Khk, short for ketohexokinase, is a key enzyme in fructose metabolism. It catalyzes the first step of fructolysis, phosphorylating fructose to fructose-1-phosphate. This enzyme plays a crucial role in the regulation of metabolic pathways related to lipogenesis, fatty acid oxidation, and glycolysis, and is thus of great biological importance in the context of metabolic diseases and cancer [1,2,3,4,5,6]. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, are valuable tools for studying its functions.

In KO/CKO mouse models and other related experiments, inhibition of Khk has shown promising results. In rats, inhibition of Khk using PF-06835919 prevented fructose-induced hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis, reversing features of metabolic dysfunction seen in type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH). This was associated with reduced de novo lipogenesis (DNL) and inactivation of the lipogenic transcription factor carbohydrate response element-binding protein (ChREBP) [4]. In diet-induced and genetic models of non-alcoholic fatty liver disease (NAFLD), liver-specific knockdown of Khk-C improved the NAFLD activity score and affected the hepatic transcriptome [3]. In oesophageal squamous cell carcinoma (ESCC), knockdown of KHK-A, a peripheral isoform of Khk, modulated cell cycle and inhibited cell proliferation, suggesting its role as a potential target for ESCC diagnosis and therapy [7].

In conclusion, Khk is essential in fructose metabolism, regulating key metabolic pathways. Model-based research, especially through Khk KO/CKO mouse models, has revealed its significant roles in metabolic diseases like T2D, NASH, and NAFLD, as well as in cancer, such as ESCC. These findings provide important insights into the mechanisms of these diseases and potential therapeutic targets.

References:

1. Herman, Mark A, Birnbaum, Morris J. 2021. Molecular aspects of fructose metabolism and metabolic disease. In Cell metabolism, 33, 2329-2354. doi:10.1016/j.cmet.2021.09.010. https://pubmed.ncbi.nlm.nih.gov/34619074/

2. Helsley, Robert N, Park, Se-Hyung, Vekaria, Hemendra J, Kahn, C Ronald, Softic, Samir. 2023. Ketohexokinase-C regulates global protein acetylation to decrease carnitine palmitoyltransferase 1a-mediated fatty acid oxidation. In Journal of hepatology, 79, 25-42. doi:10.1016/j.jhep.2023.02.010. https://pubmed.ncbi.nlm.nih.gov/36822479/

3. Park, Se-Hyung, Helsley, Robert N, Fadhul, Taghreed, Kahn, C Ronald, Softic, Samir. 2023. Fructose induced KHK-C can increase ER stress independent of its effect on lipogenesis to drive liver disease in diet-induced and genetic models of NAFLD. In Metabolism: clinical and experimental, 145, 155591. doi:10.1016/j.metabol.2023.155591. https://pubmed.ncbi.nlm.nih.gov/37230214/

4. Gutierrez, Jemy A, Liu, Wei, Perez, Sylvie, Birnbaum, Morris J, Tesz, Gregory J. 2021. Pharmacologic inhibition of ketohexokinase prevents fructose-induced metabolic dysfunction. In Molecular metabolism, 48, 101196. doi:10.1016/j.molmet.2021.101196. https://pubmed.ncbi.nlm.nih.gov/33667726/

5. Softic, Samir, Stanhope, Kimber L, Boucher, Jeremie, Johnson, Richard J, Kahn, C Ronald. 2020. Fructose and hepatic insulin resistance. In Critical reviews in clinical laboratory sciences, 57, 308-322. doi:10.1080/10408363.2019.1711360. https://pubmed.ncbi.nlm.nih.gov/31935149/

6. Krause, Nils, Wegner, Andre. 2020. Fructose Metabolism in Cancer. In Cells, 9, . doi:10.3390/cells9122635. https://pubmed.ncbi.nlm.nih.gov/33302403/

7. Yang, Jie, Yang, Senlin, Wang, Qi, Wang, Huimin, Fu, Xiaohong. 2020. KHK-A promotes the proliferation of oesophageal squamous cell carcinoma through the up-regulation of PRPS1. In Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology, 22, 40-46. doi:10.1016/j.ajg.2020.08.007. https://pubmed.ncbi.nlm.nih.gov/32928708/