Sestrin 3 Protects Against Diet-Induced Nonalcoholic Steatohepatitis in Mice Through Suppression of Transforming Growth Factor β Signal Transduction

Menghao Huang, Hyeong Geug Kim, Xiaolin Zhong, Chuanpeng Dong, Brian Zhang, Zhigang Fang, Yang Zhang, Xiaoyu Lu, Romil Saxena, Yunlong Liu, Chi Zhang, Suthat Liangpunsakul, X. Charlie Dong

Research output: Contribution to journalArticle

Abstract

Sestrin 3 (Sesn3) belongs to the three-member sestrin protein family. Sestrins have been implicated in antioxidative stress, adenosine monophosphate–activated protein kinase and mammalian target of rapamycin signal transduction, and metabolic homeostasis. However, the role of Sesn3 in the development of nonalcoholic steatohepatitis (NASH) has not been previously studied. In this work, we generated Sesn3 whole-body knockout and liver-specific transgenic mice to investigate the hepatic function of Sesn3 in diet-induced NASH. With only 4 weeks of dietary treatment, Sesn3 knockout mice developed severe NASH phenotype as characterized by hepatic steatosis, inflammation, and fibrosis. Strikingly, after 8-week feeding with a NASH-inducing diet, Sesn3 transgenic mice were largely protected against NASH development. Transcriptomic analysis revealed that multiple extracellular matrix–related processes were up-regulated, including transforming growth factor β (TGF-β) signaling and collagen production. Further biochemical and cell biological analyses have illustrated a critical control of the TGF-β–mothers against decapentaplegic homolog (Smad) pathway by Sesn3 at the TGF-β receptor and Smad3 levels. First, Sesn3 inhibits the TGF-β receptor through an interaction with Smad7; second, Sesn3 directly inhibits the Smad3 function through protein–protein interaction and cytosolic retention. Conclusion: Sesn3 is a critical regulator of the extracellular matrix and hepatic fibrosis by suppression of TGF-β–Smad3 signaling.

Original languageEnglish (US)
JournalHepatology
DOIs
StateAccepted/In press - Jan 1 2019

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Transforming Growth Factors
Signal Transduction
Diet
Liver
Transgenic Mice
Fibrosis
Smad Proteins
Sirolimus
Knockout Mice
Adenosine
Protein Kinases
Extracellular Matrix
Homeostasis
Collagen
Non-alcoholic Fatty Liver Disease
Inflammation
Phenotype
Proteins

ASJC Scopus subject areas

  • Hepatology

Cite this

Sestrin 3 Protects Against Diet-Induced Nonalcoholic Steatohepatitis in Mice Through Suppression of Transforming Growth Factor β Signal Transduction. / Huang, Menghao; Kim, Hyeong Geug; Zhong, Xiaolin; Dong, Chuanpeng; Zhang, Brian; Fang, Zhigang; Zhang, Yang; Lu, Xiaoyu; Saxena, Romil; Liu, Yunlong; Zhang, Chi; Liangpunsakul, Suthat; Dong, X. Charlie.

In: Hepatology, 01.01.2019.

Research output: Contribution to journalArticle

Huang, Menghao ; Kim, Hyeong Geug ; Zhong, Xiaolin ; Dong, Chuanpeng ; Zhang, Brian ; Fang, Zhigang ; Zhang, Yang ; Lu, Xiaoyu ; Saxena, Romil ; Liu, Yunlong ; Zhang, Chi ; Liangpunsakul, Suthat ; Dong, X. Charlie. / Sestrin 3 Protects Against Diet-Induced Nonalcoholic Steatohepatitis in Mice Through Suppression of Transforming Growth Factor β Signal Transduction. In: Hepatology. 2019.
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abstract = "Sestrin 3 (Sesn3) belongs to the three-member sestrin protein family. Sestrins have been implicated in antioxidative stress, adenosine monophosphate–activated protein kinase and mammalian target of rapamycin signal transduction, and metabolic homeostasis. However, the role of Sesn3 in the development of nonalcoholic steatohepatitis (NASH) has not been previously studied. In this work, we generated Sesn3 whole-body knockout and liver-specific transgenic mice to investigate the hepatic function of Sesn3 in diet-induced NASH. With only 4 weeks of dietary treatment, Sesn3 knockout mice developed severe NASH phenotype as characterized by hepatic steatosis, inflammation, and fibrosis. Strikingly, after 8-week feeding with a NASH-inducing diet, Sesn3 transgenic mice were largely protected against NASH development. Transcriptomic analysis revealed that multiple extracellular matrix–related processes were up-regulated, including transforming growth factor β (TGF-β) signaling and collagen production. Further biochemical and cell biological analyses have illustrated a critical control of the TGF-β–mothers against decapentaplegic homolog (Smad) pathway by Sesn3 at the TGF-β receptor and Smad3 levels. First, Sesn3 inhibits the TGF-β receptor through an interaction with Smad7; second, Sesn3 directly inhibits the Smad3 function through protein–protein interaction and cytosolic retention. Conclusion: Sesn3 is a critical regulator of the extracellular matrix and hepatic fibrosis by suppression of TGF-β–Smad3 signaling.",
author = "Menghao Huang and Kim, {Hyeong Geug} and Xiaolin Zhong and Chuanpeng Dong and Brian Zhang and Zhigang Fang and Yang Zhang and Xiaoyu Lu and Romil Saxena and Yunlong Liu and Chi Zhang and Suthat Liangpunsakul and Dong, {X. Charlie}",
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AU - Huang, Menghao

