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- Title
Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression.
- Authors
Peng Zhang; Zhimin Chen; Siming Li; Lin, Jiandie D.; Liang Guo; Houjun Xia; Weiping Zou; Yanqiao Zhang; Sune Kobberup; Guo, Liang; Zhang, Peng; Chen, Zhimin; Xia, Houjun; Li, Siming; Zhang, Yanqiao; Kobberup, Sune; Zou, Weiping
- 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.
- Subjects
NEUREGULINS; FATTY liver; ENDOCRINE genetics; LIVER cells; FATTY degeneration; CELLULAR signal transduction; GENE expression; GENETICS; PHYSIOLOGY; ADIPOSE tissues; ANIMAL experimentation; BIOLOGICAL models; CELL death; COMPARATIVE studies; EPITHELIAL cells; GROWTH factors; LIVER; RESEARCH methodology; MEDICAL cooperation; MICE; RESEARCH; EVALUATION research
- Publication
Journal of Clinical Investigation, 2017, Vol 127, Issue 12, p4449
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI96324