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Lack of Augmenter of Liver Regeneration Disrupts Cholesterol Homeostasis of Liver in Mice by Inhibiting the AMPK Pathway

It is well known that excessive cholesterol accumulation within hepatocytes deteriorates nonalcoholic fatty liver disease (NAFLD). Augmenter of liver regeneration (ALR) has been reported to alleviate NAFLD through anti‐apoptosis; however, whether ALR could protect liver from cholesterol‐induced NAFL...

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Autores principales: Wang, Xin, Dong, Ling‐yue, Gai, Qu‐jing, Ai, Wei‐lun, Wu, Yuan, Xiao, Wei‐chun, Zhang, Jing, An, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395071/
https://www.ncbi.nlm.nih.gov/pubmed/32766475
http://dx.doi.org/10.1002/hep4.1532
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author Wang, Xin
Dong, Ling‐yue
Gai, Qu‐jing
Ai, Wei‐lun
Wu, Yuan
Xiao, Wei‐chun
Zhang, Jing
An, Wei
author_facet Wang, Xin
Dong, Ling‐yue
Gai, Qu‐jing
Ai, Wei‐lun
Wu, Yuan
Xiao, Wei‐chun
Zhang, Jing
An, Wei
author_sort Wang, Xin
collection PubMed
description It is well known that excessive cholesterol accumulation within hepatocytes deteriorates nonalcoholic fatty liver disease (NAFLD). Augmenter of liver regeneration (ALR) has been reported to alleviate NAFLD through anti‐apoptosis; however, whether ALR could protect liver from cholesterol‐induced NAFLD remains unclear. Mice with heterozygous deletion of Gfer (the gene for ALR, Gfer (+/−)) were generated, and liver steatosis was induced by either choline‐deficient ethionine‐supplemented, methionine choline–deficient diet for 4 weeks, or high‐fat diet for 16 weeks. The results showed that Gfer (+/−) mice developed a more severe fatty liver phenotype than Gfer (+/+) mice. The livers of Gfer (+/−) mice exhibited a higher concentration of cholesterol and low‐density lipoprotein compared with the normal mice. Transcriptome‐based analysis predicts low‐density lipoprotein receptor (LDLR) primarily involved in the metabolic pathway. The experiments further indicate that cholesterol accumulation within hepatocytes is closely associated with enhancing the expression of LDLR and activation of sterol regulatory element binding protein 2 (SREBP2). Because adenosine monophosphate–activated protein kinase (AMPK) is a critical regulator of SREBP2 activation, we measured whether the activity of AMPK was regulated by ALR. We found that knockdown of ALR expression inhibited the phosphorylation of LKB1, an upstream activator of AMPK, followed by AMPK inactivation and SREBP2 maturation/nuclear translocation, leading to extensive cholesterol accumulation. Meanwhile, cellular oxidative stress increased as a result of ALR knockdown, indicating that ALR might also have a role in suppressing reactive oxygen species production. Conclusion: Our results confirm that ALR regulates cholesterol metabolism and alleviates hepatic steatosis probably through the LKB1‐AMPK‐SREBP2‐LDLR pathway in vivo and in vitro, providing a putative mechanism for combating fatty liver disease.
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spelling pubmed-73950712020-08-05 Lack of Augmenter of Liver Regeneration Disrupts Cholesterol Homeostasis of Liver in Mice by Inhibiting the AMPK Pathway Wang, Xin Dong, Ling‐yue Gai, Qu‐jing Ai, Wei‐lun Wu, Yuan Xiao, Wei‐chun Zhang, Jing An, Wei Hepatol Commun Original Articles It is well known that excessive cholesterol accumulation within hepatocytes deteriorates nonalcoholic fatty liver disease (NAFLD). Augmenter of liver regeneration (ALR) has been reported to alleviate NAFLD through anti‐apoptosis; however, whether ALR could protect liver from cholesterol‐induced NAFLD remains unclear. Mice with heterozygous deletion of Gfer (the gene for ALR, Gfer (+/−)) were generated, and liver steatosis was induced by either choline‐deficient ethionine‐supplemented, methionine choline–deficient diet for 4 weeks, or high‐fat diet for 16 weeks. The results showed that Gfer (+/−) mice developed a more severe fatty liver phenotype than Gfer (+/+) mice. The livers of Gfer (+/−) mice exhibited a higher concentration of cholesterol and low‐density lipoprotein compared with the normal mice. Transcriptome‐based analysis predicts low‐density lipoprotein receptor (LDLR) primarily involved in the metabolic pathway. The experiments further indicate that cholesterol accumulation within hepatocytes is closely associated with enhancing the expression of LDLR and activation of sterol regulatory element binding protein 2 (SREBP2). Because adenosine monophosphate–activated protein kinase (AMPK) is a critical regulator of SREBP2 activation, we measured whether the activity of AMPK was regulated by ALR. We found that knockdown of ALR expression inhibited the phosphorylation of LKB1, an upstream activator of AMPK, followed by AMPK inactivation and SREBP2 maturation/nuclear translocation, leading to extensive cholesterol accumulation. Meanwhile, cellular oxidative stress increased as a result of ALR knockdown, indicating that ALR might also have a role in suppressing reactive oxygen species production. Conclusion: Our results confirm that ALR regulates cholesterol metabolism and alleviates hepatic steatosis probably through the LKB1‐AMPK‐SREBP2‐LDLR pathway in vivo and in vitro, providing a putative mechanism for combating fatty liver disease. John Wiley and Sons Inc. 2020-06-02 /pmc/articles/PMC7395071/ /pubmed/32766475 http://dx.doi.org/10.1002/hep4.1532 Text en © 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Wang, Xin
Dong, Ling‐yue
Gai, Qu‐jing
Ai, Wei‐lun
Wu, Yuan
Xiao, Wei‐chun
Zhang, Jing
An, Wei
Lack of Augmenter of Liver Regeneration Disrupts Cholesterol Homeostasis of Liver in Mice by Inhibiting the AMPK Pathway
title Lack of Augmenter of Liver Regeneration Disrupts Cholesterol Homeostasis of Liver in Mice by Inhibiting the AMPK Pathway
title_full Lack of Augmenter of Liver Regeneration Disrupts Cholesterol Homeostasis of Liver in Mice by Inhibiting the AMPK Pathway
title_fullStr Lack of Augmenter of Liver Regeneration Disrupts Cholesterol Homeostasis of Liver in Mice by Inhibiting the AMPK Pathway
title_full_unstemmed Lack of Augmenter of Liver Regeneration Disrupts Cholesterol Homeostasis of Liver in Mice by Inhibiting the AMPK Pathway
title_short Lack of Augmenter of Liver Regeneration Disrupts Cholesterol Homeostasis of Liver in Mice by Inhibiting the AMPK Pathway
title_sort lack of augmenter of liver regeneration disrupts cholesterol homeostasis of liver in mice by inhibiting the ampk pathway
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395071/
https://www.ncbi.nlm.nih.gov/pubmed/32766475
http://dx.doi.org/10.1002/hep4.1532
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