Abstract
Hepcidin is an iron regulatory peptide hormone that is secreted from hepatocytes and inhibits iron efflux from tissues to plasma. Under inflammatory conditions, hepcidin is transcriptionally induced by IL-6/STAT3 signaling and promotes hypoferremia, an innate immune response to infection. If this pathway remains unresolved, chronic overexpression of hepcidin contributes to the anemia of inflammation, a common medical condition. Previous work showed that carbon monoxide (CO) releasing drugs (CORMs) can attenuate inflammatory induction of hepcidin. Because CO is physiologically generated during heme degradation by heme oxygenase 1 (HO-1), an IL-6-inducible enzyme with anti-inflammatory properties, we hypothesized that hepatocellular HO-1 may operate as a physiological feedback regulator of hepcidin that resolves inflammatory signaling. To address this, we generated and analyzed hepatocyte-specific HO-1 knockout (Hmox1Alb-Cre) mice. We show that these animals mount appropriate hepcidin-mediated hypoferremic response to LPS-induced inflammation, with kinetics similar to those of control Hmox1fl/fl mice. Likewise, primary hepatocytes from Hmox1Alb-Cre and Hmox1fl/fl mice exhibit similar degree and kinetics of hepcidin induction following IL-6 treatment. We conclude that hepatocellular HO-1 has no physiological function on hepcidin regulation by the inflammatory pathway.
Highlights
Heme oxygenase 1 (HO-1) is a stress-inducible microsomal enzyme that catalyzes the oxidative degradation of heme to ferrous (Fe2+) iron, biliverdin and carbon monoxide (CO)
This is due to high abundance of HO-1 in Kupffer cells, the major HO-1-expressing liver cells [15], which skews differences in hepatocellular Hmox1 mRNA content
HO-1 expression was only evident in hepatocytes from heme arginate-treated Hmox1fl/fl mice but not Hmox1Alb-Cre mice
Summary
Heme oxygenase 1 (HO-1) is a stress-inducible microsomal enzyme that catalyzes the oxidative degradation of heme to ferrous (Fe2+) iron, biliverdin and carbon monoxide (CO). We analyzed Hmox1 (HO-1) mRNA from livers of untreated Hmox1fl/fl and Hmox1Alb-Cre mice, or from animals previously injected with the HO-1 inducer heme arginate. HO-1 expression was only evident in hepatocytes from heme arginate-treated Hmox1fl/fl mice (arrows) but not Hmox1Alb-Cre mice.
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