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Int. J. Mol. Sci. 2018, 19(7), 1977; https://doi.org/10.3390/ijms19071977

Effect of Endoplasmic Reticular Stress on Free Hemoglobin Metabolism and Liver Injury

1
Department of Physical Medicine and Rehabilitation, Taipei Medical University Hospital, Taipei 110, Taiwan
2
Department of Physical Medicine and Rehabilitation, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
3
School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 110, Taiwan
4
School of Food Safety, College of Nutrition, Taipei Medical University, Taipei 110, Taiwan
5
Department of Pharmaceutical Science, School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan
6
Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 110, Taiwan
*
Author to whom correspondence should be addressed.
Received: 22 May 2018 / Revised: 11 June 2018 / Accepted: 29 June 2018 / Published: 6 July 2018
(This article belongs to the Special Issue Liver Damage and Repair)
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Abstract

Elevated soluble (s) CD163 and free hemoglobin (Hb) levels predict fatty liver progression; however, the molecular mechanisms underlying Hb metabolism and liver injury remain undefined. We investigated the effects of endoplasmic reticular (ER) stress on red blood cell (RBC) rheology and free Hb recycling pathways. ER stress was induced in Sprague-Dawley rats by an intraperitoneal injection of tunicamycin (TM) (50, 100, and 200 μg/100 g body weight (BW)) or an intravenous injection of Hb (5 mg/100 g BW). A TM injection increased sCD163 levels, attenuated free Hb uptake, and maintained RBC aggregability. An Hb injection increased serum LVV-hemorphin-7 and total bilirubin levels, but this effect was suppressed by TM. A Western blot analysis showed that ER stress suppressed Hb degradation in the liver through downregulation of globin degradation proteins cathepsin D and glyoxalase-1, as well as heme degradation protein heme oxyganase-1 and keap-1 expression. An ER stress activator also increased the translocation of nuclear factor (NF)-κB (p65) and nuclear factor-erythroid 2-related factor 2 (Nrf2) to nuclei. In conclusion, ER stress triggers ineffective Hb metabolism via altering globin and heme iron degradation pathways. Inability to recycle and metabolize free Hb may underlie the association between iron dysfunction and liver injury. View Full-Text
Keywords: liver injury; endoplasmic reticular stress; soluble (s) CD163; free hemoglobin liver injury; endoplasmic reticular stress; soluble (s) CD163; free hemoglobin
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Tseng, S.-H.; Chang, T.-Y.; Shih, C.-K.; Hsieh, R.-H.; Chen, C.-W.; Chen, Y.-C.; Lin, M.-H.; Chang, J.-S. Effect of Endoplasmic Reticular Stress on Free Hemoglobin Metabolism and Liver Injury. Int. J. Mol. Sci. 2018, 19, 1977.

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