AU - Kim, Hyeong Geug

AU - Zhong, Xiaolin

AU - Dong, Chuanpeng

AU - Zhang, Brian

AU - Fang, Zhigang

AU - Zhang, Yang

AU - Lu, Xiaoyu

AU - Saxena, Romil

AU - Liu, Yunlong

AU - Zhang, Chi

AU - Liangpunsakul, Suthat

AU - Dong, X. Charlie

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Sestrin 3 (Sesn3) belongs to the three-member sestrin protein family. Sestrins have been implicated in antioxidative stress, adenosine monophosphate–activated protein kinase and mammalian target of rapamycin signal transduction, and metabolic homeostasis. However, the role of Sesn3 in the development of nonalcoholic steatohepatitis (NASH) has not been previously studied. In this work, we generated Sesn3 whole-body knockout and liver-specific transgenic mice to investigate the hepatic function of Sesn3 in diet-induced NASH. With only 4 weeks of dietary treatment, Sesn3 knockout mice developed severe NASH phenotype as characterized by hepatic steatosis, inflammation, and fibrosis. Strikingly, after 8-week feeding with a NASH-inducing diet, Sesn3 transgenic mice were largely protected against NASH development. Transcriptomic analysis revealed that multiple extracellular matrix–related processes were up-regulated, including transforming growth factor β (TGF-β) signaling and collagen production. Further biochemical and cell biological analyses have illustrated a critical control of the TGF-β–mothers against decapentaplegic homolog (Smad) pathway by Sesn3 at the TGF-β receptor and Smad3 levels. First, Sesn3 inhibits the TGF-β receptor through an interaction with Smad7; second, Sesn3 directly inhibits the Smad3 function through protein–protein interaction and cytosolic retention. Conclusion: Sesn3 is a critical regulator of the extracellular matrix and hepatic fibrosis by suppression of TGF-β–Smad3 signaling.

AB - Sestrin 3 (Sesn3) belongs to the three-member sestrin protein family. Sestrins have been implicated in antioxidative stress, adenosine monophosphate–activated protein kinase and mammalian target of rapamycin signal transduction, and metabolic homeostasis. However, the role of Sesn3 in the development of nonalcoholic steatohepatitis (NASH) has not been previously studied. In this work, we generated Sesn3 whole-body knockout and liver-specific transgenic mice to investigate the hepatic function of Sesn3 in diet-induced NASH. With only 4 weeks of dietary treatment, Sesn3 knockout mice developed severe NASH phenotype as characterized by hepatic steatosis, inflammation, and fibrosis. Strikingly, after 8-week feeding with a NASH-inducing diet, Sesn3 transgenic mice were largely protected against NASH development. Transcriptomic analysis revealed that multiple extracellular matrix–related processes were up-regulated, including transforming growth factor β (TGF-β) signaling and collagen production. Further biochemical and cell biological analyses have illustrated a critical control of the TGF-β–mothers against decapentaplegic homolog (Smad) pathway by Sesn3 at the TGF-β receptor and Smad3 levels. First, Sesn3 inhibits the TGF-β receptor through an interaction with Smad7; second, Sesn3 directly inhibits the Smad3 function through protein–protein interaction and cytosolic retention. Conclusion: Sesn3 is a critical regulator of the extracellular matrix and hepatic fibrosis by suppression of TGF-β–Smad3 signaling.

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