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Theranostics 2023; 13(7):2210-2225. doi:10.7150/thno.81192 This issue Cite

Research Paper

A novel NEDD4L-TXNIP-CHOP axis in the pathogenesis of nonalcoholic steatohepatitis

Qian Guo1, Mingyang Xin1, Qingchun Lu1, Dechun Feng2, Vicky Yang1, Lee F. Peng3, Kelly A. Whelan4, Wenhui Hu5, Sheng Wu5, Xiaofeng Yang5, Hong Wang5, Brad S. Rothberg1, Ana M. Gamero1, Glenn S. Gerhard1, Bin Gao2, Ling Yang1✉

1. Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA.
2. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
3. Division of Hepatology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA.
4. Department of Cancer and Cellular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA.
5. Department of Cardiovascular Sciences/Center for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA.

✉ Corresponding author: Ling Yang, Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, 3440 N Broad St, Philadelphia, PA19140, USA. Email: ling.yangedu; Phone: +1-215-707-3779

Citation:
Guo Q, Xin M, Lu Q, Feng D, Yang V, Peng LF, Whelan KA, Hu W, Wu S, Yang X, Wang H, Rothberg BS, Gamero AM, Gerhard GS, Gao B, Yang L. A novel NEDD4L-TXNIP-CHOP axis in the pathogenesis of nonalcoholic steatohepatitis. Theranostics 2023; 13(7):2210-2225. doi:10.7150/thno.81192. https://www.thno.org/v13p2210.htm
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Abstract

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Background: Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver diseases worldwide. There is a pressing clinical need to identify potential therapeutic targets for NASH treatment. Thioredoxin interacting protein (Txnip) is a stress responsive gene that has been implicated in the pathogenesis of NASH, but its exact role is not fully understood. Here, we investigated the liver- and gene-specific role of Txnip and its upstream/downstream signaling in the pathogenesis of NASH.

Methods and Results: Using four independent NASH mouse models, we found that TXNIP protein abnormally accumulated in NASH mouse livers. A decrease in E3 ubiquitin ligase NEDD4L resulted in impaired TXNIP ubiquitination and its accumulation in the liver. TXNIP protein levels were positively correlated with that of CHOP, a major regulator of ER stress-mediated apoptosis, in NASH mouse liver. Moreover, gain- and loss-of-function studies showed that TXNIP increased protein not mRNA levels of Chop both in vitro and in vivo. Mechanistically, the C-terminus of TXNIP associated with the N-terminus of the α-helix domain of CHOP and decreased CHOP ubiquitination, thus increasing the stability of CHOP protein. Lastly, selective knockdown of Txnip by adenovirus-mediated shRNA (not targets Txnip antisense lncRNA) delivery in the livers of both young and aged NASH mice suppressed the expression of CHOP and its downstream apoptotic pathway, and ameliorated NASH by reducing hepatic apoptosis, inflammation, and fibrosis.

Conclusions: Our study revealed a pathogenic role of hepatic TXNIP in NASH and identified a novel NEDD4L-TXNIP-CHOP axis in the pathogenesis of NASH.

Keywords: TXNIP, CHOP, E3 ligase, Ubiquitination, NASH

Citation styles

APA
Guo, Q., Xin, M., Lu, Q., Feng, D., Yang, V., Peng, L.F., Whelan, K.A., Hu, W., Wu, S., Yang, X., Wang, H., Rothberg, B.S., Gamero, A.M., Gerhard, G.S., Gao, B., Yang, L. (2023). A novel NEDD4L-TXNIP-CHOP axis in the pathogenesis of nonalcoholic steatohepatitis. Theranostics, 13(7), 2210-2225. https://doi.org/10.7150/thno.81192.

ACS
Guo, Q.; Xin, M.; Lu, Q.; Feng, D.; Yang, V.; Peng, L.F.; Whelan, K.A.; Hu, W.; Wu, S.; Yang, X.; Wang, H.; Rothberg, B.S.; Gamero, A.M.; Gerhard, G.S.; Gao, B.; Yang, L. A novel NEDD4L-TXNIP-CHOP axis in the pathogenesis of nonalcoholic steatohepatitis. Theranostics 2023, 13 (7), 2210-2225. DOI: 10.7150/thno.81192.

NLM
Guo Q, Xin M, Lu Q, Feng D, Yang V, Peng LF, Whelan KA, Hu W, Wu S, Yang X, Wang H, Rothberg BS, Gamero AM, Gerhard GS, Gao B, Yang L. A novel NEDD4L-TXNIP-CHOP axis in the pathogenesis of nonalcoholic steatohepatitis. Theranostics 2023; 13(7):2210-2225. doi:10.7150/thno.81192. https://www.thno.org/v13p2210.htm

CSE
Guo Q, Xin M, Lu Q, Feng D, Yang V, Peng LF, Whelan KA, Hu W, Wu S, Yang X, Wang H, Rothberg BS, Gamero AM, Gerhard GS, Gao B, Yang L. 2023. A novel NEDD4L-TXNIP-CHOP axis in the pathogenesis of nonalcoholic steatohepatitis. Theranostics. 13(7):2210-2225.

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