Mutations of NRG4 Contribute to the Pathogenesis of Nonalcoholic Fatty Liver Disease and Related Metabolic Disorders

Neuregulin 4 (Nrg4), an adipose tissue–enriched endocrine factor, participates in adipocyte-to-hepatocyte communication, eliciting beneficial metabolic effects in nonalcoholic fatty liver disease (NAFLD). We evaluate the physiological roles of NRG4 in humans and unravel the role of NRG4 variants in the pathogenesis of NAFLD and related metabolic disorders. We identified two rare missense mutations—p.R44H and p.E47Q—in the NRG4 EGF-like domain by whole-exome sequencing in 224 severely obese subjects and exome genotyping in 2,388 subjects from the Shanghai Obesity Study. The overexpression animal models showed that wild-type (WT) Nrg4 could attenuate high-fat diet–induced hepatic lipogenesis and improve energy metabolism. Nrg4 E47Q enhanced the protective effect, whereas Nrg4 R44H lost this function. Unlike Nrg4 R44H, Nrg4 E47Q activated the phosphorylation of ErbB4 and negatively regulated de novo lipogenesis through the ErbB4-STAT5-SREBP-1C pathway. The surface plasmon resonance experiments revealed a higher affinity of E47Q Nrg4 than WT to bind ErbB4, while R44H showed no binding. In conclusion, the study suggests that genetic variations in NRG4 could produce mutant proteins with aberrant functions and that impaired or enhanced Nrg4 function could be either a risk factor or a protective factor for NAFLD and associated metabolic disorders.