THSR Mediated MiR374b Targeting C/EBP β/FOXO1 to Accelerate Thyroid Stimulating Hormone-Induced Hepatic Steatosis

Abstract

Juyi Li,1,2 Yang Ge,3 Yuwei Chai,1 Chunjia Kou,1 Tian Tian Sun,4 Jia Liu,3,5– 7 Haiqing Zhang1,3,5– 7 1Department of Endocrinology, Shandong Provincial Hospital, Shandong University; Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Jinan, Shandong, 250021, People’s Republic of China; 2Department of Endocrinology, Geriatrics Center, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, 230031, People’s Republic of China; 3Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of China; 4Department of Infectious Diseases, Jinan People’s Hospital, Jinan, Shandong, 271100, People’s Republic of China; 5Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, People’s Republic of China; 6Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, People’s Republic of China; 7Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, People’s Republic of ChinaCorrespondence: Jia Liu; Haiqing Zhang, Department of Endocrinology, Shandong Provincial Hospital, 324 Jingwu Road, Jinan, Shandong Province, 250021, People’s Republic of China, Tel [phone] ; Tel [phone], Email [email protected]; [email protected]: Thyroid-stimulating hormone (TSH) has been identified as an independent risk factor for non-alcoholic fatty liver disease (NAFLD), TSH binds to the TSH receptor (TSHR) to exert its function. However, the underlying mechanisms by which TSHR influences NAFLD development remain unclear. This study investigates the role of miR374b in NAFLD progression.Methods: Firstly, a rat model of non-alcoholic fatty liver was constructed and divided into a normal group and a model group. The liver tissue pathology and fat accumulation were detected by Oil Red O staining and hematoxylin-eosin staining. Western blot and Real time PCR were used to detect for the impact of TSHR/miR-374b/C/EBP β/ FoxO1 pathway in the NAFLD model, and the expression of relevant inflammatory factors in each group was detected by ELISA assay. A NAFLD cell model was constructed using HepG2 cells, TSHR overexpression and interference, combined with miR-374b inhibitor and mimics, were transfected simultaneously to demonstrate TSHR/miR-374b/C/EBP β/ The mechanism of FoxO1 adipogenesis in vitro.Results: TSHR stimulates miR374b secretion in human liver cancer cells (HepG2) and promotes lipid accumulation in the liver. Deficiency of miR374b in HepG2 cells attenuated NAFLD progression. Mechanistically, TSH increases miR374b expression, which then suppresses the transcription of its target genes, CCAAT/enhancer binding protein-b (C/EBP β) and Forkhead Box Protein O1 (FOXO1). This suppression influences the expression of downstream lipid metabolism proteins, including PPARγ, SREBP2, and SREBP1c. Additionally, miR374b directly targets the 3′UTR of C/EBP β and FOXO1, establishing a negative feedback loop in lipid metabolism.Conclusion: These findings suggest that TSHR-induced upregulation of miR374b accelerates NAFLD progression by modulating lipid metabolism pathways through C/EBP β and FOXO1. Keywords: NAFLD, miR374b, TSHR

Keywords

• nafld
• mir374b
• tshr