Fh1-KO Mouse

Fh1, which stands for fumarate hydratase 1, is a gene with significant biological functions. It is involved in reducing fumarate accumulation in hepatocytes. The Klf10-Fh1 axis is part of the cAMP/PKA/CREB pathway, and Fh1 plays a role in attenuating lipogenesis by decreasing the trimethyl (me3) levels of histone 3 lysine 4 (H3K4me3) on lipogenic genes promoters, thus influencing processes like free fatty acids (FFAs)-induced hepatocytes steatosis, apoptosis, insulin resistance, and the activation of macrophages and hepatic stellate cells [1].

In the context of non-alcoholic steatohepatitis (NASH), hepatocyte-specific knockout of Klf10 (Klf10LKO) in mice, which affects the Klf10-Fh1 axis, increases lipid accumulation, cell death, inflammation, and fibrosis in NASH diet-fed mice and reduces the protective effects of treadmill exercise against NASH. Conversely, hepatocyte-specific overexpression of Klf10 (Klf10LTG) works with exercise to reduce NASH in mice, highlighting the importance of the Klf10-Fh1 axis in the exercise-mediated amelioration of NASH [1].

In conclusion, Fh1, through its role in the Klf10-Fh1 axis, is crucial in regulating lipogenesis and has a significant impact on the development and amelioration of NASH. The use of gene knockout models in mice has been instrumental in uncovering these functions, providing insights into the molecular mechanisms underlying NASH and potential therapeutic targets for this disease.

References:

1. Luo, Hong-Yang, Mu, Wang-Jing, Chen, Min, Chen, Hu-Min, Guo, Liang. 2024. Hepatic Klf10-Fh1 axis promotes exercise-mediated amelioration of NASH in mice. In Metabolism: clinical and experimental, 155, 155916. doi:10.1016/j.metabol.2024.155916. https://pubmed.ncbi.nlm.nih.gov/38615945/