Loss of mucosal p32/gC1qR/HABP1 triggers energy deficiency and impairs goblet cell differentiation in ulcerative colitis, Sunderhauf et al, 2021

Andy · Jan 31, 2021

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 GCs, 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.
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Open access, https://www.cmghjournal.org/article/S2352-345X(21)00023-0/abstract

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Loss of mucosal p32/gC1qR/HABP1 triggers energy deficiency and impairs goblet cell differentiation in ulcerative colitis, Sunderhauf et al, 2021

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Loss of mucosal p32/gC1qR/HABP1 triggers energy deficiency and impairs goblet cell differentiation in ulcerative colitis, Sunderhauf et al, 2021

Andy Committee Member

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