Fatty Acid Uptake in Liver Hepatocytes Induces Relocalization and Sequestration of Intracellular Copper
Copper is an essential metal micronutrient with biological roles ranging from energy metabolism to cell signaling. Recent studies have shown that copper regulation is altered by fat accumulation in both rodent and cell models with phenotypes consistent with copper deficiency, including the elevated...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2022.863296/full |
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| author | Nathaniel H. O. Harder Hannah P. Lee Valerie J. Flood Jessica A. San Juan Skyler K. Gillette Marie C. Heffern |
| author_facet | Nathaniel H. O. Harder Hannah P. Lee Valerie J. Flood Jessica A. San Juan Skyler K. Gillette Marie C. Heffern |
| author_sort | Nathaniel H. O. Harder |
| collection | DOAJ |
| description | Copper is an essential metal micronutrient with biological roles ranging from energy metabolism to cell signaling. Recent studies have shown that copper regulation is altered by fat accumulation in both rodent and cell models with phenotypes consistent with copper deficiency, including the elevated expression of the copper transporter, ATP7B. This study examines the changes in the copper trafficking mechanisms of liver cells exposed to excess fatty acids. Fatty acid uptake was induced in liver hepatocarcinoma cells, HepG2, by treatment with the saturated fatty acid, palmitic acid. Changes in chaperones, transporters, and chelators demonstrate an initial state of copper overload in the cell that over time shifts to a state of copper deficiency. This deficiency is due to sequestration of copper both into the membrane-bound copper protein, hephaestin, and lysosomal units. These changes are independent of changes in copper concentration, supporting perturbations in copper localization at the subcellular level. We hypothesize that fat accumulation triggers an initial copper miscompartmentalization within the cell, due to disruptions in mitochondrial copper balance, which induces a homeostatic response to cytosolic copper overload. This leads the cell to activate copper export and sequestering mechanisms that in turn induces a condition of cytosolic copper deficiency. Taken together, this work provides molecular insights into the previously observed phenotypes in clinical and rodent models linking copper-deficient states to obesity-associated disorders. |
| first_indexed | 2024-12-21T04:35:58Z |
| format | Article |
| id | doaj.art-33fee75fea334050867e2d239644b924 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-12-21T04:35:58Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-33fee75fea334050867e2d239644b9242022-12-21T19:15:51ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2022-04-01910.3389/fmolb.2022.863296863296Fatty Acid Uptake in Liver Hepatocytes Induces Relocalization and Sequestration of Intracellular CopperNathaniel H. O. HarderHannah P. LeeValerie J. FloodJessica A. San JuanSkyler K. GilletteMarie C. HeffernCopper is an essential metal micronutrient with biological roles ranging from energy metabolism to cell signaling. Recent studies have shown that copper regulation is altered by fat accumulation in both rodent and cell models with phenotypes consistent with copper deficiency, including the elevated expression of the copper transporter, ATP7B. This study examines the changes in the copper trafficking mechanisms of liver cells exposed to excess fatty acids. Fatty acid uptake was induced in liver hepatocarcinoma cells, HepG2, by treatment with the saturated fatty acid, palmitic acid. Changes in chaperones, transporters, and chelators demonstrate an initial state of copper overload in the cell that over time shifts to a state of copper deficiency. This deficiency is due to sequestration of copper both into the membrane-bound copper protein, hephaestin, and lysosomal units. These changes are independent of changes in copper concentration, supporting perturbations in copper localization at the subcellular level. We hypothesize that fat accumulation triggers an initial copper miscompartmentalization within the cell, due to disruptions in mitochondrial copper balance, which induces a homeostatic response to cytosolic copper overload. This leads the cell to activate copper export and sequestering mechanisms that in turn induces a condition of cytosolic copper deficiency. Taken together, this work provides molecular insights into the previously observed phenotypes in clinical and rodent models linking copper-deficient states to obesity-associated disorders.https://www.frontiersin.org/articles/10.3389/fmolb.2022.863296/fullcopperfatty acid metabolism and signalingmetal homeostasismetabolic diseasehomeostasis |
| spellingShingle | Nathaniel H. O. Harder Hannah P. Lee Valerie J. Flood Jessica A. San Juan Skyler K. Gillette Marie C. Heffern Fatty Acid Uptake in Liver Hepatocytes Induces Relocalization and Sequestration of Intracellular Copper Frontiers in Molecular Biosciences copper fatty acid metabolism and signaling metal homeostasis metabolic disease homeostasis |
| title | Fatty Acid Uptake in Liver Hepatocytes Induces Relocalization and Sequestration of Intracellular Copper |
| title_full | Fatty Acid Uptake in Liver Hepatocytes Induces Relocalization and Sequestration of Intracellular Copper |
| title_fullStr | Fatty Acid Uptake in Liver Hepatocytes Induces Relocalization and Sequestration of Intracellular Copper |
| title_full_unstemmed | Fatty Acid Uptake in Liver Hepatocytes Induces Relocalization and Sequestration of Intracellular Copper |
| title_short | Fatty Acid Uptake in Liver Hepatocytes Induces Relocalization and Sequestration of Intracellular Copper |
| title_sort | fatty acid uptake in liver hepatocytes induces relocalization and sequestration of intracellular copper |
| topic | copper fatty acid metabolism and signaling metal homeostasis metabolic disease homeostasis |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2022.863296/full |
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