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Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: Involvement of reduced S100A11 expression

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is an important regulator of plasma asymmetric dimethylarginine (ADMA) levels, which are associated with insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). To elucidate the role of hepatic DDAH1 in the pathogenesis of NAFLD...

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Autores principales: Shen, Xiyue, Luo, Kai, Yuan, Juntao, Gao, Junling, Cui, Bingqing, Yu, Zhuoran, Lu, Zhongbing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10465955/
https://www.ncbi.nlm.nih.gov/pubmed/37655336
http://dx.doi.org/10.1016/j.apsb.2023.05.020
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author Shen, Xiyue
Luo, Kai
Yuan, Juntao
Gao, Junling
Cui, Bingqing
Yu, Zhuoran
Lu, Zhongbing
author_facet Shen, Xiyue
Luo, Kai
Yuan, Juntao
Gao, Junling
Cui, Bingqing
Yu, Zhuoran
Lu, Zhongbing
author_sort Shen, Xiyue
collection PubMed
description Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is an important regulator of plasma asymmetric dimethylarginine (ADMA) levels, which are associated with insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). To elucidate the role of hepatic DDAH1 in the pathogenesis of NAFLD, we used hepatocyte-specific Ddah1-knockout mice (Ddah1(HKO)) to examine the progress of high-fat diet (HFD)-induced NAFLD. Compared to diet-matched flox/flox littermates (Ddah1(f/f)), Ddah1(HKO) mice exhibited higher serum ADMA levels. After HFD feeding for 16 weeks, Ddah1(HKO) mice developed more severe liver steatosis and worse insulin resistance than Ddah1(f/f) mice. On the contrary, overexpression of DDAH1 attenuated the NAFLD-like phenotype in HFD-fed mice and ob/ob mice. RNA-seq analysis showed that DDAH1 affects NF-κB signaling, lipid metabolic processes, and immune system processes in fatty livers. Furthermore, DDAH1 reduces S100 calcium-binding protein A11 (S100A11) possibly via NF-κB, JNK and oxidative stress-dependent manner in fatty livers. Knockdown of hepatic S100a11 by an AAV8-shS100a11 vector alleviated hepatic steatosis and insulin resistance in HFD-fed Ddah1(HKO) mice. In summary, our results suggested that the liver DDAH1/S100A11 axis has a marked effect on liver lipid metabolism in obese mice. Strategies to increase liver DDAH1 activity or decrease S100A11 expression could be a valuable approach for NAFLD therapy.
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spelling pubmed-104659552023-08-31 Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: Involvement of reduced S100A11 expression Shen, Xiyue Luo, Kai Yuan, Juntao Gao, Junling Cui, Bingqing Yu, Zhuoran Lu, Zhongbing Acta Pharm Sin B Original Article Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is an important regulator of plasma asymmetric dimethylarginine (ADMA) levels, which are associated with insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). To elucidate the role of hepatic DDAH1 in the pathogenesis of NAFLD, we used hepatocyte-specific Ddah1-knockout mice (Ddah1(HKO)) to examine the progress of high-fat diet (HFD)-induced NAFLD. Compared to diet-matched flox/flox littermates (Ddah1(f/f)), Ddah1(HKO) mice exhibited higher serum ADMA levels. After HFD feeding for 16 weeks, Ddah1(HKO) mice developed more severe liver steatosis and worse insulin resistance than Ddah1(f/f) mice. On the contrary, overexpression of DDAH1 attenuated the NAFLD-like phenotype in HFD-fed mice and ob/ob mice. RNA-seq analysis showed that DDAH1 affects NF-κB signaling, lipid metabolic processes, and immune system processes in fatty livers. Furthermore, DDAH1 reduces S100 calcium-binding protein A11 (S100A11) possibly via NF-κB, JNK and oxidative stress-dependent manner in fatty livers. Knockdown of hepatic S100a11 by an AAV8-shS100a11 vector alleviated hepatic steatosis and insulin resistance in HFD-fed Ddah1(HKO) mice. In summary, our results suggested that the liver DDAH1/S100A11 axis has a marked effect on liver lipid metabolism in obese mice. Strategies to increase liver DDAH1 activity or decrease S100A11 expression could be a valuable approach for NAFLD therapy. Elsevier 2023-08 2023-05-23 /pmc/articles/PMC10465955/ /pubmed/37655336 http://dx.doi.org/10.1016/j.apsb.2023.05.020 Text en © 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Shen, Xiyue
Luo, Kai
Yuan, Juntao
Gao, Junling
Cui, Bingqing
Yu, Zhuoran
Lu, Zhongbing
Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: Involvement of reduced S100A11 expression
title Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: Involvement of reduced S100A11 expression
title_full Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: Involvement of reduced S100A11 expression
title_fullStr Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: Involvement of reduced S100A11 expression
title_full_unstemmed Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: Involvement of reduced S100A11 expression
title_short Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: Involvement of reduced S100A11 expression
title_sort hepatic ddah1 mitigates hepatic steatosis and insulin resistance in obese mice: involvement of reduced s100a11 expression
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10465955/
https://www.ncbi.nlm.nih.gov/pubmed/37655336
http://dx.doi.org/10.1016/j.apsb.2023.05.020
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