| First Author | Momoh M | Year | 2024 |
| Journal | Am J Physiol Gastrointest Liver Physiol | Volume | 327 |
| Issue | 6 | Pages | G877-G899 |
| PubMed ID | 39404772 | Mgi Jnum | J:362132 |
| Mgi Id | MGI:7869260 | Doi | 10.1152/ajpgi.00091.2024 |
| Citation | Momoh M, et al. (2024) Alterations in cellular metabolic pathway and epithelial cell maturation induced by MYO5B defects are partially reversible by LPAR5 activation. Am J Physiol Gastrointest Liver Physiol 327(6):G877-G899 |
| abstractText | Functional loss of the motor protein myosin Vb (MYO5B) induces various defects in intestinal epithelial function and causes a congenital diarrheal disorder, namely, microvillus inclusion disease (MVID). Utilizing the MVID model mice Vil1-Cre(ERT2);Myo5b(flox/flox) (MYO5BDeltaIEC) and Vil1-Cre(ERT2);Myo5b(flox/G519R) [MYO5B(G519R)], we previously reported that functional MYO5B loss disrupts progenitor cell differentiation and enterocyte maturation that result in villus blunting and deadly malabsorption symptoms. In this study, we determined that both absence and a point mutation of MYO5B impair lipid metabolism and alter mitochondrial structure, which may underlie the progenitor cell malfunction observed in the MVID intestine. Along with a decrease in fatty acid oxidation, the lipogenesis pathway was enhanced in the MYO5BDeltaIEC small intestine. Consistent with these observations in vivo, RNA sequencing of enteroids generated from the two MVID mouse strains showed similar downregulation of energy metabolic enzymes, including mitochondrial oxidative phosphorylation genes. In our previous studies, we reported that lysophosphatidic acid (LPA) signaling ameliorated epithelial cell defects in MYO5BDeltaIEC tissues and enteroids. The present study demonstrated that the highly soluble LPA receptor (LPAR)5-preferred agonist Compound-1 improved sodium transporter localization and absorptive function and tuft cell differentiation in patient-modeled MVID animals that carry independent mutations in MYO5B. Body weight loss in male MYO5B(G519R) mice was ameliorated by Compound-1. These observations suggest that Compound-1 treatment has a trophic effect on the intestine with MYO5B functional loss through epithelial cell-autonomous pathways that can accelerate the differentiation of progenitor cells and the maturation of enterocytes. Targeting LPAR5 may represent an effective therapeutic approach for the treatment of MVID symptoms induced by different point mutations in MYO5B.NEW & NOTEWORTHY This study demonstrates the importance of MYO5B for cellular lipid metabolism and mitochondria in intestinal epithelial cells, previously unexplored functions of MYO5B. The alterations may underlie the progenitor cell malfunction observed in microvillus inclusion disease (MVID) intestines. To examine the therapeutic potential of progenitor-targeted treatments, the effects of the LPAR5-preferred agonist Compound-1 were investigated utilizing several MVID model mice and enteroids. Our observations suggest that Compound-1 may provide a therapeutic approach for treating MVID. |
