MECHANISMS OF UHRF1 DEPENDENT MICRORNA IN REGULATING METABOLIC PATHWAYS AND ADIPOGENSIS

Abstract

Adipogenesis is a highly controlled biological process that encompasses numerous genetic and epigenetic factors, as well as microRNAs (miRNAs). Recently, the E3 ubiquitin ligase UHRF1 is identified as a essential regulator in differentiation of adipocyte and a key modulator of fibrosis; however, the specific miRNAs that play a role in this mechanism are still not well understood. For this study, we investigated the function of UHRF1-associated miRNAs in adipogenesis by UHRF1 knockout (KO) and non-targeting (NT) 3T3-L1 preadipocytes. MicroRNA profiling identified several miRNAs with differential expression, notably mmu-miR-465a-3p, which was the most significantly upregulated miRNA in UHRF1 KO cells compered to control cells. Functional validation through qPCR and miRNA mimic transfection experiments demonstrated the overexpression using miR-465a-3p resulted in reduction of lipid droplet formation, also inhibited adipogenic differentiation. This was linked to a reduction in the expression of PPAR, an essential factor of transcription for adipogenesis, along with an upregulation of fibrotic genes, including TGFB1 and GPNMB, implying the activation of pro-fibrotic signalling pathways. These results indicate that miR-465a-3p role in adipogenesis is a negative regulator , likely by obstructing UHRF1-mediated anti-fibrotic activities. In summary, this study uncovers a novel regulatory axis involving UHRF1 and miR-465a-3p that affects the equilibrium between adipocyte differentiation and fibrosis, offering new perspectives on adipose tissue remodelling and potential therapeutic targets for metabolic disorders related to obesity.

Date of Award	2025
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences