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Intestinal glucose absorption is mediated by SGLT1 whereas GLUT2 is considered to provide basolateral exit. Recently, it was proposed that GLUT2 can be recruited into the apical membrane after a high luminal glucose bolus allowing bulk absorption of glucose by facilitated diffusion. Moreover, SGLT1 and GLUT2 are suggested to play an important role in intestinal glucose sensing and incretin secretion. In mice that lack either SGLT1 or GLUT2 we re-assessed the role of these transporters in intestinal glucose uptake after radiotracer glucose gavage and performed Western blot analysis for transporter abundance in apical membrane fractions in a comparative approach. Moreover, we examined the contribution of these transporters to glucose-induced changes in plasma GIP, GLP-1 and insulin levels. In mice lacking SGLT1, tissue retention of tracer glucose was drastically reduced throughout the entire small intestine whereas GLUT2-deficient animals exhibited higher tracer contents in tissue samples than wild type animals. Deletion of SGLT1 resulted also in reduced blood glucose elevations and abolished GIP and GLP-1 secretion in response to glucose. In mice lacking GLUT2, glucose-induced insulin but not incretin secretion was impaired. Western blot analysis revealed unchanged protein levels of SGLT1 after glucose gavage. GLUT2 detected in apical membrane fractions mainly resulted from contamination with basolateral membranes but did not change in density after glucose administration. SGLT1 is unequivocally the prime intestinal glucose transporter even at high luminal glucose concentrations. Moreover, SGLT1 mediates glucose-induced incretin secretion. Our studies do not provide evidence for GLUT2 playing any role in either apical glucose influx or incretin secretion.

Exacerbations of chronic obstructive pulmonary disease (COPD) increase mortality risk and can lead to accelerated loss of lung function. The increased inflammatory response during exacerbations contributes to worsening of airflow limitation, but whether it also impacts epithelial repair is unclear. Therefore, we studied the effect of the soluble factor micro-environment during COPD exacerbations on epithelial repair using an exacerbation cocktail (EC), composed of four factors that are increased in COPD lungs during exacerbations (IL-1β, IL-6, IL-8, TNF-α). Mouse organoids (primary CD31-CD45-Epcam+ cells co-cultured with CCL206 fibroblasts) were used to study epithelial progenitor behavior. Mature epithelial cell responses were evaluated using mouse precision cut lung slices (PCLS). The expression of epithelial supportive factors was assessed in CCL206 fibroblasts and primary human lung fibroblasts. EC exposure increased the number and size of organoids formed, and upregulated , and expression in day 14 organoids. In PCLS, EC imparted no effect on epithelial marker expression. Pre-treatment of CCL206 fibroblasts with EC was sufficient to increase organoid formation. Additionally, the expression of , and was increased in CCL206 fibroblasts from EC treated organoids, but these factors individually did not affect organoid formation or size. However, TGF-α downregulated expression and upregulated expression in day 14 organoids. EC exposure stimulates organoid formation and growth, but it alters epithelial differentiation. EC changes the epithelial progenitor support function of fibroblasts which contributes to observed effects on epithelial progenitors.

Nonalcoholic fatty liver disease (NAFLD) is a major health burden in the aging society with an urging medical need for a better understanding of the underlying mechanisms. Mitochondrial fatty acid oxidation and mitochondrial‐derived reactive oxygen species (ROS) are considered critical in the development of hepatic steatosis, the hallmark of NAFLD. Our study addressed in C57BL/6J mice the effect of high fat diet feeding and age on liver mitochondria at an early stage of NAFLD development. We therefore analyzed functional characteristics of hepatic mitochondria and associated alterations in the mitochondrial proteome in response to high fat feeding in adolescent, young adult, and middle‐aged mice. Susceptibility to diet‐induced obesity increased with age. Young adult and middle‐aged mice developed fatty liver, but not adolescent mice. Fat accumulation was negatively correlated with an age‐related reduction in mitochondrial mass and aggravated by a reduced capacity of fatty acid oxidation in high fat‐fed mice. Irrespective of age, high fat diet increased ROS production in hepatic mitochondria associated with a balanced nuclear factor erythroid‐derived 2 like 2 (NFE2L2) dependent antioxidative response, most likely triggered by reduced tethering of NFE2L2 to mitochondrial phosphoglycerate mutase 5. Age indirectly influenced mitochondrial function by reducing mitochondrial mass, thus exacerbating diet‐induced fat accumulation. Therefore, consideration of age in metabolic studies must be emphasized. Our study elucidated the early changes in liver physiology upon feeding a high fat diet investigated in three age groups of C57BL/6J mice. Intriguingly, the interaction between high fat diet and increasing age enforces the accumulation of fat in the liver while reducing mitochondrial mass and function.

