(The) study for pathophysiological roles of NR1D1 in fatty liver disease

Abstract

The recent studies of nonalcoholic fatty liver diseases (NAFLD) caused by multiple steps actively involve studies of nuclear receptors which are useful as drug targets. Nuclear receptor subfamily 1, group D, member 1 (Nr1d1) is abundantly expressed in the metabolic tissues and organs such as adipose tissues, skeletal muscle, and liver, and specifically expressed in non- parenchymal cells such as hepatic stellate cells, macrophages, and T cells. Expressions of the Nr1d1 in various tissues and cells reflect its roles and functions, and Nr1d1 has been reported to contribute the adipocyte differentiation, muscle development, gluconeogenesis, inflammation and immune response. However, the role and function of NR1D1 in NAFLD was not clearly addressed. To clarify the role of NR1D1 in hepatic lipid metabolism and to understand the molecular pathogenesis of NAFLD, the Nr1d1 Δex3/4 mice, in which deletion of Nr1d1 exons 3 and 4 for a functional disruption was introduced, were generated by crossing Nr1d1 floxed mice with transgenic Zp3-Cre deleter mice. To induce NAFLD stage, the Nr1d1 Δex3/4 mice were challenged by a high fat diet (HFD), and the metabolic phenotypes that responded to these stimuli were observed. The Nr1d1 Δex3/4 mice displayed severe hepatic steatosis compared to the WT mice, and it resulted from the interaction effect between diet and genotype. In addition, to understand the potential molecular mechanism, the differential gene expression was profiled using microarray, and upstream factors and gene coexpression networks were predicted. Interestingly, neutrophils homeostasis and cAMP signaling pathways were affected by the interaction effect, and they were thought to elevate severity of hepatic steatosis in response of HFD-fed functional disruption of Nr1d1. In addition, CCAAT/enhancer-binding protein alpha and hepatocyte nuclear factor 4 alpha were predicted to tether the function of HFD-responsive Nr1d1 Δex3/4, and thyroid hormone-responsive (Thsrp) was a potential target gene of HFD-responsive Nr1d1 Δex3/4. Taken together, loss of transcriptional function of Nr1d1 was associated with deterioration in hepatic steatosis. The interaction between the Nr1d1 ex3/4 genotype with an HFD might mediate these phenotypic changes, probably through a nonclassical transcriptional function of Nr1d1.