{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T16:07:43Z","timestamp":1760890063940,"version":"build-2065373602"},"reference-count":33,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,5,8]],"date-time":"2020-05-08T00:00:00Z","timestamp":1588896000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011011","name":"Junta de Andaluc\u00eda","doi-asserted-by":"publisher","award":["P11-AGR-7648"],"award-info":[{"award-number":["P11-AGR-7648"]}],"id":[{"id":"10.13039\/501100011011","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Despite the crucial role of the liver as the central regulator of iron homeostasis, no studies have directly tested the modulation of liver gene and protein expression patterns during iron deficiency instauration and recovery with fermented milks. Fermented goat milk consumption improves the key proteins of intestinal iron metabolism during iron deficiency recovery, enhancing the digestive and metabolic utilization of iron. The aim of this study was to assess the influence of fermented goat or cow milk consumption on liver iron homeostasis during iron-deficiency anemia recovery with normal or iron-overload diets. Analysis included iron status biomarkers, gene and protein expression in hepatocytes. In general, fermented goat milk consumption either with normal or high iron content up-regulated liver DMT1, FPN1 and FTL1 gene expression and DMT1 and FPN1 protein expression. However, HAMP mRNA expression was lower in all groups of animals fed fermented goat milk. Additionally, hepcidin protein expression decreased in control and anemic animals fed fermented goat milk with normal iron content. In conclusion, fermented goat milk potentiates the up-regulation of key genes coding for proteins involved in iron metabolism, such as DMT1, and FPN1, FTL1 and down-regulation of HAMP, playing a key role in enhanced iron repletion during anemia recovery, inducing a physiological adaptation of the liver key genes and proteins coordinated with the fluctuation of the cellular iron levels, favoring whole-body iron homeostasis.<\/jats:p>","DOI":"10.3390\/nu12051336","type":"journal-article","created":{"date-parts":[[2020,5,8]],"date-time":"2020-05-08T11:26:00Z","timestamp":1588937160000},"page":"1336","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Role of Fermented Goat Milk on Liver Gene and Protein Profiles Related to Iron Metabolism during Anemia Recovery"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9690-7851","authenticated-orcid":false,"given":"Jorge","family":"Moreno-Fernandez","sequence":"first","affiliation":[{"name":"Department of Physiology, University of Granada, 18071 Granada, Spain"},{"name":"Institute of Nutrition and Food Technology \u201cJos\u00e9 Mataix Verd\u00fa\u201d, University of Granada, 18071 Granada, Spain"},{"name":"Nutrition and Food Sciences Ph.D. Program, University of Granada, 18071 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1598-7728","authenticated-orcid":false,"given":"Mar\u00eda J. M.","family":"Alf\u00e9rez","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Granada, 18071 Granada, Spain"},{"name":"Institute of Nutrition and Food Technology \u201cJos\u00e9 Mataix Verd\u00fa\u201d, University of Granada, 18071 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inmaculada","family":"L\u00f3pez-Aliaga","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Granada, 18071 Granada, Spain"},{"name":"Institute of Nutrition and Food Technology \u201cJos\u00e9 Mataix Verd\u00fa\u201d, University of Granada, 18071 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3659-1757","authenticated-orcid":false,"given":"Javier","family":"D\u00edaz-Castro","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Granada, 18071 Granada, Spain"},{"name":"Institute of Nutrition and Food Technology \u201cJos\u00e9 Mataix Verd\u00fa\u201d, University of Granada, 18071 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1017\/S1368980008002401","article-title":"Worldwide prevalence of anaemia, WHO Vitamin and Mineral Nutrition Information System, 1993\u20132005","volume":"12","author":"McLean","year":"2009","journal-title":"Public Health Nutr."},{"key":"ref_2","first-page":"51","article-title":"The Regulation of Iron Absorption and Homeostasis","volume":"37","author":"Wallace","year":"2016","journal-title":"Clin. Biochem. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.cell.2010.06.028","article-title":"Two to tango: Regulation of Mammalian iron metabolism","volume":"142","author":"Hentze","year":"2010","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.cbpa.2019.11.014","article-title":"Mammalian iron-sulfur cluster biogenesis: Recent insights into the roles of frataxin, acyl carrier protein and ATPase-mediated transfer to recipient proteins","volume":"55","author":"Maio","year":"2020","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1056\/NEJMra041809","article-title":"Anemia of chronic disease","volume":"352","author":"Weiss","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"G157","DOI":"10.1152\/ajpgi.00004.2017","article-title":"The liver in regulation of iron homeostasis","volume":"313","author":"Rishi","year":"2017","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.cmet.2012.03.017","article-title":"Molecular mechanism of hepcidin-mediated ferroportin internalization requires ferroportin lysines, not tyrosines or JAK-STAT","volume":"15","author":"Ross","year":"2012","journal-title":"Cell Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.phrs.2016.11.010","article-title":"Therapeutic potential of hepcidin\u2014The master regulator of iron metabolism","volume":"115","author":"Vyoral","year":"2017","journal-title":"Pharmacol. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2560","DOI":"10.1021\/acs.jafc.6b00108","article-title":"Fermented Goat\u2019s Milk Consumption Improves Duodenal Expression of Iron Homeostasis Genes during Anemia Recovery","volume":"64","author":"Alferez","year":"2016","journal-title":"J. Agric. Food Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1093\/jn\/123.11.1939","article-title":"AIN-93 purified diets for laboratory rodents: Final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet","volume":"123","author":"Reeves","year":"1993","journal-title":"J. