1446-P: MiRNA-103 as a Potential Therapeutic Inhibitor of Dyslipidemia through Modulation of the ANGPTL8/ANGPTL3 Axis

Introduction and Objective: Epigenetic regulation contributes to obesity-associated metabolic dysfunction, including dyslipidemia and diabetes. MicroRNA-103 (miR-103) suppresses de novo lipogenesis by targeting FASN and SCD1. Angiopoietin-like protein 8 (ANGPTL8) regulates triglyceride (TG) metabolism by inhibiting lipoprotein lipase (LPL) via interaction with ANGPTL3. The role of miR-103 in regulating ANGPTL8 in human obesity remains unclear. Our aim is to investigate miR-103 expression in obese and non-obese individuals and evaluate its regulatory and functional interaction with ANGPTL8 in lipid metabolism. Methods: miR-103 expression was measured by RT-PCR in 144 participants (82 non-obese, BMI <30 kg/m²; 62 obese, BMI ≥30 kg/m²). Plasma ANGPTL8 levels were quantified by ELISA. miR-103-ANGPTL8 interaction was validated using luciferase reporter assays. miR-103 overexpression studies assessed effects on ANGPTL8 expression and LPL activity. Structural modeling and proteomic profiling were performed to identify downstream mechanisms. Results: miR-103 levels were significantly lower in obese individuals (P = 0.002) and inversely correlated with plasma TG levels (P = 0.011), while ANGPTL8 levels were positively correlated with TGs. In vitro assays confirmed direct repression of ANGPTL8 by miR-103, resulting in increased LPL activity, further enhanced in the presence of ANGPTL3. Structural analysis showed ANGPTL8 conformational changes upon ANGPTL3 binding that promote LPL inhibition. Proteomic analysis revealed downregulation of lipid-associated proteins (FASN, SCD, FABP1), potentially mediated through SREBP1 pathway. Conclusion: Downregulation of miR-103 in obesity promotes dyslipidemia through activation of the ANGPTL8-ANGPTL3 axis and impaired LPL activity. miR-103 is a key epigenetic regulator of triglyceride metabolism and a potential therapeutic target. Disclosure J.A. Abubaker: None. P. Cherian: None. M.Z. Malik: None. A. Mohammad: None. I. Al Khairi: None. F. Al-Mulla: None. M. Abu-Farha: None. Funding Kuwait Foundation for the Advancement of Sciences (RAHM2023-027)