Apple Polyphenol Extract Improves High-Fat Diet-Induced Hepatic Steatosis by Regulating Bile Acid Synthesis and Gut Microbiota in C57BL/6 Male Mice

Abstract

Our previous study showed that apple polyphenol extract (APE) ameliorated high-fat diet-induced hepatic steatosis in C57BL/6 mice by targeting the LKB1/AMPK pathway; to investigate whether other mechanisms are involved in APE induction of improved hepatic steatosis, especially the roles of bile acid (BA) metabolism and gut microbiota, we conducted this study. Thirtythree C57BL/6 male mice were fed with high-fat diet for 12 weeks and concomitantly treated with sterilized water (CON) or 125 or 500 mg/(kg•bw•day) APE (low-dose APE, LAP; high-dose APE, HAP) by intragastric administration. APE treatment decreased total fecal BA contents, especially fecal primary BA levels, mainly including cholic acid, chenodeoxycholic acid, and muricholic acid. An upregulated hepatic Farnesoid X receptor (FXR) protein level and downregulated protein levels of cholesterol 7α-hydroxylase (CYP7A1) and cholesterol 7α-hydroxylase (CYP27A1) were observed after APE treatment, which resulted in the suppressed BA synthesis. Meanwhile, APE had no significant effects on mucosal injury and FXR expression in the jejunum. APE regulated the diversity of gut microbiota and microbiota composition, characterized by significantly increased relative abundance of Akkermansia and decreased relative abundance of Lactobacillus. Furthermore, APE might affect the reverse cholesterol transport in the ileum, evidenced by the changed mRNA levels of NPC1-like intracellular cholesterol transporter 1 (Npc1l1), liver X receptor (Lxr), ATP binding cassette subfamily A member 1 (Abca1), and ATP binding cassette subfamily G member 1 (Abcg1). However, APE did not affect the dihydroxylation and taurine metabolism of BA. The correlation analysis deduced no obvious interactions between BA and gut microbiota. In summary, APE, especially a high dose of APE, could alleviate hepatic steatosis, and the mechanisms were associated with inhibiting BA synthesis and modulating gut microbiota.

Tilapia-Head Chondroitin Sulfate Protects against Nonalcoholic Fatty Liver Disease via Modulating the Gut–Liver Axis in High-Fat-Diet-Fed C57BL/6 Mice

“…Therefore, it is urgent to develop a natural treatment for NAFLD that has superior preventive effects and a low risk of side effects. In the past few years, more and more attention has been paid to the extraction and identification of functional components from natural organisms, such as polyphenols and polysaccharides, as well as their extensive biological effects [ 8 , 9 , 10 ]. Among them, it is worth emphasizing that chondroitin sulfate (CS) has been identified as a novel dietary supplement and functional food, and it has become a recent focus of research [ 11 ].…”

l-Arabinose improves hypercholesterolemia via regulating bile acid metabolism in high-fat-high-sucrose diet-fed mice

“…Bile acid reabsorption and cholesterol absorption in the small intestine are closely related to maintaining cholesterol homeostasis, and lowering cholesterol function of other substances is closely linked to these two pathways [ 23 , 38 ]. For instance, the underlying mechanisms for the hypocholesterolemic activity of β‑sitosterol laurate involve these two pathways mediated by reducing ASBT and I-BABP levels and downregulating intestinal niemann-pick c1-like protein 1 (NPC1L1) respectively, therefore, increasing the excretion of fecal bile acids and cholesterol [ 39 ].…”

“…Moreover, the reabsorption of intestinal bile acids, which enables bile acids to return to the liver and maximizes the use of it through enterohepatic circulation, also has a vital influence on cholesterol homeostasis [ 20 , 21 ]. Previous studies have clearly revealed that the hypocholesterolemic action of functional foods supplement is closely related to enterohepatic circulation of bile acids [ 22 , 23 ]. Therefore, it is necessary to consider the regulatory effect of l -arabinose on cholesterol metabolism from the perspective of bile acid metabolism.…”

The System Profile of Renal Drug Transporters in Tubulointerstitial Fibrosis Model and Consequent Effect on Pharmacokinetics

“…Therefore, in this paper, the dynamic changes in transport proteins under the TIF model were related to Cr and Ccr by correlation analysis, and transport proteins were found that were highly correlated with Ccr. Transporter inhibitors are compounds that competitively bind or inhibit transporter activity [ 23 , 24 ]. Therefore, in the case of multi-disease combination, there will be interactions between drugs, such as P-gp [ 25 , 26 ], which has a variety of inducers in vivo, including antibacterial drug rifampicin, anti-tumor drug vincristine, doxorubicin, cardiovascular drug verapamil [ 27 ], hyperlipidemia drug atorvastatin [ 28 ], etc., which can induce the overexpression of P-gp in vivo.…”