Bdh1, or beta-hydroxybutyrate dehydrogenase 1, is the rate-limiting enzyme in ketone metabolism, playing a crucial role in the conversion between acetoacetate and β-hydroxybutyrate. The presence of β-hydroxybutyrate is essential for initiating lysine β-hydroxybutyrylation (Kbhb) modifications, and histone Kbhb at the H3K9 site is related to transcriptional activation [1].

In various disease models, Bdh1 shows distinct effects. In striated muscles of mice, Bdh1 deficiency impairs the optimization of fatty acid oxidation (FAO) efficiency and exercise tolerance during acute fasting, indicating its importance in metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding [2]. In diabetic kidney disease (DKD) mouse models, Bdh1 is downregulated. Overexpression of Bdh1 protects renal tubular epithelial cells from glucotoxicity and lipotoxicity, reversing fibrosis, inflammation, and apoptosis in the kidneys of DKD mice [3]. In a MAFLD mouse model, Bdh1 knockdown in LO2 cells leads to ROS overproduction, while its overexpression protects cells from lipotoxicity, and AAV-mediated Bdh1 overexpression reverses hepatic function indexes, fibrosis, inflammation, and apoptosis in fatty livers from db/db mice [4]. Ablation of Bdh1 in T cells aggravates the manifestation of MASH and hinders the therapeutic efficacy of empagliflozin, a SGLT2 inhibitor [5]. In acute myeloid leukemia (AML), overexpression of Bdh1 inhibits the viability and proliferation of AML cells, and low Bdh1 expression predicts poor survival [6].

In conclusion, Bdh1 is essential in ketone metabolism and associated with multiple biological processes and disease conditions. Studies using gene knockout or conditional knockout mouse models have revealed its role in metabolic remodeling, protection against diabetic complications, liver-related diseases, and anti-tumor effects in AML. These findings contribute to understanding disease mechanisms and potentially developing new therapeutic strategies.

References:

1. Huang, Jingjing, Liang, Lu, Jiang, Shiyao, Cong, Li, Jiang, Yiqun. 2023. BDH1-mediated LRRC31 regulation dependent on histone lysine β-hydroxybutyrylation to promote lung adenocarcinoma progression. In MedComm, 4, e449. doi:10.1002/mco2.449. https://pubmed.ncbi.nlm.nih.gov/38098610/

2. Williams, Ashley S, Crown, Scott B, Lyons, Scott P, Zhang, Guo-Fang, Muoio, Deborah M. . Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding. In Cell metabolism, 36, 422-437.e8. doi:10.1016/j.cmet.2024.01.007. https://pubmed.ncbi.nlm.nih.gov/38325337/

3. Wan, Sheng-Rong, Teng, Fang-Yuan, Fan, Wei, Jiang, Zong-Zhe, Xu, Yong. 2023. BDH1-mediated βOHB metabolism ameliorates diabetic kidney disease by activation of NRF2-mediated antioxidative pathway. In Aging, 15, 13384-13410. doi:10.18632/aging.205248. https://pubmed.ncbi.nlm.nih.gov/38015723/

4. Xu, Bu-Tuo, Teng, Fang-Yuan, Wu, Qi, Xu, Yong, Jiang, Zong-Zhe. 2022. Bdh1 overexpression ameliorates hepatic injury by activation of Nrf2 in a MAFLD mouse model. In Cell death discovery, 8, 49. doi:10.1038/s41420-022-00840-w. https://pubmed.ncbi.nlm.nih.gov/35115498/

5. Liu, Wenhui, You, Danming, Lin, Jiayang, Yang, Wei, Zhang, Huijie. 2024. SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8+ T cell activation. In Cell metabolism, 36, 2245-2261.e6. doi:10.1016/j.cmet.2024.08.005. https://pubmed.ncbi.nlm.nih.gov/39243758/

6. Han, Fei, Zhao, Huanhuan, Lu, Jun, Wang, Qishan, Jiang, Xi. 2021. Anti-Tumor Effects of BDH1 in Acute Myeloid Leukemia. In Frontiers in oncology, 11, 694594. doi:10.3389/fonc.2021.694594. https://pubmed.ncbi.nlm.nih.gov/34150668/