Department of Infectious Diseases, Xiangya Hospital, Central South University and Key Laboratory of Viral Hepatitis, Hunan, Changsha, China; Department of Medicine, University of California San Diego, La Jolla, California.
Department of Medicine, University of California San Diego, La Jolla, California.
Cell Mol Gastroenterol Hepatol. 2021;12(1):293-320. doi: 10.1016/j.jcmgh.2021.02.009. Epub 2021 Feb 22.
BACKGROUND & AIMS: Fucosyltransferase 2 (Fut2)-mediated intestinal α1- 2-fucosylation is important for host-microbe interactions and has been associated with several diseases, but its role in obesity and hepatic steatohepatitis is not known. The aim of this study was to investigate the role of Fut2 in a Western-style diet-induced mouse model of obesity and steatohepatitis.
Wild-type (WT) and Fut2-deficient littermate mice were used and features of the metabolic syndrome and steatohepatitis were assessed after 20 weeks of Western diet feeding.
Intestinal α1-2-fucosylation was suppressed in WT mice after Western diet feeding, and supplementation of α1-2-fucosylated glycans exacerbated obesity and steatohepatitis in these mice. Fut2-deficient mice were protected from Western diet-induced features of obesity and steatohepatitis despite an increased caloric intake. These mice have increased energy expenditure and thermogenesis, as evidenced by a higher core body temperature. Protection from obesity and steatohepatitis associated with Fut2 deficiency is transmissible to WT mice via microbiota exchange; phenotypic differences between Western diet-fed WT and Fut2-deficient mice were reduced with antibiotic treatment. Fut2 deficiency attenuated diet-induced bile acid accumulation by altered relative abundance of bacterial enzyme 7-α-hydroxysteroid dehydrogenases metabolizing bile acids and by increased fecal excretion of secondary bile acids. This also was associated with increased intestinal farnesoid X receptor/fibroblast growth factor 15 signaling, which inhibits hepatic synthesis of bile acids. Dietary supplementation of α1-2-fucosylated glycans abrogates the protective effects of Fut2 deficiency.
α1-2-fucosylation is an important host-derived regulator of intestinal microbiota and plays an important role for the pathogenesis of obesity and steatohepatitis in mice.
肠道 α1-2-岩藻糖基转移酶 2（Fut2）介导的肠道 α1-2-岩藻糖基化对宿主-微生物相互作用很重要，并且与几种疾病有关，但它在肥胖和脂肪性肝炎中的作用尚不清楚。本研究旨在研究 Fut2 在西式饮食诱导的肥胖和脂肪性肝炎小鼠模型中的作用。
使用野生型（WT）和 Fut2 缺陷型同窝小鼠，并在 20 周的西式饮食喂养后评估代谢综合征和脂肪性肝炎的特征。
在 WT 小鼠中，西式饮食喂养后肠道 α1-2-岩藻糖基化受到抑制，而补充 α1-2-岩藻糖化糖加剧了这些小鼠的肥胖和脂肪性肝炎。尽管 Fut2 缺陷型小鼠的热量摄入增加，但它们仍能免受西式饮食引起的肥胖和脂肪性肝炎的影响。这些小鼠的核心体温更高，表明它们的能量消耗和产热增加。通过微生物群交换，Fut2 缺陷型可将与 Fut2 缺乏相关的肥胖和脂肪性肝炎的保护作用传递给 WT 小鼠；抗生素治疗可降低 WT 与 Fut2 缺陷型小鼠之间与饮食相关的表型差异。Fut2 缺乏通过改变代谢胆汁酸的细菌酶 7-α-羟甾酮脱氢酶的相对丰度以及增加次级胆汁酸的粪便排泄来减轻饮食诱导的胆汁酸积累。这也与肠道法尼醇 X 受体/成纤维细胞生长因子 15 信号传导的增加有关，该信号传导抑制肝脏合成胆汁酸。α1-2-岩藻糖化糖的饮食补充可消除 Fut2 缺乏的保护作用。
α1-2-岩藻糖基化是肠道微生物群的重要宿主来源调节剂，在肥胖和脂肪性肝炎小鼠的发病机制中起重要作用。