Like most microorganisms, the yeast Saccharomyces cerevisiae is prototrophic for riboflavin (vitamin B2). Riboflavin auxotrophic mutants with deletions in any of the RIB genes frequently segregate colonies with improved growth. We demonstrate by reporter assays and Western blots that these suppressor mutants overexpress the plasma-membrane riboflavin transporter MCH5. Frequently, this overexpression is mediated by the transcription factor Put3, which also regulates the proline catabolic genes PUT1 and PUT2. The increased expression of MCH5 may increase the concentrations of FAD, which is the coenzyme required for the activity of proline oxidase, encoded by PUT1. Thus, Put3 regulates proline oxidase activity by synchronizing the biosynthesis of the apoenzyme and the coenzyme FAD. Put3 is known to bind to the promoters of PUT1 and PUT2 constitutively, and we demonstrate by gel-shift assays that it also binds to the promoter of MCH5. Put3-mediated transcriptional activation requires proline as an inducer. We find that the increased activity of Put3 in one of the suppressor mutants is caused by increased intracellular levels of proline. Alternative PUT3-dependent and -independent mechanisms might operate in other suppressed strains.

The extracellular matrix (ECM) is the common denominator of more than 50 chronic diseases. Some of these chronic pathologies lead to enhanced tissue formation and deposition, whereas others are associated with increased tissue degradation, and some exhibit a combination of both, leading to severe tissue alterations. To develop effective therapies for diseases affecting the lung, liver, kidney, skin, intestine, musculoskeletal system, heart, and solid tumors, we need to modulate the ECM’s composition to restore its organization and function. Across diverse organ diseases, there are common denominators and distinguishing factors in this fibroinflammatory axis, which may be used to foster new insights into drug development across disease indications. The 2nd Extracellular Matrix Pharmacology Congress took place in Copenhagen, Denmark, from 17 to 19 June 2024 and was hosted by the International Society of Extracellular Matrix Pharmacology. The event was attended by 450 participants from 35 countries, among whom were prominent scientists who brought together state-of-the-art research on organ diseases and asked important questions to facilitate drug development. We highlight key aspects of the ECM in the liver, kidney, skin, intestine, musculoskeletal system, lungs, and solid tumors to advance our understanding of the ECM and its central targets in drug development. We also highlight key advances in the tools and technology that enable this drug development, thereby supporting the ECM.

IL11 is linked to the pathogenesis of idiopathic pulmonary fibrosis (IPF), since IL11 induces myofibroblast differentiation and stimulates their excessive collagen deposition in the lung. The alveolar architecture is disrupted in IPF, yet the effect of IL11 on dysregulated alveolar repair associated with IPF remains to be elucidated. We hypothesized that epithelial-fibroblast communication associated with lung repair is disrupted by IL11. Thus, we studied whether IL11 affects the repair responses of alveolar lung epithelium using mouse lung organoids and precision cut lung slices (PCLS). Additionally, we assessed the anatomical distribution of IL11 and IL11 receptor in human control and IPF lungs using immunohistochemistry. IL11 protein was observed in human control lungs in airway epithelium, macrophages and in IPF lungs, in areas of AT2 cell hyperplasia. IL11R staining was predominantly present in smooth muscle and macrophages. In mouse organoid cocultures of epithelial cells with lung fibroblasts, IL11 decreased organoid number and reduced the fraction of pro-SPC expressing organoids, indicating dysfunctional regeneration initiated by epithelial progenitors. In mouse PCLS alveolar marker gene expression declined, whereas airway markers were increased. The response of primary human fibroblasts to IL11 on gene expression level was minimal, though bulk RNAsequencing revealed IL11 modulated a number of processes which may play a role in IPF, including unfolded protein response, glycolysis and Notch signaling. In conclusion, IL11 disrupts alveolar epithelial regeneration by inhibiting progenitor activation and suppressing the formation of mature alveolar epithelial cells. The contribution of dysregulated fibroblast epithelial communication to this process appears to be limited.Competing Interest StatementThis research was supported by an unrestricted research grant from Boehringer Ingelheim to the University of Groningen. Kerstin E. Geillinger-Kaestle and Megan Webster were employed by Boehringer Ingelheim when contributing to this manuscript.Footnotes* Supplemental files updated