Fibroblast growth factor 21 is required for the therapeutic effects of Lactobacillus rhamnosus GG against fructose-induced fatty liver in mice
Fibroblast growth factor 21 is required for the therapeutic effects of Lactobacillus rhamnosus GG against fructose-induced fatty liver in mice
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鼠李糖乳杆菌 GG 对果糖诱导的小鼠脂肪肝的治疗作用需要成纤维细胞生长因子 21
DOI：
10.1016/j.molmet.2019.08.020
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发表时间：
2019-09
影响因子：
8.1
通讯作者：
Feng Wenke
中科院分区：
文献类型：
--
作者：
Zhao Cuiqing;Liu Liming;Liu Qi;Li Fengyuan;Zhang Lihua;Zhu Fenxia;Shao Tuo;Barve Shirish;Chen Yiping;Li Xiaokun;McClain Craig J;Feng Wenke
目的高果糖喂养改变成纤维细胞生长因子21（FGF 21）的调节，补充鼠李糖乳杆菌GG（LGG）可减少果糖诱导的非酒精性脂肪性肝病（NAFLD）。本研究旨在探讨FGF 21在LGG保护作用中的作用及其机制。方法采用30%果糖喂养FGF 21基因敲除（KO）小鼠和C57 BL/6野生型（WT）小鼠12周。在最后4周的果糖喂养期间向小鼠施用LGG。结果在果糖诱导的NAFLD小鼠中，FGF 21的表达在5周后显著增加，12周后显著降低。在WT小鼠中，LGG给药逆转了FGF 21表达的抑制，增加了ADPN的脂肪产生，并减少了肝脏脂肪蓄积和炎症，但在KO小鼠中没有。肝细胞核碳水化合物反应元件结合蛋白（ChREBP）增加果糖和减少LGG，导致脂肪生成基因的表达减少。甲基化形式的蛋白磷酸酶2A（PP 2A）C，去磷酸化和激活ChREBP，上调果糖和LGG正常化。亮氨酸羧基甲基转移酶-1，甲基化PP 2AC，也增加了果糖和LGG减少。然而，LGG的这些有益作用在KO小鼠中减弱。肝二氢鞘氨醇-1-磷酸，抑制PP 2A，显着增加LGG在WT小鼠，但在KO小鼠减弱。LGG减少脂肪肥大，增加血清ADPN水平，ADPN调节鞘氨醇代谢。这种有益的效果是减少在KO mice.ConclusionLGG管理增加肝脏FGF 21的表达和血清ADPN浓度，导致通过二氢鞘氨醇-1-磷酸介导的PP 2A失活减少ChREBP激活，随后逆转果糖诱导的NAFLD。因此，我们的数据表明，FGF 21是LGG逆转果糖诱导的NAFLD的有益作用所必需的。
ObjectivesHigh fructose feeding changes fibroblast growth factor 21 (FGF21) regulation.Lactobacillus rhamnosusGG (LGG) supplementation reduces fructose-induced non-alcoholic fatty liver disease (NAFLD). The aim of this study was to determine the role of FGF21 and underlying mechanisms in the protective effects of LGG.MethodsFGF21 knockout (KO) mice and C57BL/6 wild type (WT) mice were fed 30% fructose for 12 weeks. LGG was administered to the mice in the last 4 weeks during fructose feeding. FGF21-adiponectin (ADPN)-mediated hepatic lipogenesis and inflammation were investigated.ResultsFGF21 expression was robustly increased after 5-weeks of feeding and significantly decreased after 12-weeks of feeding in fructose-induced NAFLD mice. LGG administration reversed the depressed FGF21 expression, increased adipose production of ADPN, and reduced hepatic fat accumulation and inflammation in the WT mice but not in the KO mice. Hepatic nuclear carbohydrate responsive-element binding protein (ChREBP) was increased by fructose and reduced by LGG, resulting in a reduction in the expression of lipogenic genes. The methylated form of protein phosphatase 2A (PP2A) C, which dephosphorylates and activates ChREBP, was upregulated by fructose and normalized by LGG. Leucine carboxyl methyltransferase-1, which methylates PP2AC, was also increased by fructose and decreased by LGG. However, those beneficial effects of LGG were blunted in the KO mice. Hepatic dihydrosphingosine-1-phosphate, which inhibits PP2A, was markedly increased by LGG in the WT mice but attenuated in the KO mice. LGG decreased adipose hypertrophy and increased serum levels of ADPN, which regulates sphingosine metabolism. This beneficial effect was decreased in the KO mice.ConclusionLGG administration increases hepatic FGF21 expression and serum ADPN concentration, resulting in a reduced ChREBP activation through dihydrosphingosine-1-phosphate-mediated PP2A deactivation, and subsequently reversed fructose-induced NAFLD. Thus, our data suggest that FGF21 is required for the beneficial effects of LGG in reversal of fructose-induced NAFLD.
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影响因子：
3.1
作者：
Softic S;Cohen DE;Kahn CR
通讯作者：
Kahn CR
DOI：
10.1073/pnas.0701600104
发表时间：
2007-05-01
影响因子：
11.1
作者：
Ogawa, Yasushi;Kurosu, Hiroshi;Kuro-o, Makoto
通讯作者：
Kuro-o, Makoto
DOI：
10.1016/j.jnutbio.2014.10.016
发表时间：
2015-04
期刊：
The Journal of nutritional biochemistry
影响因子：
--
作者：
Zhang M;Wang C;Wang C;Zhao H;Zhao C;Chen Y;Wang Y;McClain C;Feng W
通讯作者：
Feng W
影响因子：
7.7
作者：
Li H;Gao Z;Zhang J;Ye X;Xu A;Ye J;Jia W
通讯作者：
Jia W
影响因子：
4.5
作者：
Cox CL;Stanhope KL;Schwarz JM;Graham JL;Hatcher B;Griffen SC;Bremer AA;Berglund L;McGahan JP;Keim NL;Havel PJ
通讯作者：
Havel PJ