Hepatic Neuregulin 4 Signaling Defines An Endocrine Checkpoint For Steatosis-to-nash Progression

Hepatic Neuregulin 4 Signaling Defines An Endocrine Checkpoint For Steatosis-to-nash Progression

Guo L; Zhang P; Chen Z M; Xia H J; Li S M; Zhang Y Q; Kobberup S; Zou W P; Lin J D

Journal of Clinical Investigation

2017

2017-12

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.

alpha-induced apoptosis; association; brown; fatty liver-disease; Inflammation; mice; necroptosis; necrotic cell-death; nonalcoholic steatohepatitis; pathogenesis; Research & Experimental Medicine

Journal Article or Conference Abstract Publication

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4449-4461

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