Regulation of hepatic Sirt1 expression and lipid metabolism through TNF receptor signaling
The production of tumor necrosis factor -alpha (TNFα) has been associated with fatty liver disease (i.e, hepatosteatosis) for many years. In fact, cytokine production has been thought of as a consequence of hepatic lipid accumulation which then becomes a critical factor in the development of chronic...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1627433/full |
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| author | Ian N. Hines Samuel B. Stafford Blair U. Bradford Michael D. Wheeler |
| author_facet | Ian N. Hines Samuel B. Stafford Blair U. Bradford Michael D. Wheeler |
| author_sort | Ian N. Hines |
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| description | The production of tumor necrosis factor -alpha (TNFα) has been associated with fatty liver disease (i.e, hepatosteatosis) for many years. In fact, cytokine production has been thought of as a consequence of hepatic lipid accumulation which then becomes a critical factor in the development of chronic liver pathologies as well as in the pathogenesis of insulin resistance. The purpose of this study was to test the hypothesis that TNFα directly regulated lipid metabolism in liver. Wild type mice and mice lacking the receptor for TNFα (TNFR1-/-) were fed control diet or a choline-deficient diet. In addition to pro-inflammatory response, choline-deficient diet increased hepatic lipid accumulation and liver injury, serum triglyceride and insulin levels, as well as increased fasting glucose levels in wildtype mice but to a significantly lesser extent in TNFR1-/- mice. Liver perfusion and metabolic cage studies revealed that TNFR1-/- mice exhibited higher rates of lipid oxidation than wildtype mice. Importantly, TNFR1-/- mice have elevated hepatic expression of metabolic and circadian rhythm regulator SIRT1 in comparison to wild type mice. In isolated hepatocytes, TNF suppressed sirt1 expression while inducing expression of DBC1, a known inhibitor of sirt1 function and expression. These data suggest that TNFα and possibly other innate immune factors play a critical role in the development of hepatosteatosis and the onset of metabolic syndrome. This data also suggests an interplay among innate immunity, hepatic metabolism, and circadian rhythm in the pathogenesis of metabolic syndrome. |
| format | Article |
| id | doaj-art-3f03e19f29b04a1aaa02f9f5553b0dfd |
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| issn | 1664-3224 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
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| spelling | doaj-art-3f03e19f29b04a1aaa02f9f5553b0dfd2025-07-22T04:10:09ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-07-011610.3389/fimmu.2025.16274331627433Regulation of hepatic Sirt1 expression and lipid metabolism through TNF receptor signalingIan N. Hines0Samuel B. Stafford1Blair U. Bradford2Michael D. Wheeler3Department of Nutrition Science, East Carolina University, Greenville, NC, United StatesDepartment of Nutrition Science, East Carolina University, Greenville, NC, United StatesDepartment of Pharmacology, University of North Carolina, Chapel Hill, NC, United StatesDepartment of Nutrition Science, East Carolina University, Greenville, NC, United StatesThe production of tumor necrosis factor -alpha (TNFα) has been associated with fatty liver disease (i.e, hepatosteatosis) for many years. In fact, cytokine production has been thought of as a consequence of hepatic lipid accumulation which then becomes a critical factor in the development of chronic liver pathologies as well as in the pathogenesis of insulin resistance. The purpose of this study was to test the hypothesis that TNFα directly regulated lipid metabolism in liver. Wild type mice and mice lacking the receptor for TNFα (TNFR1-/-) were fed control diet or a choline-deficient diet. In addition to pro-inflammatory response, choline-deficient diet increased hepatic lipid accumulation and liver injury, serum triglyceride and insulin levels, as well as increased fasting glucose levels in wildtype mice but to a significantly lesser extent in TNFR1-/- mice. Liver perfusion and metabolic cage studies revealed that TNFR1-/- mice exhibited higher rates of lipid oxidation than wildtype mice. Importantly, TNFR1-/- mice have elevated hepatic expression of metabolic and circadian rhythm regulator SIRT1 in comparison to wild type mice. In isolated hepatocytes, TNF suppressed sirt1 expression while inducing expression of DBC1, a known inhibitor of sirt1 function and expression. These data suggest that TNFα and possibly other innate immune factors play a critical role in the development of hepatosteatosis and the onset of metabolic syndrome. This data also suggests an interplay among innate immunity, hepatic metabolism, and circadian rhythm in the pathogenesis of metabolic syndrome.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1627433/fullTNFαnon-alcoholic fatty liverSIRT1lipid metabolismfatty livercholine deficiency model |
| spellingShingle | Ian N. Hines Samuel B. Stafford Blair U. Bradford Michael D. Wheeler Regulation of hepatic Sirt1 expression and lipid metabolism through TNF receptor signaling Frontiers in Immunology TNFα non-alcoholic fatty liver SIRT1 lipid metabolism fatty liver choline deficiency model |
| title | Regulation of hepatic Sirt1 expression and lipid metabolism through TNF receptor signaling |
| title_full | Regulation of hepatic Sirt1 expression and lipid metabolism through TNF receptor signaling |
| title_fullStr | Regulation of hepatic Sirt1 expression and lipid metabolism through TNF receptor signaling |
| title_full_unstemmed | Regulation of hepatic Sirt1 expression and lipid metabolism through TNF receptor signaling |
| title_short | Regulation of hepatic Sirt1 expression and lipid metabolism through TNF receptor signaling |
| title_sort | regulation of hepatic sirt1 expression and lipid metabolism through tnf receptor signaling |
| topic | TNFα non-alcoholic fatty liver SIRT1 lipid metabolism fatty liver choline deficiency model |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1627433/full |
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