Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis

Research output: Contribution to journalArticlepeer-review

Authors

  • Kae Matsuda
  • Hitomi Ogino
  • Hiroaki Yashiro
  • Jason Pickens
  • Ryan E. Feaver
  • Banumathi K. Cole
  • Stephen A. Hoang
  • Mark J. Lawson
  • Matthew Olson
  • Robert A. Figler
  • John E. Reardon
  • Nobuhiro Nishigaki
  • Brian R. Wamhoff
  • Derek M. Erion
  • Trish Lalor

Abstract

Background and Aims
It is estimated that Non-Alcoholic Fatty Liver Disease (NAFLD) may affect up to 25% of the adult population worldwide presenting an enormous challenge for healthcare providers and significant mortality risk for those affected. Increasing evidence highlights dietary fructose as a major driver of NAFLD pathogenesis, the majority of which is cleared on first pass through the hepatic circulation by enzymatic phosphorylation to fructose-1-phosphate via ketohexokinase (KHK) enzyme. Without a current approved therapy, disease management emphasizes lifestyle interventions, but few patients adhere to such strategies. New targeted therapies are urgently required.
Methods
We have used a unique combination of human liver specimens, a murine dietary model of NAFLD and human multicellular coculture systems to understand the hepatocellular consequences of fructose administration. We have also performed a detailed NMR-based metabolic tracing of the fate of isotopically-labelled fructose upon administration to the human liver.
Results
Expression of KHK isoforms is found in multiple human hepatic cell types, although hepatocyte expression predominates. KHK-KO mice show a reduction in serum transaminase, reduced steatosis and altered fibrogenic response on Amylin diet. Human cocultures exposed to fructose exhibit steatosis and activation of lipogenic and fibrogenic gene expression which were reduced by pharmacological inhibition of KHK activity. Analysis of human livers exposed to 13C-labelled fructose confirmed the steatosis, and associated effects were due to accumulation of lipogenic precursors such as glycerol and enhanced glycolytic activity. All of these were dose-dependently reduced by administration of KHK inhibitor.
Conclusions
We have provided pre-clinical evidence using human livers to support use of KHK inhibition to improve steatosis, fibrosis and inflammation in the context of NAFLD.
Lay Summary
We have used a mouse model, human cells and liver tissue to test how exposure to fructose can cause the liver to store excess fat and become damaged and scarred. We have then inhibited a key enzyme within the liver that is responsible for fructose metabolism. Our findings show that inhibition of fructose metabolism reduces liver injury and fibrosis in mouse and human livers and thus this may represent a potential route for treating patients with fatty liver disease in the future.

Details

Original languageEnglish
Article number100217
JournalJHEP Reports
Volume2020
Publication statusPublished - 20 Nov 2020

Keywords

  • treatment, NAS, fibrosis, fructose, metabolism, NAFLD