenuated Hepatic Lipid Accumulation and Microcirculation Dysfunction Associated with Nonalcoholic Fatty Liver Disease |
| title_sort | cx08005 a protein tyrosine phosphatase 1b inhibitor attenuated hepatic lipid accumulation and microcirculation dysfunction associated with nonalcoholic fatty liver disease |
| topic | CX08005 PTP1B inhibitor insulin sensitivity microcirculation NAFLD |
| url | https://www.mdpi.com/1424-8247/16/1/106 |
| work_keys_str_mv | AT jiangli cx08005aproteintyrosinephosphatase1binhibitorattenuatedhepaticlipidaccumulationandmicrocirculationdysfunctionassociatedwithnonalcoholicfattyliverdisease AT xiaolinzhang cx08005aproteintyrosinephosphatase1binhibitorattenuatedhepaticlipidaccumulationandmicrocirculationdysfunctionassociatedwithnonalcoholicfattyliverdisease AT jinyingtian cx08005aproteintyrosinephosphatase1binhibitorattenuatedhepaticlipidaccumulationandmicrocirculationdysfunctionassociatedwithnonalcoholicfattyliverdisease AT juanli cx08005aproteintyrosinephosphatase1binhibitorattenuatedhepaticlipidaccumulationandmicrocirculationdysfunctionassociatedwithnonalcoholicfattyliverdisease AT xuechenli cx08005aproteintyrosinephosphatase1binhibitorattenuatedhepaticlipidaccumulationandmicrocirculationdysfunctionassociatedwithnonalcoholicfattyliverdisease AT songwu cx08005aproteintyrosinephosphatase1binhibitorattenuatedhepaticlipidaccumulationandmicrocirculationdysfunctionassociatedwithnonalcoholicfattyliverdisease AT yuyingliu cx08005aproteintyrosinephosphatase1binhibitorattenuatedhepaticlipidaccumulationandmicrocirculationdysfunctionassociatedwithnonalcoholicfattyliverdisease AT jingyanhan cx08005aproteintyrosinephosphatase1binhibitorattenuatedhepaticlipidaccumulationandmicrocirculationdysfunctionassociatedwithnonalcoholicfattyliverdisease AT feiye cx08005aproteintyrosinephosphatase1binhibitorattenuatedhepaticlipidaccumulationandmicrocirculationdysfunctionassociatedwithnonalcoholicfattyliverdisease |