Heterogeneity of Monocarboxylate Transporter Function in Gastrointestinal Epithelium

Abstract

Short-chain fatty acids and ketone bodies are important energy fuels of GI epithelial cells. Slc16a family encodes proton-coupled monocarboxylate transporters (MCTs) that mediate cellular metabolism of those energy fuels. Increasing evidence demonstrates that adenocarcinomas with overexpression of MCTs are better able to maintain microenvironmental pH and high energy metabolism to grow. However, the precise distribution and function of each MCT subtype in normal epithelial or precancerous cell lineages are mostly unknown. We investigated cell type-specific expressions of MCT subtypes MCT1, MCT2, and MCT4 by immunofluorescence in normal and gastric metaplasia model mice. As total MCT knockout leads to early lethality, we generated inducible, intestine-targeted knockout mouse models for MCT1 and MCT4, respectively. In normal GI tissues, MCT1 was strongly expressed on basolateral membranes of gastric surface cells and enterocytes, with intense staining of proliferating cells and enteroendocrine cells. No staining was observed in Brunner’s glands or Paneth cells. The low affnity subtype, MCT4 expression was localized to the first corpus glands and tuft cells in the stomach, suggesting that these cells may monitor the luminal chemical environment. Intestinal MCT4 was localized on basolateral membranes of mature enterocytes and tuft cells. In contrast, MCT2, which has the highest affnity for lactate, was localized reciprocally to MCT1. Strong MCT2 staining was identified on the basolateral membrane of secretory cells, including gastric parietal and chief cells, Brunner’s glands, and Paneth cells. The distinct MCT2 expression suggests that those secretory cells possess different energy metabolism and MCT2 may contribute to their intracellular pH homeostasis. In gastric metaplasia tissues of Mist1-Kras(G12D) mice, MCT1+ metaplastic cells were increased, and Ki67+ cells were more dependent on MCT1 than normal tissues. MCT2 expression in chief cells was disappeared during metaplasia development. MCT1ΔIEC mice lost MCT1 expression on day 8 after tamoxifen injection and decreased transcriptions of other subtypes, Mct4, Mct7, and Mct10 in intestinal mucosa. MCT1ΔIEC jejunum showed significant increase in crypt length, indicating that MCT1 loss disrupted proliferative cell function. Contrary, MCT4ΔIEC mice had no change in crypt length or Mct1 expression, but increased Mct7, and Mct10. These observations indicate that different cell types require a different MCT subtype. The increase in MCT1-dependency in proliferative metaplastic glands is consistent with the predicted effect of MCT1 inhibitors for cancer treatment. Alterations in MCT subtype expression might be a marker for early diagnosis of metaplastic cells. R37 CA244970 and R01 CA272687 to EC, VDDRC P30-058404 and VICC GI SPORE P50-CA236733 to IK. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.