Altered cellular metabolic pathway and epithelial cell maturation induced by MYO5B defects are partially reversible
Abstract:
Functional loss of the motor protein, Myosin Vb (MYO5B), induces various defects in intestinal epithelial function and causes a congenital diarrheal disorder, microvillus inclusion disease (MVID). Utilizing the MVID model mice, Vil1-Cre ERT2 ;Myo5b flox/flox (MYO5BΔIEC) 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 MVID intestine. Along with a decrease in fatty acid oxidation, the lipogenesis pathway was enhanced in the MYO5BΔIEC small intestine. Consistent with these observations in vivo , RNA-sequencing of enteroids generated from two MVID mouse strains showed similar downregulation of energy metabolic enzymes, including mitochondrial oxidative phosphorylation genes. In our previous studies, lysophosphatidic acid (LPA) signaling ameliorates epithelial cell defects in MYO5BΔIEC tissues and enteroids. The present study demonstrates that the highly soluble LPAR5-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 intestine with MYO5B functional loss through epithelial cell-autonomous pathways that may improve the differentiation of progenitor cells and the maturation of enterocytes. Targeting LPAR5 may represent an effective therapeutic approach for treatment of MVID symptoms induced by different point mutations in MYO5B.
New & Notewothy:
This study demonstrates the importance of MYO5B for cellular lipid metabolism and mitochondria in intestinal epithelial cells, a previously unexplored function of MYO5B. Alterations in cellular metabolism may underlie the progenitor cell malfunction observed in microvillus inclusion disease (MVID). To examine the therapeutic potential of progenitor-targeted treatments, the effects of LPAR5-preferred agonist, Compound-1, was investigated utilizing several MVID model mice and enteroids. Our observations suggests that Compound-1 may provide a therapeutic approach for treating MVID.
Insights
Microvillus inclusion disease (MVID) impairs intestinal function due to Myosin Vb (MYO5B) loss. Targeting LPAR5 with Compound-1 shows therapeutic potential by improving intestinal cell function and ameliorating symptoms in MVID models.
Area of Science:
- Gastroenterology and Hepatology
- Cell Biology
- Developmental Biology
Background:
- Functional loss of Myosin Vb (MYO5B) causes microvillus inclusion disease (MVID), leading to intestinal epithelial dysfunction, villus blunting, and malabsorption.
- MYO5B is crucial for intestinal epithelial cell function, but its role in lipid metabolism and mitochondrial structure in MVID remains largely unexplored.
Purpose of the Study:
- To investigate the impact of MYO5B functional loss on intestinal lipid metabolism and mitochondrial structure in MVID.
- To evaluate the therapeutic potential of LPAR5-preferred agonist, Compound-1, in ameliorating MVID-associated intestinal defects.
Main Methods:
- Utilized MVID model mice (MYO5BΔIEC and MYO5B(G519R)) and patient-derived enteroids.
- Performed RNA-sequencing to analyze metabolic gene expression.
- Administered Compound-1 to MVID model animals to assess its effects on intestinal function and symptoms.
Main Results:
- MYO5B absence or mutation impairs lipid metabolism, enhancing lipogenesis and decreasing fatty acid oxidation.
- Downregulation of energy metabolic enzymes, including mitochondrial oxidative phosphorylation genes, was observed in MVID models.
- Compound-1 treatment improved sodium transporter localization, absorptive function, and tuft cell differentiation, ameliorating weight loss in MVID mice.
Conclusions:
- MYO5B is essential for intestinal lipid metabolism and mitochondrial integrity.
- LPAR5 signaling, via Compound-1, offers a potential therapeutic strategy for MVID by improving epithelial cell function and maturation.
- Targeting LPAR5 may be a promising approach for treating MVID symptoms caused by various MYO5B mutations.
