Dissecting the NRG4 hormonal checkpoint in metabolic liver disease

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Inter-organ crosstalk via endocrine hormones is a fundamental feature of mammalian metabolic physiology. Disruptions of hormonal signaling have been linked to the development of insulin resistance, type 2 diabetes, and non-alcoholic steatohepatitis (NASH). We recently discovered Neuregulin 4 (NRG4) as a fat-derived hormone that is reduced in mouse and human obesity. Using gain- and loss-of-function mouse models, we demonstrated that NRG4 preserves metabolic health by acting on the liver to attenuate hepatic lipogenesis and stress-induced liver injury. These findings illustrate a novel adipose-hepatic hormonal axis mediated by NRG4 in metabolic signaling and disease pathogenesis. The non-parenchymal cells (NPCs) of the liver represent approximately 30% of total liver cells and play an important role in tissue homeostasis, hepatic metabolism, and disease progression. To delineate the landscape and regulation of liver cell heterogeneity, we performed single-cell RNA sequencing on NPCs isolated from healthy and diet-induced NASH mouse livers. This single-cell analysis revealed unprecedented insights into transcriptomic reprogramming of liver cells during NASH pathogenesis. Based on a body of preliminary data, we hypothesize that NRG4 signaling shapes the liver microenvironment to impinge on the progression of NASH and its associated liver disease. In this proposal, we plan to delineate how NRG4 regulates the transcriptomic and functional properties of liver cells at single-cell resolution. We will determine the mechanisms and significance of the regulation of hepatic immune cell landscape by NRG4 in mediating its effects on NASH pathogenesis. Finally, we plan to assess the therapeutic potential of targeting NRG4 for the treatment of metabolic liver disease.