The small intestine shields the liver from fructose-induced steatosis.

TitleThe small intestine shields the liver from fructose-induced steatosis.
Publication TypeJournal Article
Year of Publication2020
AuthorsJang, C, Wada, S, Yang, S, Gosis, B, Zeng, X, Zhang, Z, Shen, Y, Lee, G, Arany, Z, Rabinowitz, JD
JournalNat Metab
Date Published2020 Jul
KeywordsAcetyl Coenzyme A, Administration, Oral, Animals, Diet, Fatty Acids, Nonesterified, Fatty Liver, Fructokinases, Fructose, Gastrointestinal Microbiome, Humans, Hyperlipidemias, Intestine, Small, Lipogenesis, Metabolic Syndrome, Mice, Mice, Knockout, Mice, Transgenic

<p>Per capita fructose consumption has increased 100-fold over the last century. Epidemiological studies suggest that excessive fructose consumption, and especially consumption of sweet drinks, is associated with hyperlipidaemia, non-alcoholic fatty liver disease, obesity and diabetes. Fructose metabolism begins with its phosphorylation by the enzyme ketohexokinase (KHK), which exists in two alternatively spliced forms. The more active isozyme, KHK-C, is expressed most strongly in the liver, but also substantially in the small intestine where it drives dietary fructose absorption and conversion into other metabolites before fructose reaches the liver. 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.</p>

Alternate JournalNat Metab
PubMed ID32694791
PubMed Central IDPMC8020332
Grant ListDP1 DK113643 / DK / NIDDK NIH HHS / United States
P30 DK019525 / DK / NIDDK NIH HHS / United States
R01 DK107667 / DK / NIDDK NIH HHS / United States