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The small intestine shields the liver from fructose-induced steatosis
- Source :
- Nat Metab, Nature metabolism, vol 2, iss 7
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- Per capita fructose consumption has increased 100-fold over the last century1. Epidemiological studies suggest that excessive fructose consumption, and especially consumption of sweet drinks, is associated with hyperlipidaemia, non-alcoholic fatty liver disease, obesity and diabetes2–7. Fructose metabolism begins with its phosphorylation by the enzyme ketohexokinase (KHK), which exists in two alternatively spliced forms8. The more active isozyme, KHK-C, is expressed most strongly in the liver, but also substantially in the small intestine9,10 where it drives dietary fructose absorption and conversion into other metabolites before fructose reaches the liver11–13. It is unclear whether intestinal fructose metabolism prevents or contributes to fructose-induced lipogenesis and liver pathology. Here we show that intestinal fructose catabolism mitigates fructose-induced hepatic lipogenesis. In mice, intestine-specific KHK-C deletion increases dietary fructose transit to the liver and gut microbiota and sensitizes mice to fructose’s hyperlipidaemic effects and hepatic steatosis. In contrast, intestine-specific KHK-C overexpression promotes intestinal fructose clearance and decreases fructose-induced lipogenesis. Thus, intestinal fructose clearance capacity controls the rate at which fructose can be safely ingested. Consistent with this, we show that the same amount of fructose is more strongly lipogenic when drunk than eaten, or when administered as a single gavage, as opposed to multiple doses spread over 45 min. Collectively, these data demonstrate that fructose induces lipogenesis when its dietary intake rate exceeds the intestinal clearance capacity. In the modern context of ready food availability, the resulting fructose spillover drives metabolic syndrome. Slower fructose intake, tailored to intestinal capacity, can mitigate these consequences. Modulating the capacity of the intestinal epithelium to catabolize fructose is shown to alter fructose-induced lipogenesis in the mouse liver, suggesting that fructose clearance in the small intestine protects from steatosis.
- Subjects :
- Endocrinology, Diabetes and Metabolism
Administration, Oral
Fatty Acids, Nonesterified
Gut flora
Small
Transgenic
Oral and gastrointestinal
Mice
chemistry.chemical_compound
Intestine, Small
2.1 Biological and endogenous factors
Aetiology
Metabolic Syndrome
Mice, Knockout
biology
Chemistry
Liver Disease
Fatty Acids
Fatty liver
Intestine
medicine.anatomical_structure
Administration
Lipogenesis
Oral
medicine.medical_specialty
Knockout
Chronic Liver Disease and Cirrhosis
Hyperlipidemias
Mice, Transgenic
Context (language use)
Fructose
Article
Fructokinases
Acetyl Coenzyme A
Physiology (medical)
Internal medicine
Internal Medicine
medicine
Animals
Humans
Nutrition
Catabolism
Prevention
Cell Biology
medicine.disease
biology.organism_classification
Small intestine
Diet
Gastrointestinal Microbiome
Fatty Liver
Endocrinology
Nonesterified
Steatosis
Digestive Diseases
Subjects
Details
- ISSN :
- 25225812
- Volume :
- 2
- Database :
- OpenAIRE
- Journal :
- Nature Metabolism
- Accession number :
- edsair.doi.dedup.....96e0aea69e9f420826a643e8e8a6b105