Adipocytokine Regulation and Antiangiogenic Activity Underlie the Molecular Mechanisms of Therapeutic Effects of Phyllanthus niruri against Non-Alcoholic Fatty Liver Disease.

Raghdaa Al Zarzour,Muhammad Asif,Mohd Asmawi,Mohammed Alshawsh,Dhamraa Al-Dualimi,Amin Abdul Majid,Majed Al-Mansoub,Zahurin Mohamed,Mariam Ahmad,Mun Yam,Gurjeet Kaur

doi:10.3390/nu10081057

Abstract

The growth of adipose tissues is considered angiogenesis-dependent during non-alcoholic fatty liver disease (NAFLD). We have recently reported that our standardized 50% methanolic extract (ME) of Phyllanthus niruri (50% ME of P. niruri) has alleviated NAFLD in Sprague–Dawley rats. This study aimed to assess the molecular mechanisms of action, and to further evaluate the antiangiogenic effect of this extract. NAFLD was induced by eight weeks of high-fat diet, and treatment was applied for four weeks. Antiangiogenic activity was assessed by aortic ring assay and by in vitro tests. Our findings demonstrated that the therapeutic effects of 50% ME among NAFLD rats, were associated with a significant increase in serum adiponectin, reduction in the serum levels of RBP4, vaspin, progranulin, TNF-α, IL-6, and significant downregulation of the hepatic gene expression of PPARγ, SLC10A2, and Collα1. Concomitantly, 50% ME of P. niruri has exhibited a potent antiangiogenic activity on ring assay, cell migration, vascular endothelial growth factor (VEGF), and tube formation, without any cytotoxic effect. Together, our findings revealed that the protective effects of P. niruri against NAFLD might be attributed to its antiangiogenic effect, as well as to the regulation of adipocytokines and reducing the expression of adipogenic genes.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is an emerging metabolic disorder that encompasses a wide range of liver injuries, extending from simple steatosis to non-alcoholic steatohepatitis (NASH)which can develop to fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC) [1].Nutrients 2018, 10, 1057; doi:10.3390/nu10081057 www.mdpi.com/journal/nutrientsLiver is an essential organ for normal lipid homeostasis [2]
Thehepatocytes hepatocytesininthis thisgroup groupwere were significantly greater in size, compared to normal control group which was fed with normal diet
Many recent studies proposed that adipose visceral tissue is an essential metabolic and

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is an emerging metabolic disorder that encompasses a wide range of liver injuries, extending from simple steatosis to non-alcoholic steatohepatitis (NASH). Liver is an essential organ for normal lipid homeostasis [2]. Free fatty acids (FFAs) are released into the bloodstream through lipolysis process in adipose tissues, and the hepatocytes are responsible for their uptake by fatty acid carriers [3]. In fasting state, they are oxidized in the mitochondria and peroxisomes to produce energy, while in fed state, they might be re-esterified into triglycerides. Glucose is converted to FFAs in the liver by means of de novo lipogenesis (DNL) which produces triglycerides [4]

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