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

Emma L. Shepherd, Raquel Saborano, Ellie Northall, 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, Ulrich L. Günther, Gideon Hirschfield, Derek M. Erion, Patricia F. Lalor*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background & Aims: Increasing evidence highlights dietary fructose as a major driver of non-alcoholic fatty liver disease (NAFLD) pathogenesis, the majority of which is cleared on first pass through the hepatic circulation by enzymatic phosphorylation to fructose-1-phosphate via the ketohexokinase (KHK) enzyme. Without a current approved therapy, disease management emphasises 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 co-culture systems to understand the hepatocellular consequences of fructose administration. We have also performed a detailed nuclear magnetic resonance-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 knockout mice show a reduction in serum transaminase, reduced steatosis and altered fibrogenic response on an Amylin diet. Human co-cultures 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 that steatosis, and associated effects, resulted from the accumulation of lipogenic precursors (such as glycerol) and enhanced glycolytic activity. All of these were dose-dependently reduced by administration of a KHK inhibitor. Conclusions: We have provided preclinical evidence using human livers to support the 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.

Original languageEnglish
Article number100217
Number of pages13
JournalJHEP Reports
Volume3
Issue number2
Early online date20 Nov 2020
DOIs
Publication statusPublished - Apr 2021

Bibliographical note

© 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Funding Information:
This study includes independent research supported by the Birmingham National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, based at the University of Birmingham. The views expressed are those of the authors and not necessarily those of the NHS, the National Institute of Health Research or the Department of Health and Social Care. The work was part funded by a collaborative research grant to the University of Birmingham from Takeda Pharmaceuticals Inc. Both parties were involved in experimental design/data generation, and manuscript drafting.

Keywords

  • Fibrosis
  • Fructose
  • Metabolism
  • NAFLD
  • NASH
  • Treatment

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