Myo5b knockout in mice reduced liver proliferation, disrupted metabolic zonation, and altered bile acid homeostasis, demonstrating its critical role in maintaining hepatobiliary function.
Myo5b plays a critical role in liver proliferation, metabolic zonation, and bile acid homeostasis, which may explain the liver cholestasis seen in microvillus inclusion disease.
Background: Myosin 5b (Myo5b) is a motor protein critical for trafficking proteins to the apical surface of intestinal epithelial cells. Inactivating mutations in MYO5B cause microvillus inclusion disease (MVID), a congenital diarrhea disorder that often leads to liver cholestasis. While Myo5b’s role in the intestine is well characterized, its function in the liver remains unclear. Methods and Results: To define the hepatic consequences of Myo5b loss, we analyzed germline Myo5b knockout (KO) mice. Bulk RNAseq of KO livers revealed significant transcriptomic alterations, notably downregulation of genes linked to cell proliferation. Immunostaining confirmed reduced Ki67, phospho-histone H3, and cyclin D1 expression, along with impaired growth of liver organoids in Myo5b-deficient mice. Histology and lipid staining showed steatosis and enlarged lipid droplets, with gene signatures favoring lipogenesis and ketogenesis in mice lacking Myo5b. Myo5b KO livers also displayed disrupted zonated gene expression and loss of zone 1 and zone 3 markers. Bile acid profiling revealed reduced hepatic bile acid levels, decreased expression of classical pathway genes ( Cyp7a1 , Cyp7b1 ), and compensatory upregulation of Cyp27a1 . In the ileum, we observed mislocalization of the apical bile acid transporter ASBT and decreased levels of basolateral OSTβ, leading to impaired enterohepatic recycling and increased luminal bile acids. Conclusions: These findings reveal a previously unrecognized role for Myo5b in liver proliferation, metabolic zonation, and bile acid homeostasis, highlighting its importance in maintaining hepatobiliary function.
McKee et al. (Thu,) conducted a other in Myosin 5b deficiency. Myo5b knockout was evaluated on Liver proliferation, zonation, and bile acid composition. Myo5b knockout in mice reduced liver proliferation, disrupted metabolic zonation, and altered bile acid homeostasis, demonstrating its critical role in maintaining hepatobiliary function.