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LKB1 in Intestinal Epithelial Cells Regulates Bile Acid Metabolism by Modulating FGF15/19 Production

BACKGROUND & AIMS: Liver kinase B1 (LKB1) is a master upstream protein kinase involved in nutrient sensing and glucose and lipid metabolism in many tissues; however, its metabolic role in intestinal epithelial cells (IEC) remains unclear. In this study, we investigated the regulatory role of LKB...

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Detalles Bibliográficos
Autores principales: Kim, Yeji, Lee, Sohyeon, Kim, Seungil, Kim, Tae-Young, Lee, Su-Hyun, Chang, Jae-Hoon, Kweon, Mi-Na
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8873961/
https://www.ncbi.nlm.nih.gov/pubmed/34973477
http://dx.doi.org/10.1016/j.jcmgh.2021.12.017
Descripción
Sumario:BACKGROUND & AIMS: Liver kinase B1 (LKB1) is a master upstream protein kinase involved in nutrient sensing and glucose and lipid metabolism in many tissues; however, its metabolic role in intestinal epithelial cells (IEC) remains unclear. In this study, we investigated the regulatory role of LKB1 on bile acid (BA) homeostasis. METHODS: We generated mice with IEC-specific deletion of LKB1 (LKB1(ΔIEC)) and analyzed the characteristics of IEC development and BA level. In vitro assays with small interfering RNA, liquid chromatography/mass spectrometry, metagenomics, and RNA-sequencing were used to elucidate the regulatory mechanisms underlying perturbed BA homeostasis. RESULTS: LKB1 deletion resulted in abnormal differentiation of secretory cell lineages. Unexpectedly, BA pool size increased substantially in LKB1(ΔIEC) mice. A significant reduction of the farnesoid X receptor (FXR) target genes, including fibroblast growth factor 15/19 (FGF15/19), known to inhibit BA synthesis, was found in the small intestine (SI) ileum of LKB1(ΔIEC) mice. We observed that LKB1 depletion reduced FGF15/19 protein level in human IECs in vitro. Additionally, a lower abundance of bile salt hydrolase-producing bacteria and elevated levels of FXR antagonist (ie, T-βMCA) were observed in the SI of LKB1(ΔIEC) mice. Moreover, LKB1(ΔIEC) mice showed impaired conversion of retinol to retinoic acids in the SI ileum. Subsequently, vitamin A treatment failed to induce FGF15 production. Thus, LKB1(ΔIEC) mice fed with a high-fat diet showed improved glucose tolerance and increased energy expenditure. CONCLUSIONS: LKB1 in IECs manages BA homeostasis by controlling FGF15/19 production.