biostudies-literatureUnknownPark SHNCATS NIH HHSNICHD NIH HHSNIDDK NIH HHSNHLBI NIH HHSNIGMS NIH HHSNIH HHSNon-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 increases endoplasmic reticulum (ER) stress in a dose dependent fashion, so when fructose is coupled with a HFD intake it leads to unresolved ER stress. Conversely, a liver-specific knockdown of KHK in C57BL/6J male mice consuming fructose on a HFD is adequate to improve the NAFLD activity score and exert a profound effect on the hepatic transcriptome. OverbioRxiv : the preprint server for biology2023.01.27.525605https://www.ebi.ac.uk/biostudies/studies/S-EPMC9900898biostudies-literatureFructose Induced KHK-C Increases ER Stress and Modulates Hepatic Transcriptome to Drive Liver Disease in Diet-Induced and Genetic Models of NAFLD.PMC9900898K01 DK128022R01 DK117850P30 GM127211K12 HD000850R01 HL147883UL1 TR001998R01 DK067536R01 DK099222S10 OD028654Softic SHelsley RNRose JFadhul TFujisaka STu HCSchilling BPan HDivanovic SBons JPan CKahn CRKing CDKulkarni RNLusis AJPark SHWilloughby JLSFitzgerald KGupta MNoetzli LKern PASolheim MHDreyfuss JMfalseFructose Induced KHK-C Increases ER Stress and Modulates Hepatic Transcriptome to Drive Liver Disease in Diet-Induced and Genetic Models of NAFLD.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 increases endoplasmic reticulum (ER) stress in a dose dependent fashion, so when fructose is coupled with a HFD intake it leads to unresolved ER stress. Conversely, a liver-specific knockdown of KHK in C57BL/6J male mice consuming fructose on a HFD is adequate to improve the NAFLD activity score and exert a profound effect on the hepatic transcriptome. Over2023-01-01T00:00:00Z2023 Jan2025-05-29T20:25:04.969Z2025-05-29T20:25:04.969ZS-EPMC99008983674775810.1101/2023.01.27.525605