Division of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany.
Cell Mol Gastroenterol Hepatol. 2021;12(1):229-250. doi: 10.1016/j.jcmgh.2021.01.017. Epub 2021 Jan 27.
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.
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.
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.
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.
结肠隐窝中的细胞分化是由从糖酵解到线粒体氧化的代谢转换驱动的。线粒体和杯状细胞功能障碍归因于溃疡性结肠炎（UC）的病理学。我们假设 p32/gC1qR/HABP1 是氧化磷酸化的关键维持者，参与杯状细胞分化，从而参与 UC 的发病机制。
在 UC 患者与对照组的组织活检中，研究了 p32 表达和线粒体功能与杯状细胞分化的关系。在体外进行了类似杯状细胞的 HT29-MTX 细胞的功能研究。利用线粒体呼吸链复合物 V 缺陷、ATP8 突变小鼠作为确证模型。在 C57BL/6 小鼠中进行了营养干预研究。
在缓解期的 UC 患者中，与对照组相比，p32 依赖性的结肠杯状细胞分化显著降低。血浆/血清 L-乳酸和结肠 pAMPK 水平升高，表明糖酵解活性和能量缺乏较高。一致地，在分泌粘液的 HT29-MTX 细胞中沉默 p32 可消除丁酸盐诱导的分化并诱导向糖酵解的转变。在 ATP8 突变小鼠中，结肠 p32 表达与分化的杯状细胞丢失相关，导致粘液层变薄。相反，用等热量无葡萄糖高蛋白饮食喂养小鼠可增加粘膜能量供应，促进结肠 p32 水平、杯状细胞分化和粘液产生。
我们在这里描述了一个新的分子机制，将 UC 中的粘膜能量缺乏与受损的、p32 依赖性杯状细胞分化联系起来，这种分化可能通过营养干预来预防。
