Leptin Increases the Expression of the Iron Regulatory Hormone Hepcidin in HuH7 Human Hepatoma Cells

• Published in: The Journal of nutrition Vol. 137; no. 11; pp. 2366 - 2370
• Main Authors: Chung, Bomee, Matak, Pavle, McKie, Andrew T, Sharp, Paul
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Nutrition 01.11.2007; American Society for Nutritional Sciences
• Subjects: adipokinetic hormone; Antimicrobial Cationic Peptides - genetics; Biological and medical sciences; Carcinoma, Hepatocellular; Cell Line, Tumor; cytokines; dietary minerals; disease prevalence; DNA Primers; Feeding. Feeding behavior; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic - drug effects; Genes, Reporter; hepatoma; hepcidin; Hepcidins; human cell lines; Humans; inflammation; interleukin-6; iron; iron deficiency anemia; kinases; leptin; Leptin - pharmacology; Liver Neoplasms; messenger RNA; metabolism; mineral metabolism; molecular sequence data; nutrient availability; nutrient deficiencies; overweight; Polymerase Chain Reaction; promoter regions; Promoter Regions, Genetic; RNA, Messenger - genetics; RNA, Neoplasm - genetics; signal transduction; Transfection; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Human; Hormone; Nutrition; Hepatic disease; Hepatocellular carcinoma; Iron; Adipokine; Malignant tumor; Gene expression; Micronutrient; Leptin; Digestive diseases; Cancer
• ISSN: 0022-3166; 1541-6100
• DOI: 10.1093/jn/137.11.2366

Obesity is a major global health problem and is associated with low-grade inflammation and, in a number of cases, poor iron status. We speculated that the adipokine leptin might play a role in regulating iron metabolism in the overweight population because it shares a number of common biological features with IL-6, a major factor in the development of the anemia of chronic disease via its stimulatory actions on the production and release of the iron regulatory hormone hepcidin. To test this hypothesis, we exposed HuH7 human hepatoma cells to leptin and measured hepcidin mRNA expression by quantitative PCR. HuH7 cells were also transfected with a hepcidin promoter-luciferase reporter gene construct to investigate transcriptional regulation of hepcidin. In leptin-treated cells, hepcidin mRNA expression was enhanced significantly. Preincubation with a Janus kinase (JAK) 2 inhibitor significantly diminished this response. Hepcidin promoter activity was also increased in the presence of leptin. This effect was decreased either by mutation of the signal transducer and activator of transcription (STAT) 3 binding motif in the hepcidin promoter or by coexpressing a dominant-negative STAT3 mutant. These data suggest that leptin upregulates hepatic hepcidin expression through the JAK2/STAT3 signaling pathway. As a consequence, the increased production of leptin in overweight individuals might be a major contributor to the aberrant iron status observed in these population groups.