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Sünderhauf A, Hicken M, Schlichting H, et al. Loss of Mucosal p32/gC1qR/HABP1 Triggers Energy Deficiency and Impairs Goblet Cell Differentiation in Ulcerative Colitis. Cell Mol Gastroenterol Hepatol. 2021;12(1):229-250doi: 10.1016/j.jcmgh.2021.01.017.
Sünderhauf, A., Hicken, M., Schlichting, H., Skibbe, K., Ragab, M., Raschdorf, A., Hirose, M., Schäffler, H., Bokemeyer, A., Bettenworth, D., Savitt, A. G., Perner, S., Ibrahim, S., Peerschke, E. I., Ghebrehiwet, B., Derer, S., & Sina, C. (2021). Loss of Mucosal p32/gC1qR/HABP1 Triggers Energy Deficiency and Impairs Goblet Cell Differentiation in Ulcerative Colitis. Cellular and molecular gastroenterology and hepatology, 12(1), 229-250. https://doi.org/10.1016/j.jcmgh.2021.01.017
Sünderhauf, Annika, et al. "Loss of Mucosal p32/gC1qR/HABP1 Triggers Energy Deficiency and Impairs Goblet Cell Differentiation in Ulcerative Colitis." Cellular and molecular gastroenterology and hepatology vol. 12,1 (2021): 229-250. doi: https://doi.org/10.1016/j.jcmgh.2021.01.017
Sünderhauf A, Hicken M, Schlichting H, Skibbe K, Ragab M, Raschdorf A, Hirose M, Schäffler H, Bokemeyer A, Bettenworth D, Savitt AG, Perner S, Ibrahim S, Peerschke EI, Ghebrehiwet B, Derer S, Sina C. Loss of Mucosal p32/gC1qR/HABP1 Triggers Energy Deficiency and Impairs Goblet Cell Differentiation in Ulcerative Colitis. Cell Mol Gastroenterol Hepatol. 2021;12(1):229-250. doi: 10.1016/j.jcmgh.2021.01.017. Epub 2021 Jan 27. PMID: 33515804; PMCID: PMC8135049.
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Cell Mol Gastroenterol Hepatol. 2021;12(1):229-250. doi: 10.1016/j.jcmgh.2021.01.017. Epub 2021 Jan 27.

Loss of Mucosal p32/gC1qR/HABP1 Triggers Energy Deficiency and Impairs Goblet Cell Differentiation in Ulcerative Colitis.

Cellular and molecular gastroenterology and hepatology

Annika Sünderhauf, Maren Hicken, Heidi Schlichting, Kerstin Skibbe, Mohab Ragab, Annika Raschdorf, Misa Hirose, Holger Schäffler, Arne Bokemeyer, Dominik Bettenworth, Anne G Savitt, Sven Perner, Saleh Ibrahim, Ellinor I Peerschke, Berhane Ghebrehiwet, Stefanie Derer, Christian Sina

Affiliations

  1. Division of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
  2. Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany.
  3. Division of Gastroenterology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany.
  4. Gastroenterology and Hepatology, Department of Medicine B, University Hospital Münster, Münster, Germany.
  5. Department of Medicine, Stony Brook University, Stony Brook, New York.
  6. Institute of Pathology, University Hospital Schleswig-Holstein, Lübeck, Germany; Pathology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany.
  7. Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
  8. Division of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. Electronic address: [email protected].
  9. Division of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany; Division of Nutritional Medicine, 1st Department of Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. Electronic address: [email protected].

PMID: 33515804 PMCID: PMC8135049 DOI: 10.1016/j.jcmgh.2021.01.017

Abstract

BACKGROUND & AIMS: Cell differentiation in the colonic crypt is driven by a metabolic switch from glycolysis to mitochondrial oxidation. Mitochondrial and goblet cell dysfunction have been attributed to the pathology of ulcerative colitis (UC). We hypothesized that p32/gC1qR/HABP1, which critically maintains oxidative phosphorylation, is involved in goblet cell differentiation and hence in the pathogenesis of UC.

METHODS: Ex vivo, goblet cell differentiation in relation to p32 expression and mitochondrial function was studied in tissue biopsies from UC patients versus controls. Functional studies were performed in goblet cell-like HT29-MTX cells in vitro. Mitochondrial respiratory chain complex V-deficient, ATP8 mutant mice were utilized as a confirmatory model. Nutritional intervention studies were performed in C57BL/6 mice.

RESULTS: In UC patients in remission, colonic goblet cell differentiation was significantly decreased compared to controls in a p32-dependent manner. Plasma/serum L-lactate and colonic pAMPK level were increased, pointing at high glycolytic activity and energy deficiency. Consistently, p32 silencing in mucus-secreting HT29-MTX cells abolished butyrate-induced differentiation and induced a shift towards glycolysis. In ATP8 mutant mice, colonic p32 expression correlated with loss of differentiated goblet cells, resulting in a thinner mucus layer. Conversely, feeding mice an isocaloric glucose-free, high-protein diet increased mucosal energy supply that promoted colonic p32 level, goblet cell differentiation and mucus production.

CONCLUSION: We here describe a new molecular mechanism linking mucosal energy deficiency in UC to impaired, p32-dependent goblet cell differentiation that may be therapeutically prevented by nutritional intervention.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: C1QBP; Inflammatory Bowel Disease; Mitochondrial Function; Mucus Barrier

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