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Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression
Liang Guo, … , Weiping Zou, Jiandie D. Lin
Liang Guo, … , Weiping Zou, Jiandie D. Lin
Published November 6, 2017
Citation Information: J Clin Invest. 2017;127(12):4449-4461. https://doi.org/10.1172/JCI96324.
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Research Article Hepatology

Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression

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Abstract

Nonalcoholic steatohepatitis (NASH) is characterized by progressive liver injury, inflammation, and fibrosis; however, the mechanisms that govern the transition from hepatic steatosis, which is relatively benign, to NASH remain poorly defined. Neuregulin 4 (Nrg4) is an adipose tissue–enriched endocrine factor that elicits beneficial metabolic effects in obesity. Here, we show that Nrg4 is a key component of an endocrine checkpoint that preserves hepatocyte health and counters diet-induced NASH in mice. Nrg4 deficiency accelerated liver injury, fibrosis, inflammation, and cell death in a mouse model of NASH. In contrast, transgenic expression of Nrg4 in adipose tissue alleviated diet-induced NASH. Nrg4 attenuated hepatocyte death in a cell-autonomous manner by blocking ubiquitination and proteasomal degradation of c-FLIPL, a negative regulator of cell death. Adeno-associated virus–mediated (AAV-mediated) rescue of hepatic c-FLIPL expression in Nrg4-deficent mice functionally restored the brake for steatosis to NASH transition. Thus, hepatic Nrg4 signaling serves as an endocrine checkpoint for steatosis-to-NASH progression by activating a cytoprotective pathway to counter stress-induced liver injury.

Authors

Liang Guo, Peng Zhang, Zhimin Chen, Houjun Xia, Siming Li, Yanqiao Zhang, Sune Kobberup, Weiping Zou, Jiandie D. Lin

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Figure 5

Stabilization of c-FLIPL by Nrg4 attenuates stress-induced cell death in hepatoma cells.

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Stabilization of c-FLIPL by Nrg4 attenuates stress-induced cell death in...
The following experiments were performed in Hepa 1 cells stably expressing ErbB4. Cells were cultured in serum-free medium during treatment. (A) Immunoblots of total lysates from cells treated with PA/TNF-α in the absence or presence of 100 ng/ml Nrg4 for 6 hours. (B) Immunoblots of total lysates from cells treated with PA/TNF-α without or with 100 ng/ml Nrg4 and chased for different times in the presence of 2 μM CHX. (C) Immunoblots of total lysates from cells treated with PA/TNF-α without or with 100 ng/ml Nrg4 and chased for 6 hours in the presence of 10 μM MG132. (D) Immunoblots of total lysates from treated cells. Hepa 1 cells stably expressing ErbB4 were transduced with Ad-GFP or Ad–c-FLIPL adenoviral vector. Transduced cells were treated with 100 μM PA for 2 hours followed by addition of 20 ng/ml TNF-α and 100 ng/ml Nrg4 for 20 hours. (E) LDH release by treated Hepa 1 cells (20 hours treatment). Data represent mean ± SEM. **P < 0.01, 1-way ANOVA. (F) Flow cytometry analysis (20 hours treatment). Data represent mean ± SEM. **P < 0.01; ***P < 0.001, 1-way ANOVA.
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