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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 December 1, 2017; First published November 6, 2017
Citation Information: J Clin Invest. 2017;127(12):4449-4461. https://doi.org/10.1172/JCI96324.
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Categories: 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 4

Nrg4 signaling protects hepatocytes from stress-induced cell death.

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Nrg4 signaling protects hepatocytes from stress-induced cell death.
(A) ...
(A) Immunoblots of total lysates from primary hepatocytes transduced with GFP or ErbB4 adenovirus and treated with Nrg4 for 20 minutes. (B) Immunoblots of total lysates from primary hepatocytes transduced with GFP or ErbB4 adenovirus treated with 150 μM PA for 2 hours followed by addition of 40 ng/ml TNF-α (PA/TNF-α) and 100 ng/ml Nrg4 for 20 hours. (C) LDH activity in culture media from hepatocytes transduced with Ad-ErbB4 and treated as indicated for 20 hours. Data represent mean ± SEM. **P < 0.01, 1-way ANOVA. (D) Flow cytometry analysis of hepatocytes (20 hours treatment) following annexin V and PI staining. Double-positive cells are considered dead, whereas annexin V–positive and PI-negative cells are apoptotic. (E) Quantitation of hepatocyte cell death based on annexin V/PI staining. Data represent mean ± SEM. ***P < 0.001, 1-way ANOVA. (F) LDH activity in culture media from Hepa 1 cells stably expressing ErbB4 and treated as indicated for 20 hours. Data represent mean ± SEM. **P < 0.01, 1-way ANOVA. (G) Flow cytometry analysis of cell death in treated Hepa 1 cells stably expressing ErbB4 (20 hours treatment). Data represent mean ± SEM. ***P < 0.001, 1-way ANOVA.
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ISSN: 0021-9738 (print), 1558-8238 (online)

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