GRHL2 induces liver fibrosis and intestinal mucosal barrier dysfunction in non‐alcoholic fatty liver disease via microRNA‐200 and the MAPK pathway
Open Access
- 23 April 2020
- journal article
- research article
- Published by Wiley in Journal of Cellular and Molecular Medicine
- Vol. 24 (11), 6107-6119
- https://doi.org/10.1111/jcmm.15212
Abstract
Non‐alcoholic fatty liver disease (NAFLD) serves as the most common subtype of liver diseases and cause of liver dysfunction, which is closely related to obesity and insulin resistance. In our study, we sought to investigate effect of transcription factor grainyhead‐like 2 (GRHL2) on NAFLD and the relevant mechanism. NAFLD mouse model was established with a high‐fat feed. Then, serum was extracted from NAFLD patients and mice, followed by ectopic expression and depletion experiments in NAFLD mice and L02 cells. Next, the correlation between GRHL2 and microRNA (miR)‐200 and between miR‐200 and sirtuin‐1 (SIRT1) was evaluated. The observations demonstrated that miR‐200 and GRHL2 were overexpressed in the serum of NAFLD patients and mice, while SIRT1 was poorly expressed. GRHL2 positively regulated miR‐200 by binding to miR‐200 promoter region, which negatively targeted SIRT1. The inhibition of miR‐200 and GRHL2 or SIRT1 overexpression lowered HA and LN in mouse liver tissue, occludin and ZO‐1 in mouse small intestine tissue, TNF‐α and IL‐6 in mouse serum, glucose, total cholesterol (TC), triglyceride (TG), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in mouse serum, and also inhibited liver fibrosis and intestinal mucosal barrier dysfunction. Meanwhile, GRHL2 induced activation of MAPK signalling pathway in NAFLD mice. Collectively, GRHL2 played a contributory role in NAFLD by exacerbating liver fibrosis and intestinal mucosal barrier dysfunction with the involvement of miR‐200‐dependent SIRT1 and the MAPK signalling pathway.Keywords
This publication has 35 references indexed in Scilit:
- Sirtuins: guardians of mammalian healthspanTrends in Genetics, 2014
- Impact of sterol regulatory element-binding factor-1c polymorphism on incidence of nonalcoholic fatty liver disease and on the severity of liver disease and of glucose and lipid dysmetabolismThe American Journal of Clinical Nutrition, 2013
- Cancer drug resistance: an evolving paradigmNature Reviews Cancer, 2013
- MicroRNAs in metabolism and metabolic disordersNature Reviews Molecular Cell Biology, 2012
- miR-200a Regulates SIRT1 Expression and Epithelial to Mesenchymal Transition (EMT)-like Transformation in Mammary Epithelial CellsOnline Journal of Public Health Informatics, 2011
- Human Fatty Liver Disease: Old Questions and New InsightsScience, 2011
- Inactivation of p38 MAPK during liver regenerationThe International Journal of Biochemistry & Cell Biology, 2011
- Prevalence of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among a Largely Middle-Aged Population Utilizing Ultrasound and Liver Biopsy: A Prospective StudyGastroenterology, 2011
- Noninvasive assessment of liver fibrosisJournal of Hepatology, 2010
- Nonalcoholic Fatty Liver Disease: Pathology and PathogenesisAnnual review of pathology, 2010