Angiopoietin-like protein 8 (ANGPTL8)/betatrophin is liver and adipocyte produced hormone that has been associated with insulin resistance and dyslipidaemia. The interaction of ANGPTL8 with ANGPTL3 causes an inhibition of lipoprotein lipase (LPL) activity and ultimately increases serum levels of triglyceride. Identification of ANGPTL8 and ANGPTL3 inhibitors have been pursued as potential drug target to treat dyslipidaemia. In this study we used target prediction algorithms to show that mir103 has a putative binding sites in the 3' untranslated region of ANGPTL8. Overexpression of mir103 in HepG2 cells or its mimic resulted in decreased ANGPTL8 RNA and protein level compared to scrambled microRNA control. Cloning the 3’UTR of ANGPTL8 with Luciferase reporter assay confirmed the direct binding and repression of luciferase activity by mir103 to ANGPTL8 compared to its control. Palmitic acid treatment of HepG2 cells mimicked dyslipidaemia and increased ANGPTL8 level which was reduced after treatment with mir103. Additionally, expression of miR103 and ANGPTL8 in circulation and adipose tissue was evaluated in 144 participants that included 82 non-obese (BMI <30 kg/m2) and 62 obese (BMI >30 kg/m2). Mir103 levels in small RNA extracted from plasma and adipose tissue was measured by RT-PCR. Mir103 was higher in non-obese people in both plasma and adipose tissue. ANGPTL8 level on the other hand was higher in obese individuals (1200.5 ±110.2 pg/ml) compared to non-obese (720.7 ±80.9 pg/ml, p-value =0007). MiR103 was inversely associated with BMI (p-value < 0.001), leptin (p-value = 0.010) and triglyceride (p-value =0.011). Taken together, our data confirms the binding and inhibition of mir103 to ANGPTL8 under normal and high fat conditions. It also sheds light on the potential role of mir103 in regulating lipid metabolism which can be used as a future therapeutic target for dyslipidaemia and other metabolic related diseases.


M. Abu-Farha: None. P.T. Cherian: None. I. Al Khairi: None. F. Al-Mulla: None. J. Abubaker: None.


Dasman Diabetes Institute; Kuwait Foundation for the Advancement of Sciences (RA2016-025)

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