Nr1h4-flox Mouse

Nr1h4, also known as Farnesoid X receptor (FXR), is a nuclear receptor involved in metabolic and inflammatory regulation [1,2,3,4,5,7]. It plays a key role in bile acid and lipid homeostasis, and is involved in regulating numerous metabolic pathways via activation of the nuclear farnesoid X receptor and the G protein-coupled membrane receptor 5 [2,3,4].

In Parkinson's disease (PD), Nr1h4 was found to be down-regulated. In vitro experiments showed that Nr1h4 knockdown led to inflammatory response, reactive oxygen species generation and astrocytes activation, while overexpression had the opposite effects. Nr1h4 manipulated neuroinflammation in a CEBPβ/NF-κB dependent manner, and pharmacological activation of Nr1h4 via Obeticholic acid ameliorated neuroinflammation and promoted neuronal survival [1]. In the MPTP mouse model of PD, activation of Nr1h4 by its ligand GW4064 reduced MPP +-induced dissipation of mitochondrial membrane potential and ROS generation in neuronal cells, protected mice from ER stress, dopaminergic cell death, and functional deficits [6]. In non-alcoholic fatty liver disease (NAFLD), the NR1H4 rs35724 CC genotype was protective against severity of steatosis, steatohepatitis and severity of fibrosis. The C allele was associated with higher total circulating cholesterol and higher hepatic mRNA levels of FXR [5].

In conclusion, Nr1h4 is crucial for maintaining metabolic and inflammatory homeostasis. Studies using models such as in vitro cell experiments and mouse models of PD and NAFLD have revealed its protective roles in these disease conditions. These findings highlight the importance of Nr1h4 in understanding the mechanisms of related diseases and potentially developing new therapeutic strategies.