title: Counteract of bone marrow of blotchy mice against the increases of plasma copper levels induced by high-fat diets in LDLR-/- mice.
abstract: BACKGROUND
  Bone marrow of blotchy mouse (blotchy marrow) reflects the function of transmembrane domain and relevant intramembrane sites of ATP7A in myeloid cells. By chronic infusion of angiotensin II, we previously found that blotchy marrow plays a minor role in regulating plasma copper. Moreover, the recipients of blotchy marrow presented a moderate reduction of plasma lipids and inflammatory mediator production. Little is known about whether these changes are a specific response to angiotensin II or reveal a more general role of ATP7A.
  
  
  OBJECTIVE
  We investigated if blotchy marrow reduces plasma lipids and inflammatory mediators induced by high-fat diets. To test this hypothesis, blotchy and control marrows were reconstituted to the recipient mice (irradiated male LDLR-/- mice), followed by high-fat-diet feeding for 4 months. At the end points, plasma metals (copper, zinc and iron), lipid profiling (cholesterol, triglyceride, phospholipids and lipoprotein) and six inflammatory mediators (lymphotacin, MCP3, MCP5, TIMP1, VEGF-A and IP-10) were measured. Parallel experiments were performed using male LDLR-/- mice fed either high-fat diets or chow diets for 4 months.
  
  
  RESULTS
  In addition to hyperlipidemia and low-grade inflammation, high-fat diets selectively increased plasma copper concentration compared to chow diets in LDLR-/- mice. After high-fat-diet feeding, the recipients with blotchy marrow showed a decrease in plasma copper (p < 0.01) and an increase in plasma iron (p < 0.05). The recipients with blotchy marrow also presented decreases in cholesterol (p < 0.01) and phospholipids (p < 0.05) in plasma. Surprisingly, plasma levels of MCP3 (p < 0.05), MCP5 (p < 0.05), TIMP1 (p < 0.01), VEGF-A (p < 0.01) and IP-10 (p < 0.01) were significantly increased in the recipients with blotchy marrow compared to controls; the increased levels of MCP3, MCP5 and TIMP1 were more than 50%.
  
  
  CONCLUSIONS
  Our studies showed that blotchy marrow counteracts the increased copper levels induced by high-fat diets, indicating that circulating myeloid cells can regulate blood copper levels via ATP7A. Moreover, transplantation of blotchy marrow followed by high-fat diets leads to a decrease in lipid profile and an increase in inflammatory mediator production. Overall, blotchy marrow mediates divergent responses to angiotensin II and high-fat diets in vivo.
authors.affiliation: Division of Vascular Surgery, Department of Surgery, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Yao
authors.affiliation: Division of Vascular Surgery, Department of Surgery, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States. Electronic address: qinz@uthscsa.edu.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Qin
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism* / Q000503:physiopathology; D016026:Bone Marrow Transplantation / Q000379:methods; D027682:Cation Transport Proteins / Q000235:genetics; D054410:Chemokine CCL7 / Q000097:blood; D002784:Cholesterol / Q000097:blood; D003300:Copper / Q000097:blood*; D000073840:Copper-Transporting ATPases; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D006949:Hyperlipidemias / Q000097:blood / Q000235:genetics; D008055:Lipids / Q000097:blood; D008297:Male; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D015032:Zinc / Q000097:blood
chemical_list: C486201:Atp7a protein, mouse; C515450:CCL7 protein, human; D027682:Cation Transport Proteins; D054410:Chemokine CCL7; D008055:Lipids; D011973:Receptors, LDL; D003300:Copper; D002784:Cholesterol; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases; D015032:Zinc
keywords: ATP7A; Bone marrow; Copper; Inflammation; Lipid metabolism