Role of Angiogenesis in the Pathogenesis of NAFLD

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, exposing to the risk of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Angio-genesis is a complex process leading to the development of new vessels from pre-existing vessels. Angiogenesis is triggered by hypoxia and inflammation and is driven by the action of proangiogenic cytokines, mainly vascular endothelial growth factor (VEGF). In this review, we focus on liver angiogenesis associated with NAFLD and analyze the evidence of liver angiogenesis in animal models of NAFLD and in NAFLD patients. We also report the data explaining the role of angiogenesis in the progression of NAFLD and discuss the potential of targeting angiogenesis, notably VEGF, to treat NAFLD.

Keywords: liver sinusoidal endothelial cells; non-alcoholic steatohepatitis; vascular endothelial growth factor.

Figure 1

Mechanisms promoting angiogenesis in NAFLD and effects of antiangiogenic treatments in animal models. In NAFLD, steatotic hepatocytes produce proangiogenic extracellular vesicles. Steatosis induces hypoxia both by an increased lipid metabolism which enhances oxygen consumption and by a mechanical pressure on sinusoids. Hepatic stellate cells, portal myofibroblasts and macrophages stimulate angiogenesis by secreting VEGF. Proangiogenic signals also come from the adipose tissue which secretes leptin. In animal models of NAFLD, several antiangiogenic treatments (anti-VEGR2, L1-10 peptibody, angiotensin II receptor blockers) have shown efficacy to reduce steatosis, inflammation, fibrosis and HCC. Abbreviations: HCC, hepatocellular carcinoma; LSECs, liver sinusoidal endothelial cells; NAFLD, non-alcoholic fatty liver disease; VEGF, vascular endothelial growth factor; VEGFR-2, vascular endothelial growth factor receptor-2.