Hnf4a, short for hepatocyte nuclear factor 4 alpha, encodes a transcription factor crucial for the development and function of the pancreas and liver [3]. It is involved in multiple biological processes such as cell differentiation, metabolism regulation, and maintaining liver function. Mutations in Hnf4a have been linked to Maturity Onset Diabetes of the Young (MODY), type 2 diabetes, and liver-related diseases, highlighting its significance in disease-associated pathways [3,4]. Genetic models like KO/CKO mouse models are valuable tools for studying its functions.

In mouse models, repeated in vivo delivery of LNP-encapsulated Hnf4a mRNA robustly inhibited fibrogenesis in 4 independent mouse models of hepatotoxin-and cholestasis-induced liver fibrosis. Mechanistically, paraoxonase 1 was found to be a direct target of Hnf4a, contributing to Hnf4a-mediated attenuation of liver fibrosis via modulation of liver macrophages and hepatic stellate cells. This provides pre-clinical evidence for the applicability of Hnf4a mRNA therapeutics for liver fibrosis treatment [1]. In human pluripotent stem cell-derived kidney organoids, the loss of Hnf4a, but not Hnf4g, impaired reabsorption-related molecule expression and microvilli formation in human proximal tubules, suggesting its role in human nephrogenesis [2].

In summary, Hnf4a is essential for normal development and function in the pancreas and liver. Its functions in metabolism, cell differentiation, and disease-related processes have been revealed through model-based research. KO/CKO mouse models have contributed significantly to understanding its role in liver fibrosis and potentially other disease areas such as kidney development [1,2].

References:

1. Yang, Taihua, Poenisch, Marion, Khanal, Rajendra, Ott, Michael, Sharma, Amar Deep. 2021. Therapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model. In Journal of hepatology, 75, 1420-1433. doi:10.1016/j.jhep.2021.08.011. https://pubmed.ncbi.nlm.nih.gov/34453962/

2. Yoshimura, Yasuhiro, Muto, Yoshiharu, Omachi, Kohei, Miner, Jeffrey H, Humphreys, Benjamin D. 2023. Elucidating the Proximal Tubule HNF4A Gene Regulatory Network in Human Kidney Organoids. In Journal of the American Society of Nephrology : JASN, 34, 1672-1686. doi:10.1681/ASN.0000000000000197. https://pubmed.ncbi.nlm.nih.gov/37488681/

3. Ng, Natasha Hui Jin, Ghosh, Soumita, Bok, Chek Mei, Hoon, Shawn, Teo, Adrian Kee Keong. 2024. HNF4A and HNF1A exhibit tissue specific target gene regulation in pancreatic beta cells and hepatocytes. In Nature communications, 15, 4288. doi:10.1038/s41467-024-48647-w. https://pubmed.ncbi.nlm.nih.gov/38909044/

4. Love-Gregory, Latisha, Permutt, M Alan. . HNF4A genetic variants: role in diabetes. In Current opinion in clinical nutrition and metabolic care, 10, 397-402. doi:. https://pubmed.ncbi.nlm.nih.gov/17563455/