HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD.

Publisher: Springer International Country of Publication: Germany NLM ID: 9504370 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-1440 (Electronic) Linking ISSN: 09462716 NLM ISO Abbreviation: J Mol Med (Berl) Subsets: MEDLINE

Publication: Berlin : Springer International
Original Publication: Berlin : Springer, c1994-

Carbohydrate Metabolism*/genetics ; Thermogenesis*/genetics; Fructose/*metabolism ; Hypoxia-Inducible Factor-Proline Dioxygenases/*antagonists & inhibitors ; Non-alcoholic Fatty Liver Disease/*etiology ; Non-alcoholic Fatty Liver Disease/*metabolism; Animals ; Biomarkers ; Diet ; Disease Models, Animal ; Disease Susceptibility ; Hypoxia-Inducible Factor-Proline Dioxygenases/genetics ; Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism ; Lipid Metabolism ; Lipids/blood ; Liver/metabolism ; Liver/pathology ; Mice ; Mice, Transgenic ; Non-alcoholic Fatty Liver Disease/pathology

Non-alcoholic fatty liver disease (NAFLD) parallels the global obesity epidemic with unmet therapeutic needs. We investigated whether inhibition of hypoxia-inducible factor prolyl 4-hydroxylase-2 (HIF-P4H-2), a key cellular oxygen sensor whose inhibition stabilizes HIF, would protect from NAFLD by subjecting HIF-P4H-2-deficient (Hif-p4h-2 ^gt/gt ) mice to a high-fat, high-fructose (HFHF) or high-fat, methionine-choline-deficient (HF-MCD) diet. On both diets, the Hif-p4h-2 ^gt/gt mice gained less weight and had less white adipose tissue (WAT) and its inflammation, lower serum cholesterol levels, and lighter livers with less steatosis and lower serum ALT levels than the wild type (WT). The intake of fructose in majority of the Hif-p4h-2 ^gt/gt tissues, including the liver, was 15-35% less than in the WT. We found upregulation of the key fructose transporter and metabolizing enzyme mRNAs, Slc2a2, Khka, and Khkc, and higher ketohexokinase activity in the Hif-p4h-2 ^gt/gt small intestine relative to the WT, suggesting enhanced metabolism of fructose in the former. On the HF-MCD diet, the Hif-p4h-2 ^gt/gt mice showed more browning of the WAT and increased thermogenesis. A pharmacological pan-HIF-P4H inhibitor protected WT mice on both diets against obesity, metabolic dysfunction, and liver damage. These data suggest that HIF-P4H-2 inhibition could be studied as a novel, comprehensive treatment strategy for NAFLD. KEY MESSAGES: • HIF-P4H-2 inhibition enhances intestinal fructose metabolism protecting the liver. • HIF-P4H-2 inhibition downregulates hepatic lipogenesis. • Induced browning of WAT and increased thermogenesis can also mediate protection. • HIF-P4H-2 inhibition offers a novel, comprehensive treatment strategy for NAFLD.

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Keywords: Fructose; HIF; Hypoxia response; Metabolism; NAFLD

0 (Biomarkers)
0 (Lipids)
30237-26-4 (Fructose)
EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)

Date Created: 20200417 Date Completed: 20210607 Latest Revision: 20210607

20221213

PMC7220983

10.1007/s00109-020-01903-0

32296880