Osteopontin deletion drives hematopoietic stem cell mobilization to the liver and increases hepatic iron contributing to alcoholic liver disease.

The copy of record is available from the publisher at https://doi.org/10.1002/hep4.1116. Copyright © 2017 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Abstract: The aim of this study was to investigate the role of osteopontin (OPN) in hematopoietic stem cell (HPSC) mobilization to the liver and its contribution to alcoholic liver disease (ALD). We analyzed young (14‐16 weeks) and old (\u3e1.5 years) wild‐type (WT) littermates and global Opn knockout (Opn−/−) mice for HPSC mobilization to the liver. In addition, WT and Opn−/− mice were chronically fed the Lieber–DeCarli diet for 7 weeks. Bone marrow (BM), blood, spleen, and liver were analyzed by flow cytometry for HPSC progenitors and polymorphonuclear neutrophils (PMNs). Chemokines, growth factors, and cytokines were measured in serum and liver. Prussian blue staining for iron deposits and naphthol AS‐D chloroacetate esterase staining for PMNs were performed on liver sections. Hematopoietic progenitors were lower in liver and BM of young compared to old Opn−/− mice. Granulocyte colony‐stimulating factor and macrophage colony‐stimulating factor were increased in Opn−/− mice, suggesting potential migration of HPSCs from the BM to the liver. Furthermore, ethanol‐fed Opn−/− mice showed significant hepatic PMN infiltration and hemosiderin compared to WT mice. As a result, ethanol feeding caused greater liver injury in Opn−/− compared to WT mice. Conclusion: Opn deletion promotes HPSC mobilization, PMN infiltration, and iron deposits in the liver and thereby enhances the severity of ALD. The age‐associated contribution of OPN to HPSC mobilization to the liver, the prevalence of PMNs, and accumulation of hepatic iron, which potentiates oxidant stress, reveal novel signaling mechanisms that could be targeted for therapeutic benefit in patients with ALD

VitD Regulates Prostatic Metabolism via Transcriptional and Mitochondrial, Redox-Dependent Mechanisms

Vitamin D deficiency has been associated with increased risk for aggressive prostate cancer (PCa). Prostate epithelium has a unique metabolism compared to other tissues. Normal prostate exhibits low levels of mitochondrial respiration and there is a metabolic switch to increased oxidative phosphorylation in PCa. 25-hydroxyvitamin D (25(OH)D) is the major circulating form of vitamin D and is used clinically to determine vitamin D status. Activation of 25(OH)D to the transcriptionally active form, 1,25(OH)2D occurs via a reduction-oxidation (redox) reaction within the mitochondria that is catalyzed by the P450 enzyme, CYP27B1. We sought to determine if hydroxylation of 25(OH)D by CYP27B1 contributes to non-genomic activity of vitamin D by altering the redox-dependent state of the mitochondria in benign prostate epithelial cells. Exposure to 25(OH)D produced a transient pro-oxidant effect and change in mitochondrial membrane potential that was dependent on CYP27B1. Extended exposure ultimately suppressed mitochondrial respiration, consistent with a protective effect of 25(OH)D in supporting benign prostate metabolism. To model physiologically relevant changes in vitamin D, cells were cultured in constant 25(OH)D then changed to high or deficient concentrations. This model also incurred a biphasic effect with a pro-oxidant shift after short exposure followed by decreased respiration after 16 hours. Several genes involved in redox cycling and mitochondrial health were regulated by 25(OH)D in these cells. These results indicate a secondary non-genomic mechanism for vitamin D to contribute to prostate cell health by supporting normal mitochondrial respiration

Key Events Participating in the Pathogenesis of Alcoholic Liver Disease

Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. It ranges from fatty liver to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma.The most prevalent forms of ALD are alcoholic fatty liver, alcoholic hepatitis (AH) and alcoholic cirrhosis, which frequently progress as people continue drinking. ALD refers to a number of symptoms/deficits that contribute to liver injury. These include steatosis, inflammation, fibrosis and cirrhosis, which, when taken together, sequentially or simultaneously lead to significant disease progression. The pathogenesis of ALD, influenced by host and environmental factors, is currentlyonly partially understood. To date, lipopolysaccharide (LPS) translocation from the gut to the portal blood, aging, gender, increased infiltration and activation of neutrophils and bone marrow-derived macrophages along with alcohol plus iron metabolism, with its associated increase in reactive oxygen species (ROS), are all key events contributing to the pathogenesis of ALD. This review aimsto introduce the reader to the concept of alcohol‐mediated liver damage and the mechanisms driving injury

Osteopontin deletion drives hematopoietic stem cell mobilization to the liver and increases hepatic iron contributing to alcoholic liver disease

The copy of record is available from the publisher at https://doi.org/10.1002/hep4.1116. Copyright © 2017 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Abstract: The aim of this study was to investigate the role of osteopontin (OPN) in hematopoietic stem cell (HPSC) mobilization to the liver and its contribution to alcoholic liver disease (ALD). We analyzed young (14‐16 weeks) and old (\u3e1.5 years) wild‐type (WT) littermates and global Opn knockout (Opn−/−) mice for HPSC mobilization to the liver. In addition, WT and Opn−/− mice were chronically fed the Lieber–DeCarli diet for 7 weeks. Bone marrow (BM), blood, spleen, and liver were analyzed by flow cytometry for HPSC progenitors and polymorphonuclear neutrophils (PMNs). Chemokines, growth factors, and cytokines were measured in serum and liver. Prussian blue staining for iron deposits and naphthol AS‐D chloroacetate esterase staining for PMNs were performed on liver sections. Hematopoietic progenitors were lower in liver and BM of young compared to old Opn−/− mice. Granulocyte colony‐stimulating factor and macrophage colony‐stimulating factor were increased in Opn−/− mice, suggesting potential migration of HPSCs from the BM to the liver. Furthermore, ethanol‐fed Opn−/− mice showed significant hepatic PMN infiltration and hemosiderin compared to WT mice. As a result, ethanol feeding caused greater liver injury in Opn−/− compared to WT mice. Conclusion: Opn deletion promotes HPSC mobilization, PMN infiltration, and iron deposits in the liver and thereby enhances the severity of ALD. The age‐associated contribution of OPN to HPSC mobilization to the liver, the prevalence of PMNs, and accumulation of hepatic iron, which potentiates oxidant stress, reveal novel signaling mechanisms that could be targeted for therapeutic benefit in patients with ALD