biostudies-literatureHelsley RNNational Center for Advancing Translational SciencesNational Center for Research ResourcesAlnylam PharmaceuticalsNICHD NIH HHSNCATS NIH HHSNIDDK NIH HHSNASPGHAN FoundationNCI NIH HHSNational Institutes of HealthNIGMS NIH HHSNIH HHS25-42https://www.ebi.ac.uk/biostudies/studies/S-EPMC10679901biostudies-literatureUnknown79(1)<h4>Background & aims</h4>The consumption of sugar and a high-fat diet (HFD) promotes the development of obesity and metabolic dysfunction. Despite their well-known synergy, the mechanisms by which sugar worsens the outcomes associated with a HFD are largely elusive.<h4>Methods</h4>Six-week-old, male, C57Bl/6 J mice were fed either chow or a HFD and were provided with regular, fructose- or glucose-sweetened water. Moreover, cultured AML12 hepatocytes were engineered to overexpress ketohexokinase-C (KHK-C) using a lentivirus vector, while CRISPR-Cas9 was used to knockdown CPT1α. The cell culture experiments were complemented with in vivo studies using mice with hepatic overexpression of KHK-C and in mice with liver-specific CPT1α knockout. We used comprehensive metabolomics, electron microsJournal of hepatologyKetohexokinase-C regulates global protein acetylation to decrease carnitine palmitoyltransferase 1a-mediated fatty acid oxidation.PMC10679901K01 DK128022R01 DK121967UL1TR001998K12 HD000850P30 GM127211K01DK128022P30 DK036836T32 CA165990UL1 TR001998S10 OD0286541S10 OD028654Sun RCSoftic SMeyer JGHelsley RNRose JSchilling BBons JRomero MDMKahn CRKing CDHerrero LConroy LRPark SHSullivan PGVekaria HJfalseKetohexokinase-C regulates global protein acetylation to decrease carnitine palmitoyltransferase 1a-mediated fatty acid oxidation.<h4>Background & aims</h4>The consumption of sugar and a high-fat diet (HFD) promotes the development of obesity and metabolic dysfunction. Despite their well-known synergy, the mechanisms by which sugar worsens the outcomes associated with a HFD are largely elusive.<h4>Methods</h4>Six-week-old, male, C57Bl/6 J mice were fed either chow or a HFD and were provided with regular, fructose- or glucose-sweetened water. Moreover, cultured AML12 hepatocytes were engineered to overexpress ketohexokinase-C (KHK-C) using a lentivirus vector, while CRISPR-Cas9 was used to knockdown CPT1α. The cell culture experiments were complemented with in vivo studies using mice with hepatic overexpression of KHK-C and in mice with liver-specific CPT1α knockout. We used comprehensive metabolomics, electron micros2023-01-01T00:00:00Z2023 Jul2025-04-22T18:09:17.742Z2025-04-06T02:21:43.819ZS-EPMC106799013682247910.1016/j.jhep.2023.02.010