Abstract
Obesity impacts the endocrine and metabolic functions of the adipose tissue. There is increasing interest in the role of epigenetic factors in obesity and its impact on diabetes and dyslipidemia. One such substance, miR-181, reduces plasma triglyceride levels in mice by targeting isocitrate dehydrogenase 1. In the other hand, the adipocyte differentiation and lipid regulating hormone angiopoietin-like 3 (ANGPTL3) is a known regulator of circulating apolipoproteins through its inhibition of the lipoprotein lipase activity. We aimed to study the miR-181d expression in the blood and adipose tissue in a cohort of obese and non-obese people, assessing its possible role in obesity. We also aimed to confirm whether miR-181d can bind and regulate ANGPTL3. miR-181d expression levels were investigated in 144 participants, 82 who were non-obese (body mass index [BMI] < 30) and 62 who were obese (BMI > 30). miR-181d levels in plasma and adipose tissue were measured by RT-PCR. Hepatocyte cell cultures were assessed by overexpression and 3′-UTR-luciferase assays for miR-181d binding to its target protein and its effect on the protein. The plasma levels of ANGPTL3 were also measured by ELISA. The miR-181d levels were significantly lower in obese than in non-obese individuals. In vitro analysis confirmed miR-181 binding to and repression of the ANGPTL3 transcript. Obesity leads to alterations in miR-181d expression. Its downregulation in obese humans was inversely correlated with ANGPTL3, a protein involved in adipocyte differentiation and lipid metabolism. miR-181d can be used as an inhibitor of ANGPTL3 to reduce the TG plasma level.
Highlights
Obesity is a global epidemic and an increasing concern worldwide for peoples’ health and well-being
Earlier studies showed that loss of function mutations identified in angiopoietin-like 3 (ANGPTL3) was associated with reduced levels of very low-density lipoprotein (VLDL), LDL, high-density lipoprotein (HDL) and TG23
This study was designed to evaluate the expression of miR-181d in obesity and to shed light on its role in lipid metabolism by modulating an important lipid-regulating protein, ANGPTL3
Summary
Obesity is a global epidemic and an increasing concern worldwide for peoples’ health and well-being. One of the key enzymes involved in regulating plasma TG level is lipoprotein lipase (LPL)[11,12,13,14] It is responsible for the hydrolysis of TG-rich lipoprotein into fatty acids that can be utilised by peripheral tissues or stored in adipocytes. Earlier studies showed that loss of function mutations identified in ANGPTL3 was associated with reduced levels of very low-density lipoprotein (VLDL), LDL, HDL and TG23. Our recent study showed increased ANGPTL3 levels in obese humans without diabetes as compared with healthy normal-weight controls[24]. This study was designed to examine the miR-181d expression levels in obesity and to investigate its association with ANGPTL3. We studied the impact of its overexpression and its mimics on the expression of ANGPTL3 in a hepatocyte cell model under normal conditions and after treatment with free fatty acids
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