METTL3 inhibition ameliorates liver damage in mouse with hepatitis B virus-associated acute-on-chronic liver failure by regulating miR-146a-5p maturation |
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| Affiliation: | 1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Key Lab of Glycoconjugate Research, Ministry of Public Health, Shanghai, PR China;2. Beng Bu Medical College, Bengbu, 233000, Anhui, PR China;3. Department of the 3rd ward of Special Treatment, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, PR China;4. Department of Gastric Surgery, Fudan University Shanghai Cancer Center, 270 Dong''an Road, Shanghai 200032, PR China;1. Department of Gastroenterology, Peking University Third Hospital, 49 North Garden Road, Beijing, China;2. Beijing Key Laboratory of Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Peking University Third Hospital, 49 North Garden Road, Beijing, China;3. Department of Pathology, School of Basic Medical Science, Peking University Third Hospital, Peking University Health Science Center, 49 North Garden Road, Beijing, China;1. Faculty of Chinese Medicine, Macau University of Science and Technology and State Key Laboratory of Quality Research in Chinese Medicine (Macau University of Science and Technology), Taipa, Macao, PR China;2. Basic Medical College, Guizhou University of Traditional Chinese Medicine, Guian District, Guiyang, Guizhou, PR China;3. Key Laboratory of Plant Ex-situ Conservation and Research Center of Resource Plant, Lushan Botanical Garden, Chinese Academy of Science, Jiujiang City, Jiangxi Province, PR China;4. School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua, Hunan, PR China;5. Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, Guangdong, PR China;6. Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People''s Republic of China, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China |
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| Abstract: | Hepatitis B virus (HBV)-associated acute-on-chronic liver failure (ACLF) is a clinical syndrome of severe liver damage. HBV infection is affected by N6-methyladenosine (m6A) RNA modification. Here, we investigated whether methyltransferase-like 3 (METTL3)-mediated m6A methylation can affect ACLF. Human hepatic cells (THLE-2) were treated with lipopolysaccharide (LPS) to induce cell damage. Proliferation, apoptosis and m6A modification were measured by MTT assay, flow cytometry and Dot blot assay. Our results showed that HBV infection significantly enhanced the levels of m6A modification and elevated the expression of METTL3 and mature-miR-146a-5p in THLE-2 cells, which was repressed by cycloleucine (m6A inhibitor). METTL3 overexpression enhanced m6A modification and promoted mature-miR-146a-5p expression. METTL3 overexpression promoted HBV replication and apoptosis, enhanced the levels of pro-inflammatory cytokines, hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg), and repressed cell proliferation in THLE-2 cells, which attributed to repress miR-146a-5p maturation. Moreover, a severe liver failure mouse model was established by HBV infection to verify the impact of METTL3 knockdown on liver damage in vivo. HBV-infection led to a severe liver damage and increase of apoptosis in hepatic tissues of mice, which was abolished by METTL3 knockdown. METTL3 knockdown reduced METTL3 expression and impeded miR-146a-5p maturation in HBV-infected mice. In conclusion, this work demonstrates that METTL3 inhibition ameliorates liver damage in mouse with HBV-associated ACLF, which contributes to repress miR-146a-5p maturation. Thus, this article suggests a novel therapeutic avenue to prevent and treat HBV-associated ACLF. |
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