{"doi":"10.1016/j.jcmgh.2021.01.017","title":"Loss of Mucosal p32/gC1qR/HABP1 Triggers Energy Deficiency and Impairs Goblet Cell Differentiation in Ulcerative Colitis","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.","journal":"Cellular and Molecular Gastroenterology and Hepatology","year":2021,"id":161835,"datarank":0.6064576901751826,"base_score":4.04305126783455,"endowment":4.04305126783455,"self_citation_contribution":0.6064576901751826,"citation_network_contribution":0.0,"self_endowment_contribution":0.6064576901751826,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":56,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9598,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":578047,"name":"Maren Hicken","orcid":null,"position":1,"is_corresponding":false},{"id":578048,"name":"Heidi Schlichting","orcid":null,"position":2,"is_corresponding":false},{"id":578049,"name":"Kerstin Skibbe","orcid":null,"position":3,"is_corresponding":false},{"id":386377,"name":"Mohab Ragab","orcid":null,"position":4,"is_corresponding":false},{"id":578050,"name":"Annika Raschdorf","orcid":null,"position":5,"is_corresponding":false},{"id":577307,"name":"Misa Hirose","orcid":"0000-0002-8909-4693","position":6,"is_corresponding":false},{"id":577308,"name":"Holger Schäffler","orcid":"0000-0002-8475-3741","position":7,"is_corresponding":false},{"id":294482,"name":"Arne Bokemeyer","orcid":"0000-0002-4238-751X","position":8,"is_corresponding":false},{"id":294481,"name":"Dominik Bettenworth","orcid":"0000-0002-1435-4825","position":9,"is_corresponding":false},{"id":577309,"name":"Anne G. Savitt","orcid":"0000-0002-5604-5393","position":10,"is_corresponding":false},{"id":71329,"name":"Sven Perner","orcid":"0000-0002-0449-8462","position":11,"is_corresponding":false},{"id":577310,"name":"Saleh Ibrahim","orcid":"0000-0001-7827-2290","position":12,"is_corresponding":false},{"id":218303,"name":"Ellinor I.B. 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