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  • Previous studies have documented that


    Previous studies have documented that SCFAs may elicit effects on lipid metabolism via de novo synthesis and transport. Acetate is not only used as an energy source, but is also constituted as a substrate for the cholesterol synthesis in the liver through acetyl-CoA, thus affecting plasma cholesterol levels [9]. In addition, propionate was shown to reduce plasma cholesterol concentrations in rodents and humans by inhibiting de novo synthesis of cholesterol through inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) [10], [11]. Furthermore, butyrate has been shown to stimulate the ApoA-IV-containing lipoprotein secretion and therefore regulate reverse cholesterol transport [12], [13]. Thus, microbiota-dependent SCFA generations plays an essential role in modifying lipid metabolism and thus may partly account for the beneficial impacts of dietary fiber on atherosclerotic CVD prevention. The small intestine is a unique organ that provides dietary and Cy3 NHS ester mass reabsorbed biliary cholesterol to the body and plays a critical role in the regulation of whole-body cholesterol balance [14], [15]. Intestinal cholesterol Cy3 NHS ester mass has recently been considered as an important procedure in the modulation of cholesterol homeostasis [16]. Several key regulators were found to play a crucial role in the modulation of cholesterol absorption in intestine. Niemann-Pick C1-Like 1 (NPC1L1) protein was discovered as an intestinal phytosterol and cholesterol transporter to regulate intestinal cholesterol absorption and hepatobiliary cholesterol excretion [17]. Moreover, NPC1L1 also functions as the molecular target of ezetimibe, a potent cholesterol absorption inhibitor, and is widely used for the treatment of hypercholesterolemia [18]. In addition, the family of ATP-binding cassette (ABC) transporters G5 and G8 (ABCG5 and ABCG8) form an obligate heterodimer that limits cholesterol and plant sterol absorption by effectively transporting these sterols from enterocytes into the intestinal lumen [19]. However, the impact of the SCFAs on the intestinal cholesterol absorption is still unknown. The objective of this study was to investigate the potential effect of SCFAs by fiber intestinal fermentation on atherosclerosis in high-fat and high-cholesterol-fed apolipoprotein E-deficient (apoE−/−) mice. Furthermore, the underlying mechanism involved in the effects of SCFAs was determined in vitro.
    Materials and methods
    Discussion In this study, we showed that supplementation of PE resulted in improved blood lipid profiles and the reduction in atherosclerotic plaque formation, whereas the depletion of gut microbiota by antibiotic treatment suppressed or exacerbated these effects in apoE−/− mice. Then, we found that PE-feeding stimulated Lxrα expression, resulting in changes in expression of LXR-mediated target genes, including the decrease in Npc1l1 and increase in Abcg5 and Abcg8 expression, which are related to intestinal cholesterol uptake and excretion, in the small intestinal mucosa of apoE−/− mice. Finally, we demonstrated that butyrate treatment prohibited intestinal cholesterol absorption by regulating related transporter expression at the mRNA level. Thus, the present study reveals a novel mechanism through which PE may attenuate atherosclerosis by inhibiting intestinal cholesterol absorption via gut microbiota-dependent butyrate production. A growing number of studies have reported that the abnormal elevation of circulating cholesterol is considered as a well-documented risk factor for the formation of atherosclerosis. Consumption of different dietary fibers such as inulin, oat bran and PE were inversely associated with CVD and effectively lowered the plasma cholesterol [27], [28], [29]. The hypocholesterolemic properties of soluble dietary fiber may be realized through its physical effects such as viscosity and water-holding capacity, which affect cholesterol absorption and bile acid excretion [30], [31]. Furthermore, growing numbers of studies suggest that dietary fiber fermentation by gut microbiota also serves a physiological function through the regulation of metabolism. SCFAs, the end products from dietary fermentation, play a crucial role in the prevention of many disorders such as allergic airway disease [32], food allergy [33], and modulation of glucose homeostasis [34], [35], [36]. In addition, SCFAs per se have been shown to be involved in lowering plasma cholesterol levels by decreasing cholesterol synthesis [9]. HCD+PE mice exhibited a lower rate of atherosclerotic lesions than did the HCD group, whereas antibiotic treatment suppressed these effects, implying that the beneficial effects on lipid profiles and atherogenesis by incorporating PE into HCD may be caused, at least in part, by the fermentation products, SCFAs. We did not find any significant changes of glucose levels in our study, suggesting that the beneficial role of SCFAs against atherosclerosis may not be attributed to alteration of glucose metabolism. The antibiotics used in this study was referred to previous well-established protocols [37], [38], which was showed to effectively deplete the intestinal microbiota [39], [40].