(+)-Dehydrovomifoliol Alleviates Oleic Acid-Induced Lipid Accumulation in HepG2 Cells via the PPARα-FGF21 Pathway.

Yiyuan Xi,Xudong Zhou,Namki Cho,Xiangwei Xu,Jujia Zheng,Xiaomin Yu,Wei Xie

doi:10.3389/fphar.2021.750147

Abstract

An overload of hepatic fatty acids, such as oleic acid is a key trigger of non-alcoholic fatty liver disease (NAFLD). Here, we investigated whether Artemisia frigida, a valuable traditional medicine used to treat various diseases, could mitigate OA-induced lipid accumulation in HepG2 cells. Then, to identify the active substances in A. frigida, a phytochemistry investigation was conducted using a bioassay-guided isolation method. Consequently, one terpene (1) and one flavone (2) were identified. Compound 1 ((+)-dehydrovomifoliol) exhibited potent effects against lipid accumulation in OA-induced HepG2 cells, without causing cyto-toxicity. Notably, treatment with (+)-dehydrovomifoliol decreased the expression levels of three genes related to lipogenesis (SREBP1, ACC, and FASN) and increased those of three genes related to fatty acid oxidation (PPARα, ACOX1, and FGF21). In addition, similar results were observed for SREBP1, PPARα, and FGF21 protein levels. The effects of (+)-dehydrovomifoliol were partially reversed by treatment with the PPARα antagonist GW6471, indicating the important role of the PPARα–FGF21 axis in the effects of (+)-dehydrovomifoliol. Based on its effects on hepatic lipogenesis and fatty acid oxidation signaling via the PPARα–FGF21 axis, (+)-dehydrovomifoliol isolated from A. frigida could be a useful early lead compound for developing new drugs for NAFLD prevention.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease that is prevalent in China, affecting approximately 29% of the population when compared with the global prevalence of approximately 25%) (Loomba et al, 2021)
Through bioassay-guided fractionation of the 95% aqueous EtOH extract of A. frigida aerial parts, we found that the methylene dichloride (CH2Cl2) fraction exerted lipid accumulation decreasing effects in oleic acid (OA)-induced HepG2 cells
HepG2 cells were pretreated for 30 min with different concentrations of compound 1 and stimulated with 10 μM oleic acid (OA)

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease that is prevalent in China, affecting approximately 29% of the population when compared with the global prevalence of approximately 25%) (Loomba et al, 2021). A subset (15–20%) of patients with NAFLD progresses to develop the more severe disease nonalcoholic steatohepatitis (NASH) (Tilg and Moschen, 2010). Targeting lipid dysregulation is extremely important for developing additional complex treatment options for patients with NAFLD. Fibroblast growth factor 21 (FGF21) is a direct target gene of PPARα and a key mediator of hepatic lipid metabolism (Badman et al, 2007). Because of its ability to directly modulate lipid metabolism in the liver and to improve whole-body metabolic homeostasis, the PPARα–FGF21 axis has emerged as a promising target for the treatment of NAFLD and NASH. Other studies have shown that activation of the PPARα–FGF21 pathway has protective effects against lipid accumulation and NAFLD and NASH development (Marino et al, 2016; Zeng et al, 2017). Innocuous, more effective therapeutic agents—possibly of natural origin—are needed to treat hepatic TG accumulation in patients with NAFLD

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Conclusion