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您的检索式：作者名="Kristopher W.Krausz"
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| 1 | Caffeic acid phenethyl ester suppresses intestinal FXR signaling and ameliorates nonalcoholic fatty liver disease by inhibiting bacterial bile salt hydrolase activity显示文摘Propolis is commonly used in traditional Chinese medicine.Studies have demonstrated the therapeutic effects of propolis extracts and its major bioactive compound caffeic acid phenethyl ester(CAPE)on obesity and diabetes.Herein,CAPE was found to have pharmacological activity against nonalcoholic fatty liver disease(NAFLD)in diet-induced obese mice.CAPE,previously reported as an inhibitor of bacterial bile salt hydrolase(BSH),inhibited BSH enzymatic activity in the gut microbiota when administered to mice.Upon BSH inhibition by CAPE,levels of tauro-β-muricholic acid were increased in the intestine and selectively suppressed intestinal farnesoid X receptor(FXR)signaling.This resulted in lowering of the ceramides in the intestine that resulted from increased diet-induced obesity.Elevated intestinal ceramides are transported to the liver where they promoted fat production.Lowering FXR signaling was also accompanied by increased GLP-1 secretion.In support of this pathway,the therapeutic effects of CAPE on NAFLD were absent in intestinal FXR-deficient mice,and supplementation of mice with C16-ceramide significantly exacerbated hepatic steatosis.Treatment of mice with an antibiotic cocktail to deplete BSH-producing bacteria also abrogated the therapeutic activity of CAPE against NAFLD.These findings demonstrate that CAPE ameliorates obesity-related steatosis at least partly through the gut microbiota-bile acid-FXR pathway via inhibiting bacterial BSH activity and suggests that propolis enriched with CAPE might serve as a promising therapeutic agent for the treatment of NAFLD. | Xian-chun Zhong Ya-meng Liu Xiao-xia Gao Kristopher W.Krausz Bing Niu Frank J.Gonzale Cen Xie | 2023 | Acta Pharmacologica Sinica2023，44，1： | 2 |
| 2 | Crosstalk between CYP2E1 and PPARα substrates and agonists modulate adipose browning and obesity显示文摘Although the functions of metabolic enzymes and nuclear receptors in controlling physiological homeostasis have been established, their crosstalk in modulating metabolic disease has not been explored.Genetic ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2 E1 in mice markedly induced adipose browning and increased energy expenditure to improve obesity. CYP2 E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha(PPARa) target genes,including fibroblast growth factor(FGF) 21, that upon release from the liver, enhanced adipose browning and energy expenditure to decrease obesity. Nineteen metabolites were increased in Cyp2 e1-null mice as revealed by global untargeted metabolomics, among which four compounds, lysophosphatidylcholine and three polyunsaturated fatty acids were found to be directly metabolized by CYP2 E1 and to serve as PPARa agonists, thus explaining how CYP2 E1 deficiency causes hepatic PPARa activation through increasing cellular levels of endogenous PPARa agonists. Translationally, a CYP2 E1 inhibitor was found to activate the PPARa-FGF21-beige adipose axis and decrease obesity in wild-type mice, but not in liver-specific Pparanull mice. The present results establish a metabolic crosstalk between PPARa and CYP2 E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue browning by targeting the CYP2 E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism. | Youbo Zhang Tingting Yan Tianxia Wang Xiaoyan Liu Keisuke Hamada Dongxue Sun Yizheng Sun Yanfang Yang Jing Wang Shogo Takahashi Qiong Wang Kristopher W.Krausz Changtao Jiang Cen Xie Xiuwei Yang Frank J.Gonzalez | 2022 | Acta Pharmaceutica Sinica B2022，12，5： | 1 |
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