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.
View: Text | PDF
Research Article Hepatology

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

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

×

Figure 2

Nrg4 deficiency exacerbates diet-induced NASH in mice.

Options: View larger image (or click on image) Download as PowerPoint
Nrg4 deficiency exacerbates diet-induced NASH in mice. Control WT (n = 1...
Control WT (n = 12, black) and Nrg4-KO (n = 12, gray) male mice were fed NASH diet for 20 weeks, starting at 3 months of age. (A) Plasma ALT, AST, and HMGB1 levels and liver TAG content. Data represent mean ± SEM. *P < 0.05; **P < 0.01, 2-tailed unpaired Student’s t test. (B) H&E, sirius red, F4/80 immunofluorescence, and TUNEL staining of liver sections. Scale bars: 100 μm. (C) Quantification of sirius red, F4/80, and TUNEL staining images and liver hydroxyproline content. Data represent mean ± SEM. **P < 0.01; ***P < 0.001, 2-tailed unpaired Student’s t test. (D) Immunoblots of total liver lysates from NASH diet–fed mice. (E) Heatmap representation of hepatic genes up- or downregulated by Nrg4 deficiency following NASH diet feeding (top). Enrichment of biological processes in these 2 clusters (bottom). (F) qPCR analysis of hepatic gene expression. Data represent mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, 2-tailed unpaired Student’s t test. (G) Flow cytometry analysis of liver CD4+ T cells. Results are expressed as percentage (%) of IL-17+, TNF-α+, RORγt+, and FOXP3+ cells in total liver CD4+ T cells. Data represent mean ± SEM. *P < 0.05; **P < 0.01, 2-tailed unpaired Student’s t test.