The Angiogenesis Inhibitor ALS-L1023 from Lemon-Balm Leaves Attenuates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease through Regulating the Visceral Adipose-Tissue Function.

Jeongjun Kim,Jaeho Oh,Michung Yoon,Soon Shin,Haerim Lee,Jonghoon Lim

doi:10.3390/ijms18040846

Abstract

Similar to neoplastic tissues, growth and development of adipose tissue are thought to be angiogenesis-dependent. Since visceral adipose tissue (VAT) is associated with development and progression of nonalcoholic fatty liver disease (NAFLD), we hypothesized that angiogenesis inhibition would attenuate obesity-induced NAFLD. We fed C57BL/6J mice a low-fat diet (LFD, chow 10% kcal fat), a high-fat diet (HFD, 45% kcal fat) or HFD supplemented with the lemon-balm extract ALS-L1023 (HFD-ALS) for 15 weeks. ALS-L1023 reduced endothelial cell-tube formation in vitro. HFD increased VAT angiogenesis and induced weight gains including body weight, VAT mass and visceral adipocyte size compared with LFD. However, HFD-ALS led to weight reductions without affecting calorie intake compared with HFD. HFD-ALS also reduced serum ALT and AST levels and improved lipid metabolism. HFD-ALS suppressed steatosis, infiltration of inflammatory cells, and accumulation of collagen in livers. HFD-ALS modulated hepatic expression of genes involved in lipid metabolism, inflammation, fibrosis, antioxidation, and apoptosis. Concomitantly, analysis of VAT function revealed that HFD-ALS led to fewer CD68-positive macrophage numbers and lower expression of inflammatory cytokines compared with HFD. Our findings show that the anti-angiogenic herbal extract ALS-L1023 attenuates NAFLD by targeting VAT during obesity, suggesting that angiogenesis inhibitors could aid in the treatment and prevention of obesity-induced human NAFLD.

Highlights

Angiogenesis—the formation of new blood vessels from pre-existing vessels—is a strictly regulated process
We found that the anti-angiogenic herbal extract ALS-L1023 ameliorates visceral obesity and obesity-induced nonalcoholic fatty liver disease (NAFLD) by inhibiting visceral adipose tissue (VAT) angiogenesis and reducing VAT mass
Inhibition by ALS-L1023 was not due to cytotoxic effects because 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide disodium salt (XTT) assays showed that ALS-L1023 at concentrations between 0.1 and 10 μg/mL had no effects on human umbilical vein endothelial cell (HUVEC) viability (Figure 1C)

Summary

Introduction

Angiogenesis—the formation of new blood vessels from pre-existing vessels—is a strictly regulated process. Angiogenesis takes place only during embryonic development, wound healing, and menstruation [1]. Most tissues normally do not grow throughout adulthood and the supporting vasculature is quiescent [5], whereas adipose tissue can grow and regress throughout life. The growth and expansion of adipose tissue requires the formation of new blood vessels to provide oxygen and nutrients to adipocytes [6]. It is suggested, that adipose tissue growth is angiogenesis-dependent and may be inhibited by angiogenesis inhibitors. We demonstrated that the anti-angiogenic dietary supplement Ob-X reduces adipose tissue mass and suppresses obesity by inhibiting angiogenesis [7]

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