Abstract

Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened beverages are risk-factors for NAFLD development, but how their combined intake promotes progression to a more severe form of liver injury is unknown. Here we show that fructose metabolism via ketohexokinase (KHK) C isoform leads to unresolved endoplasmic reticulum (ER) stress when coupled with a HFD intake. Conversely, a liver-specific knockdown of KHK in mice consuming fructose on a HFD is adequate to improve the NAFLD activity score and exert a profound effect on the hepatic transcriptome. Overexpression of KHK-C in cultured hepatocytes is sufficient to induce ER stress in fructose free media. Upregulation of KHK-C is also observed in mice with genetically induced obesity or metabolic dysfunction, whereas KHK knockdown in these mice improves metabolic function. Additionally, in over 100 inbred strains of male or female mice hepatic KHK expression correlates positively with adiposity, insulin resistance, and liver triglycerides. Similarly, in 241 human subjects and their controls, hepatic Khk expression is upregulated in early, but not late stages of NAFLD. In summary, we describe a novel role of KHK-C in triggering ER stress, which offers a mechanistic understanding of how the combined intake of fructose and a HFD propagates the development of metabolic complications.

Document Type

Article

Publication Date

8-2023

Notes/Citation Information

0026-0495/© 2023 Elsevier Inc. All rights reserved.

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.metabol.2023.155591

Funding Information

Alnylam Pharmaceuticals, Inc., sponsored the research with grant funding and performed KHK knockdown experiment at their institution. JW, LN, HCT and KF are employees of Alnylam Pharmaceuticals. Experimental Pathology Laboratories, Inc., was hired by Alnylam to objectively grade liver histology. This work was also supported by NASPGHAN Foundation Young Investigator Award, Pediatric Scientist Development Program Award (HD000850) and COCVD Pilot and Feasibility Grant (GM127211) awarded to SS; K01DK128022 and UL1TR001998 to RNH; R01 DK067536 to RNK; R01DK099222, Department of Defense grant W81XWH2010392, & CCRF Endowed Scholar Award to SD and R01 DK117850, and R01 HL147883 grants to AJL. We acknowledge the support of instrumentation for the Orbitrap Eclipse Tribrid from the NCRR shared instrumentation grant 1S10 OD028654 to B.S. Rashmi Nemade, Ph.D. of BioMedText, Inc. helped edit the manuscript.

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