Abstract
Scope: Gut microbiome-derived metabolites are the major mediators of diet-induced host-microbial interactions. Aryl hydrocarbon receptor (AHR) plays a crucial role in glucose, lipid, and cholesterol metabolism in the liver. In this study, we aimed to investigate the role of indole-3-acetic acid (IAA) and AHR in sulforaphane (SFN) alleviates hepatic steatosis in mice fed on a high-fat diet (HFD).Methods and Results: The HFD-fed male C57BL/6 mice were intervened with SFN for 6 weeks. HFD-mice showed classical pathophysiological characteristics of hepatic steatosis. The results showed that SFN significantly reduced body weight, liver inflammation and hepatic steatosis in HFD-fed mice. SFN reduced hepatic lipogenesis by activating AHR/SREBP-1C pathway, which was confirmed in HepG2 cell experiments. Moreover, SFN increased hepatic antioxidant activity by modulating Nrf-2/NQO1 expression. SFN increased serum and liver IAA level in HFD mice. Notably, SFN manipulated the gut microbiota, resulting in reducing Deferribacteres and proportions of the phylum Firmicutes/Bacteroidetes and increasing the abundance of specific bacteria that produce IAA. Furthermore, SFN upregulated Ahr expression and decreased the expression of inflammatory cytokines in Raw264.7 cells.Conclusions: SFN ameliorated hepatic steatosis not only by modulating lipid metabolism via AHR/SREBP-1C pathway but regulating IAA and gut microbiota in HFD-induced NAFLD mice.
Highlights
We aimed to investigate the role of indole-3-acetic acid (IAA) and aryl hydrocarbon receptor (AHR) in sulforaphane (SFN) alleviates hepatic steatosis in mice fed on a high-fat diet (HFD)
The results showed that SFN significantly reduced body weight, liver inflammation and hepatic steatosis in HFD-fed mice
25% of the global population struggles with nonalcoholic fatty liver disease (NAFLD) with a dramatically growing prevalence [1]
Summary
25% of the global population struggles with nonalcoholic fatty liver disease (NAFLD) with a dramatically growing prevalence [1]. The widely accepted pathogenesis of NAFLD is that lipid deposits accumulate in the liver, followed by the activation of immune cells and the production of proinflammatory cytokines [2, 3]. Regulating metabolic nuclear receptors, such as the sterol regulatory element-binding protein1c (Srebp-1c), carbohydrate response element-binding protein (ChREBP), and peroxisome proliferator-activated receptor γ (PPAR-γ) prevents hepatic steatosis caused by a high-fat diet (HFD), indicating that uncontrolled de novo lipogenesis contributes to the development of NAFLD [4,5,6]. A myriad of studies has reported the effects of gut microbial metabolites on host health and disease, which might be mediated partially through the metabolome, such as short-chain fatty acid, serotonin, bile acids, and tryptophan metabolites [13]. Previous studies reported that tryptophan catabolite promotes the differentiation of naive CD4+ T helper cells into Treg cells and TH17 cells via aryl hydrocarbon receptor (AHR) [17]
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