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1079\/BJN19930152","article-title":"Effect of iron deficiency on the digestive utilization of iron, phosphorus, calcium and magnesium in rats","volume":"70","author":"Pallares","year":"1993","journal-title":"Br. J. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1111\/j.1365-2141.1994.tb03267.x","article-title":"Intestinal iron absorption studies in mouse models of iron-overload","volume":"86","author":"Raja","year":"1994","journal-title":"Br. J. Haematol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Moreno-Fernandez, J., Diaz-Castro, J., Alferez, M.J.M., and Lopez-Aliaga, I. (2019). Iron Deficiency and Neuroendocrine Regulators of Basal Metabolism, Body Composition and Energy Expenditure in Rats. Nutrients, 11.","DOI":"10.3390\/nu11030631"},{"key":"ref_14","unstructured":"Burtis, C.A., and Ashwood, E.R. (1999). Liver function. Tietz Textbook of Clinical Chemistry, W.B. Saunders."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4057","DOI":"10.1021\/acs.jafc.7b00666","article-title":"Changes in Adiposity and Body Composition during Anemia Recovery with Goat or Cow Fermented Milks","volume":"65","author":"Alferez","year":"2017","journal-title":"J. Agric. Food Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.molmet.2019.03.008","article-title":"Ferritin regulates organismal energy balance and thermogenesis","volume":"24","author":"Blankenhaus","year":"2019","journal-title":"Mol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1136\/gut.46.2.270","article-title":"Localisation of divalent metal transporter 1 (DMT1) to the microvillus membrane of rat duodenal enterocytes in iron deficiency, but to hepatocytes in iron overload","volume":"46","author":"Trinder","year":"2000","journal-title":"Gut"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/jn\/135.1.27","article-title":"Low vitamin a intake affects milk iron level and iron transporters in rat mammary gland and liver","volume":"135","author":"Kelleher","year":"2005","journal-title":"J. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.idairyj.2005.08.001","article-title":"Dietary goat milk improves iron bioavailability in rats with induced ferropenic anaemia in comparison with cow milk","volume":"16","author":"Nestares","year":"2006","journal-title":"Int. Dairy J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"147","DOI":"10.3168\/jds.2013-7250","article-title":"Goat milk consumption modulates liver divalent metal transporter 1 (DMT1) expression and serum hepcidin during Fe repletion in Fe-deficiency anemia","volume":"97","author":"Pulido","year":"2014","journal-title":"J. Dairy Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1182\/blood-2002-10-3235","article-title":"Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein","volume":"101","author":"Nemeth","year":"2003","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4425","DOI":"10.1182\/blood-2011-01-258467","article-title":"Hepcidin and iron regulation, 10 years later","volume":"117","author":"Ganz","year":"2011","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ueda, N., and Takasawa, K. (2018). Impact of Inflammation on Ferritin, Hepcidin and the Management of Iron Deficiency Anemia in Chronic Kidney Disease. Nutrients, 10.","DOI":"10.3390\/nu10091173"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1177\/0004563216675185","article-title":"Ferritin and iron studies in anaemia and chronic disease","volume":"54","author":"Peng","year":"2017","journal-title":"Ann. Clin. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3195","DOI":"10.1039\/C8FO00552D","article-title":"Fermented goat milk consumption improves iron status and evokes inflammatory signalling during anemia recovery","volume":"9","author":"Alferez","year":"2018","journal-title":"Food Funct."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1016\/j.foodchem.2013.08.091","article-title":"Structural elucidation of olive pomace fed sea bass (Dicentrarchus labrax) polar lipids with cardioprotective activities","volume":"145","author":"Nasopoulou","year":"2014","journal-title":"Food Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s13594-014-0161-x","article-title":"In vitro anti-atherogenic properties of traditional Greek cheese lipid fractions","volume":"94","author":"Tsorotioti","year":"2014","journal-title":"Dairy Sci. Technol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1002\/hep.27636","article-title":"Dysregulated iron homeostasis is strongly associated with multiorgan failure and early mortality in acute-on-chronic liver failure","volume":"61","author":"Maras","year":"2015","journal-title":"Hepatology"},{"key":"ref_29","first-page":"1","article-title":"Influence of cow or goat milk consumption on antioxidant defence and lipid peroxidation during chronic iron repletion","volume":"108","author":"Nestares","year":"2012","journal-title":"Br. J. Nutr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1017\/S0022029914000624","article-title":"Folic acid supplemented goat milk has beneficial effects on hepatic physiology, haematological status and antioxidant defence during chronic Fe repletion","volume":"82","author":"Alferez","year":"2015","journal-title":"J. Dairy Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12735","DOI":"10.1074\/jbc.R117.786632","article-title":"Iron transport proteins: Gateways of cellular and systemic iron homeostasis","volume":"292","author":"Knutson","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.cell.2016.12.034","article-title":"A Red Carpet for Iron Metabolism","volume":"168","author":"Muckenthaler","year":"2017","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1089\/ars.2013.5666","article-title":"Coupling heme and iron metabolism via ferritin H chain","volume":"20","author":"Gozzelino","year":"2014","journal-title":"Antioxid. Redox Signal."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/5\/1336\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:26:38Z","timestamp":1760174798000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/5\/1336"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,8]]},"references-count":33,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["nu12051336"],"URL":"https:\/\/doi.org\/10.3390\/nu12051336","relation":{},"ISSN":["2072-6643"],"issn-type":[{"type":"electronic","value":"2072-6643"}],"subject":[],"published":{"date-parts":[[2020,5,8]]}}}