Increased ANGPTL3, 4 and ANGPTL8/betatrophin expression levels in obesity and T2D

Mohamed Abu-Farha,Betty Chandy,Faisal Al-Refaei,Devarajan Sriraman,Jehad Abubaker,Asma Alhubail,Abdulmohsen Alterki,Preethi Cherian,Irina Al-Khairi

doi:10.1186/s12944-016-0337-x

Mohamed Abu-Farha, Betty Chandy + Show 7 more

Open Access

https://doi.org/10.1186/s12944-016-0337-x

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Journal: Lipids in Health and Disease	Publication Date: Oct 13, 2016
Citations: 76	License type: cc-by

Affiliation: Dasman Diabetes Institute

Abstract

BackgroundHypertriglyceridemia is associated with increased risk for cardiovascular diseases and type 2 diabetes (T2D). Angiopoietin like proteins particularly 3, 4 and recently 8 are well established regulators of plasma triglyceride level through regulating the activity of lipoprotein lipase. Plasma level and association between ANGPTL3, 4 and 8 is not well established in human subjects. This study was designed to establish the level of these proteins in plasma and adipose tissues and investigate the association between ANGPTL8 with ANGPTL3 and 4 in T2D and non-diabetics subjects.MethodsA total of 235 subjects were enrolled in this study, 144 non-diabetics and 91 T2D. ANGPTL 3, 4 and 8 levels were measured in plasma by ELISA and using real time RT-PCR in adipose tissues.ResultsIn this study, we showed that ANGPTL3, 4 and 8 were higher in T2D subjects. Dividing the non-diabetic subjects according to their BMI showed higher level of ANGPTL3, 4 and 8 in obese subjects compared to non-obese subjects. No significant difference was observed between the T2D subjects. ANGPTL8 was showed positive correlation with ANGPTL3 in the non-diabetic subjects in the non-obese (r = 0.2437, p-Value = 0.0543) and obese subjects (r = 0.418, p-Value = 0.0125). No association was observed in the T2D subjects. On the other hand, ANGPTL4 was positively associated with the obese subjects in both the non-diabetics (r = 0.3322, p-Value = 0.0316) and the obese T2D subjects (r = 0.3161, p-Value = 0.0211).ConclusionIn conclusion, our data shows that ANGPTL3, 4 and 8 are increased in obesity and T2D. ANGPTL8 associates with ANGPTL3 in the non-diabetic subjects while it associated more with ANGPTL4 in the obese and T2D subjects. Taken together, this data highlight the role of these proteins in metabolic diseases and how they interact with each other’s under different physiological and pathophysiological conditions.

Highlights

Hypertriglyceridemia is associated with increased risk for cardiovascular diseases and type 2 diabetes (T2D)
ANGPTL3 is produced by the liver it is proteolytically cleaved by proprotein convertases to generate an active N-terminal domain that acts as an inhibitor of lipoprotein lipase (LPL) activity [12, 13]
ANGPTL4 was higher in T2D subjects (203.78 ± 11.68 ng/ml compared to 144.47 ± 4.47 ng/ml for the non-diabetics) (p-Value < 0.001)

Summary

Introduction

Hypertriglyceridemia is associated with increased risk for cardiovascular diseases and type 2 diabetes (T2D). One study showed that loss of function mutations identified in ANGPTL3 associated with decreased VLDL, LDL, HDL and TG [14]. This was linked to a recessive disorder disease termed familial combined hypobetalipoproteinemia [14, 15]. Recent data has linked loss of function mutations in ANGPTL4 to reduced incidences of Coronary heart disease [17, 18] Due to their role in regulating LPL activity and the fact that many genome wide association studies has linked them to dyslipidemia, ANGPTL3 and 4 are being explored as drug targets for metabolic diseases [16]. Specific monoclonal antibodies targeting ANGPTL3 and 4 has been shown to decrease plasma lipid content [16]

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