RGD Reference Report - Ketohexokinase knockout mice, a model for essential fructosuria, exhibit altered fructose metabolism and are protected from diet-induced metabolic defects. - Rat Genome Database
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Ketohexokinase knockout mice, a model for essential fructosuria, exhibit altered fructose metabolism and are protected from diet-induced metabolic defects.

Authors: Miller, Corin O  Yang, Xiaodong  Lu, Ku  Cao, Jin  Herath, Kithsiri  Rosahl, Thomas W  Askew, Roger  Pavlovic, Guillaume  Zhou, Gaochao  Li, Cai  Akiyama, Taro E 
Citation: Miller CO, etal., Am J Physiol Endocrinol Metab. 2018 Sep 1;315(3):E386-E393. doi: 10.1152/ajpendo.00027.2018. Epub 2018 Jun 5.
RGD ID: 13782360
Pubmed: (View Article at PubMed) PMID:29870677
DOI: Full-text: DOI:10.1152/ajpendo.00027.2018

Fructose consumption in humans and animals has been linked to enhanced de novo lipogenesis, dyslipidemia, and insulin resistance. Hereditary deficiency of ketohexokinase (KHK), the first enzymatic step in fructose metabolism, leads to essential fructosuria in humans, characterized by elevated levels of blood and urinary fructose following fructose ingestion but is otherwise clinically benign. To address whether KHK deficiency is associated with altered glucose and lipid metabolism, a Khk knockout (KO) mouse line was generated and characterized. NMR spectroscopic analysis of plasma following ingestion of [6-13C] fructose revealed striking differences in biomarkers of fructose metabolism. Significantly elevated urine and plasma 13C-fructose levels were observed in Khk KO vs. wild-type (WT) control mice, as was reduced conversion of 13C-fructose into plasma 13C-glucose and 13C-lactate. In addition, the observation of significant levels of fructose-6-phosphate in skeletal muscle tissue of Khk KO, but not WT, mice suggests a potential mechanism, whereby fructose is metabolized via muscle hexokinase in the absence of KHK. Khk KO mice on a standard chow diet displayed no metabolic abnormalities with respect to ambient glucose, glucose tolerance, body weight, food intake, and circulating trigylcerides, ß-hydroxybutyrate, and lactate. When placed on a high-fat and high-fructose (HF/HFruc) diet, Khk KO mice had markedly reduced liver weight, triglyceride levels, and insulin levels. Together, these results suggest that Khk KO mice may serve as a good model for essential fructosuria in humans and that inhibition of KHK offers the potential to protect from diet-induced hepatic steatosis and insulin resistance.

Annotation

Disease Annotations    

Objects Annotated

Genes (Rattus norvegicus)
Khk  (ketohexokinase)

Genes (Mus musculus)
Khk  (ketohexokinase)

Genes (Homo sapiens)
KHK  (ketohexokinase)


Additional Information