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

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

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageBritish English
Pages (from-to)229-250
Number of pages22
JournalCMGH
Volume12
Issue number1
DOIs
StatePublished - Jan 2021

Keywords

  • C1QBP
  • Inflammatory Bowel Disease
  • Mitochondrial Function
  • Mucus Barrier

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