Fructose Metabolism and Regulation of Extracellular Matrix Protein Gene Expression in Activated Macrophages
| Autor: | Peter M. Thompson, Xiaojing Liu, Arion Kennedy, Mareca Lodge, Denitra Breuer, Grace Scheidemantle |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Nutrition and Dietetics
Nutritional Immunology and Inflammation/Immunometabolism Chemistry Medicine (miscellaneous) Inflammation Fructose Metabolism Mitochondrion Cell biology Extracellular matrix Citric acid cycle chemistry.chemical_compound Extracellular Matrix Protein Gene Gene expression medicine medicine.symptom Food Science |
| Zdroj: | Curr Dev Nutr |
| Popis: | OBJECTIVES: Recently fructose has been linked to the development of Nonalcoholic Fatty Liver Disease (NAFLD), but the mechanisms behind the progression remain to be elucidated. Kupffer cells have been identified as regulators of hepatic inflammation and extracellular matrix (ECM) proteins. Activated macrophages are known to express tissue inhibitor of metalloproteinase (TIMP1), which inhibits matrix metalloproteinase 9 (MMP9) activity of reconstructing ECM which leads to fibrosis. In humans and mouse models, TIMP1 expression is positively correlated with the progression of NAFLD. Based on these findings, we hypothesize that fructose regulates TIMP1 gene expression in activated proinflammatory macrophages. METHODS: Using an in vitro model of J774 macrophages and primary Kupffer cells, cells were treated to induce an M1 phenotype in the presence of glucose or fructose. Cells were harvested for RNA and RT-PCR was conducted to measure ECM gene expression. Isolated Kupffer cells were collected from C57BL/6J mice fed a high fat diet (HFD) supplemented with 30% fructose or 30% glucose and analyzed for ECM expression. To examine fructose uptake and intra- and extracellular metabolites, mass spectrophotometry and nuclear magnetic resonance was conducted. RESULTS: Timp1 gene expression was significantly increased in J77.4 cells treated with fructose compared to glucose. Surprisingly, fructose treatment decreased Mmp9 gene expression. Likewise, fructose treatment increased TIMP1 protein expression in isolated Kupffer cells. In vivo, isolated hepatic macrophages from mice fed HF and high fructose diet had elevated Timp1 gene expression compared to mice fed high glucose diet. Extracellular levels of lactate decreased by 1.5-fold in fructose treated J77.4 cells compared to glucose. Metabolites involved in the TCA cycle and mitochondrial function were decreased when treated with fructose compared to glucose in non-activated macrophages. However, fructose treatment increased intracellular methanol and acetate levels in M1 macrophages compared to glucose. CONCLUSIONS: Our data suggest that fructose upregulates Timp1 expression and possibly decreases mitochondrial function while increasing acetate and methanol production, identifying new mechanisms by which fructose drives the progression of NAFLD. FUNDING SOURCES: Kenan Institute North Carolina University. |
| Databáze: | OpenAIRE |
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