Nr1h4, also known as the 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 activates transcriptional networks and signaling cascades controlling genes involved in bile acid, lipid and carbohydrate metabolism, energy expenditure, and inflammation [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. RNA-seq on astrocytes revealed that Nr1h4 manipulated neuroinflammation in a CEBPβ/NF-κB dependent manner. 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 ameliorated 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 metabolic and inflammatory regulation, especially in maintaining bile acid and lipid homeostasis. Studies using mouse models, such as those for PD and NAFLD, have revealed its protective role in these disease conditions. These findings highlight the importance of Nr1h4 in understanding the mechanisms of relevant diseases and developing potential therapeutic strategies.

References:

1. Li, Jingwen, Liu, Hanshu, Hu, Xinyu, Wang, Tao, Xiong, Nian. 2024. NR1H4 ameliorates Parkinson's disease via inhibiting astrocyte activation and neuroinflammation in a CEBPβ/NF-κB dependent manner. In International immunopharmacology, 142, 113087. doi:10.1016/j.intimp.2024.113087. https://pubmed.ncbi.nlm.nih.gov/39241522/

2. Bull, Laura N, Thompson, Richard J. 2018. Progressive Familial Intrahepatic Cholestasis. In Clinics in liver disease, 22, 657-669. doi:10.1016/j.cld.2018.06.003. https://pubmed.ncbi.nlm.nih.gov/30266155/

3. Wahlström, Annika, Sayin, Sama I, Marschall, Hanns-Ulrich, Bäckhed, Fredrik. 2016. Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism. In Cell metabolism, 24, 41-50. doi:10.1016/j.cmet.2016.05.005. https://pubmed.ncbi.nlm.nih.gov/27320064/

4. Chávez-Talavera, Oscar, Tailleux, Anne, Lefebvre, Philippe, Staels, Bart. 2017. Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease. In Gastroenterology, 152, 1679-1694.e3. doi:10.1053/j.gastro.2017.01.055. https://pubmed.ncbi.nlm.nih.gov/28214524/

5. Grimaudo, Stefania, Dongiovanni, Paola, Pihlajamäki, Jussi, Valenti, Luca, Petta, Salvatore. 2021. NR1H4 rs35724 G>C variant modulates liver damage in nonalcoholic fatty liver disease. In Liver international : official journal of the International Association for the Study of the Liver, 41, 2712-2719. doi:10.1111/liv.15016. https://pubmed.ncbi.nlm.nih.gov/34268860/

6. Ahuja, Nancy, Gupta, Shalini, Arora, Rashmi, Kumar, Sumit, Gupta, Pawan. 2024. Nr1h4 and Thrb ameliorate ER stress and provide protection in the MPTP mouse model of Parkinson's. In Life science alliance, 7, . doi:10.26508/lsa.202302416. https://pubmed.ncbi.nlm.nih.gov/38609183/

7. Ma, Yingxuan, Lu, Li, Tan, Kezhe, Mo, Jiayu, Gong, Zhenhua. 2022. Reduced peroxisome proliferator-activated receptor-α and bile acid nuclear receptor NR1H4/FXR may affect the hepatic immune microenvironment of biliary atresia. In Frontiers in immunology, 13, 875593. doi:10.3389/fimmu.2022.875593. https://pubmed.ncbi.nlm.nih.gov/36090996/