| First Author | Guo L | Year | 2017 |
| Journal | J Clin Invest | Volume | 127 |
| Issue | 12 | Pages | 4449-4461 |
| PubMed ID | 29106384 | Mgi Jnum | J:264895 |
| Mgi Id | MGI:6198786 | Doi | 10.1172/JCI96324 |
| Citation | Guo L, et al. (2017) Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression. J Clin Invest 127(12):4449-4461 |
| abstractText | 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. |
