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  • Cholesterol homeostasis is maintained through a tight


    Cholesterol homeostasis is maintained through a tight regulation between endogenous de novo synthesis, dietary absorption, utilization and excretion of bile salts. The cotransporter of cholesterol from the intestine constitutes the central part of cholesterol homeostasis in the body [41]. In particular, the small intestine plays a vital role in the absorption of alimentary fat. Our study showed that PE down-regulated Npc1l1 gene expression and up-regulated Abcg5 and Abcg8 gene expression in the intestinal tissue, whereas HCD+PE+A prevented their expression. The activation of Lxrα increases transcription of these proteins [25], [42]; notably, our results also showed that HCD+PE, but not HCD+PE+A, also up-regulated Lxrα expression in the small intestine tissue. These findings collectively suggested that microbiota-dependent SCFA generation contributed to the beneficial effects exerted by PE on intestinal cholesterol absorption. More significantly, we observed that PE supplementation markedly improved the intestine length, gut permeability and villus structure in comparison with HCD, but this phenomenon was not observed in the HCD+PE+A group. Recent study reported that the improvement of gut permeability could protect against atherosclerosis in apoE−/− mice by decreasing lipopolysaccharide penetration from the gut lumen into the bloodstream [43]. Because high-fat diet feeding was associated with the reduction of Akkermansia muciniphila abundance in the gut, we speculated that PE treatment may produce more beneficial bacteria after fermentation of intestinal flora, thus affecting the composition of the flora and then exerts benefit effects on gut permeability and morphology which resulting in the effects on lightening or inhibiting atherosclerosis. Further studies are needed to support this hypothesis. HCD+PE+A treatment only affected acetate concentration in this study, and this finding was comparable to the previous report [44]. Several studies demonstrated that the physicochemical properties of dietary fiber PE were critical in the determination of physiological effects, SCFAs profiles and gut microbiota composition in animal experiments [45], [46]. On the other side, high-fat diet was shown to disrupt the composition of the gut microbiota, resulting in a reduction in beneficial flora compared to the standard chow diet [47]. In contrast to germ-free mice, cocktail of antibiotics cannot delete all the bacteria in the gut [48], [49]. In the context of HCD treatment, long-term antibiotic treatment might reduce the abundance of some undesirable species and partly restore the dysbiosis, thus contributing to the increased level of acetate in the antibiotic group. However, this speculation may require future investigation. We further explored whether these SCFAs play a leading role in intestinal cholesterol absorption in vitro. Although the level of SCFAs is low in circulation, their concentrations could reach 20–140 mmol/L in the colon. Therefore, we continued to examine the local effects of butyrate in the Caco-2 cell model. The result showed that treatment of Caco-2 cells with butyrate suppressed the cholesterol uptake in a dose-dependent manner. As expected, butyrate treatment inhibited NPC1L1 and increased ABCG5/G8 gene expression in a dose-dependent fashion. Previous studies have documented that LXRα was upon the upstream of NPC1L1 and ABCG5/G8 through a molecular transcription pathway involving LXRα activation [50]. We therefore determined the effect of butyrate on LXR activation and found that butyrate significantly unregulated the LXR transcriptional activity. This result may further explain the potential molecular mechanism by which butyrate regulates cholesterol homeostasis. However, we did not observe any significant effects of the other two SCFAs, including acetic and propionic acid, on the gene expression related to intestinal cholesterol absorption.