Knockdown of ketohexokinase versus inhibition of its kinase activity exert divergent effects on fructose metabolism

• DOI: 10.1172/jci.insight.184396
• Publication Date: 2024-10-17T16:00:36Z
• Authors: Se-Hyung Park; Taghreed Fadhul; Lindsey R. Conroy; Harrison A Clarke; Ramon C. Sun; Kristina Wallenius; Jeremie Boucher; Gavin O’Mahony; Alessandro Boianelli; Marie Persson; Sunhee Jung; Cholsoon Jang; Analia S. Loria; Genesee J. Martinez; Zachary A. Kipp; Evelyn A. Bates; Terry D. Hinds; Senad Divanovic; Samir Softic
• Keywords: Carbohydrate Metabolism

Excessive fructose intake is a risk factor for the development of obesity and its complications. Targeting ketohexokinase (KHK), first enzyme metabolism, has been investigated management MASLD. We compared effects systemic, small molecule inhibitor KHK enzymatic activity to hepatocyte-specific, GalNAc-siRNA mediated knockdown in mice on HFD. measured activity, extensively quantified glycogen accumulation, performed RNAseq analysis, enumerated hepatic metabolites using mass spectrometry. Both siRNA led an improvement liver steatosis, however, via substantially different mechanisms. decreased de novo lipogenesis pathway, whereas increased fatty acid oxidation pathway. Moreover, completely prevented fructolysis improved glucose tolerance. Conversely, only partially reduced fructolysis, but it also targeted triokinase, mediating third step fructolysis. This leads accumulation fructose-1 phosphate, resulting hepatomegaly, impaired Overexpression wild-type, not kinase-dead cultured hepatocytes hepatocyte injury when treated with fructose. The differences between inhibition are, part, explained by kinase-dependent independent metabolism.