Ilexsaponin A1 Ameliorates Diet-Induced Nonalcoholic Fatty Liver Disease by Regulating Bile Acid Metabolism in Mice.

Wen-Wen Zhao,Ting Zhao,Xiao-Qing Chen,Xiu-Wei Li,Meng Xiao,Xia Wu,Lan Yu,Xiao-Xi Li

doi:10.3389/fphar.2021.771976

Abstract

Bile acid (BA) metabolism is an attractive therapeutic target in nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the effect of ilexsaponin A1 (IsA), a major bioactive ingredient of Ilex, on high-fat diet (HFD)-induced NAFLD in mice with a focus on BA homeostasis. Male C57BL/6J mice were fed an HFD to induce NAFLD and were treated with IsA (120 mg/kg) for 8 weeks. The results showed that administration of IsA significantly decreased serum total cholesterol (TC), attenuated liver steatosis, and decreased total hepatic BA levels in HFD-induced NAFLD mice. IsA-treated mice showed increased BA synthesis in the alternative pathway by upregulating the gene expression levels of sterol 27-hydroxylase (CYP27A1) and cholesterol 7b-hydroxylase (CYP7B1). IsA treatment accelerated efflux and decreased uptake of BA in liver by increasing hepatic farnesoid X receptor (FXR) and bile salt export pump (BSEP) expression, and reducing Na+-taurocholic acid cotransporting polypeptide (NTCP) expression. Alterations in the gut microbiota and increased bile salt hydrolase (BSH) activity might be related to enhanced fecal BA excretion in IsA-treated mice. This study demonstrates that consumption of IsA may prevent HFD-induced NAFLD and exert cholesterol-lowering effects, possibly by regulating the gut microbiota and BA metabolism.

Highlights

Nonalcoholic fatty liver disease (NAFLD), recently named metabolic-associated fatty liver disease (MAFLD), is a rapidly growing metabolic disease associated with type-2 diabetes and obesity (Tilg et al, 2021)
It is noteworthy that compared with the high-fat diet (HFD) group, serum total cholesterol (TC) levels were significantly decreased in the ilexsaponin A1 (IsA) group, with lower values than that of the mice treated with fenofibrate (Figure 1D)
After 8 weeks of HFD, the intraperitoneal glucose tolerance test (ipGTT)-area under the curve (AUC) (Figures 1F, G), fasting blood glucose concentration (Figure 1H), insulin concentration (Figure 1I), and HOMA-Insulin resistance (IR) index (Figure 1J) were enhanced remarkably in the HFD group compared with the chow group

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD), recently named metabolic-associated fatty liver disease (MAFLD), is a rapidly growing metabolic disease associated with type-2 diabetes and obesity (Tilg et al, 2021). Bile acid (BA) synthesis and excretion are critical in the progression of NAFLD, and represent major pathways of cholesterol catabolism (Sciarrillo et al, 2021). Many drugs targeting BA metabolism have been shown to be effective against metabolic diseases, including apical sodiumdependent bile acid transporter (ASBT) inhibitors and FXR agonists/antagonists (Matye et al, 2021a; Matye et al, 2021b; Clifford et al, 2021). Studies highlighted efforts to activate BA synthesis, accelerate BA circulation, and fecal excretion as potential therapeutic strategies for NAFLD (Jia et al, 2020). Farnesoid X receptor (FXR) is a BA-activated nuclear receptor that modulates the

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