Intestinal farnesoid X receptor signaling controls hepatic fatty acid oxidation

doi:10.1016/j.bbalip.2021.159089

	Intestinal farnesoid X receptor signaling controls hepatic fatty acid oxidation
	Lu, Dasheng 1,2; Liu, Yameng 3; Luo, Yuhong 1; Zhao, Jie 1; Feng, Chao 2; Xue, Liming 2; Xu, Jiale 2; Wang, Qiong 1; Yan, Tingting 1; Xiao, Ping 2
刊名	BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
	2022-02-01
卷号	1867 期号:2 页码:13
关键词	Fatty acid oxidation Acylcarnitines FXR FGF15/19 PGC1 alpha Transcriptomics Metabolomics
ISSN号	1388-1981
DOI	10.1016/j.bbalip.2021.159089
通讯作者	Gonzalez, Frank J.(gonzalef@mail.nih.gov) ; Xie, Cen(xiecen@simm.ac.cn)
英文摘要	In addition to maintaining bile acid, cholesterol and glucose homeostasis, farnesoid X receptor (FXR) also regulates fatty acid beta-oxidation (FAO). To explore the different roles of hepatic and intestinal FXR in liver FAO, FAO-associated metabolites, including acylcarnitines and fatty acids, and FXR target gene mRNAs were profiled using an integrated metabolomic and transcriptomic analysis in control (Fxr(fl/fl)) , liver-specific Fxr-null (Fxr(Delta Hep)) and intestine-specific Fxr-null (Fxr(Delta)(IE)) mice, treated either with the FXR agonist obeticholic acid (OCA) or vehicle (VEH). Activation of FXR by OCA treatment significantly increased fatty acyl-CoA hydrolysis (Acot1) and decreased FAO-associated mRNAs in Fxr(fl/fl) mice, resulting in reduced levels of total acylcarnitines and relative accumulation of long/medium chain acylcarnitines and fatty acids in liver. Fxr(Delta Hep) mice responded to OCA treatment in a manner similar to Fxr(fl/fl) mice while Fxr(Delta)(IE) mice responded differently, thus illustrating that intestinal FXR plays a critical role in the regulation of hepatic FAO. A significant negative-correlation between intestinal FXR-FGF15 and hepatic CREB-PGC1A pathways was observed after both VEH and OCA treatment, suggesting that OCA-induced activation of the intestinal FXR-FGF15 axis downregulates hepatic PGC1 alpha signaling via inactivation of hepatic CREB, thus repressing FAO. This mechanism was confirmed in experiments based on human recombinant FGF19 treatment and intestinal Fgf15-null mice. This study revealed an important role for the intestinal FXR-FGF15 pathway in hepatic FAO repression.
资助项目	Na-tional Institutes of Health, National Cancer Institute, Center for Cancer Research[NIH U01 DK119702] ; National Natural Science Foundation of China[81872643] ; National Natural Science Foundation of China[91957116] ; Shanghai Municipal Science Foundation[18ZR1432200] ; Shanghai Rising-Star Program[20QA1411200] ; Shanghai Municipal Overseas High-End Talent Training of Public Health[GWTD2015S03] ; 3-year Action Program of Shanghai Municipal Government ; Shanghai Municipal Science andTechnology Major Project
WOS关键词	FIBROBLAST GROWTH FACTOR-19 ; PPAR-ALPHA ; COACTIVATOR PGC-1 ; PGC-1-ALPHA ; METABOLISM ; IDENTIFICATION
WOS研究方向	Biochemistry & Molecular Biology ; Biophysics ; Cell Biology
语种	英语
出版者	ELSEVIER
WOS记录号	WOS:000729063500004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/299235]
专题	中国科学院上海药物研究所
通讯作者	Gonzalez, Frank J.; Xie, Cen
作者单位	1.NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA 2.Shanghai Municipal Ctr Dis Control & Prevent, State Environm Protect Key Lab Environm Hlth Impa, Shanghai, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Lu, Dasheng,Liu, Yameng,Luo, Yuhong,et al. Intestinal farnesoid X receptor signaling controls hepatic fatty acid oxidation[J]. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS,2022,1867(2):13.
APA	Lu, Dasheng.,Liu, Yameng.,Luo, Yuhong.,Zhao, Jie.,Feng, Chao.,...&Xie, Cen.(2022).Intestinal farnesoid X receptor signaling controls hepatic fatty acid oxidation.BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS,1867(2),13.
MLA	Lu, Dasheng,et al."Intestinal farnesoid X receptor signaling controls hepatic fatty acid oxidation".BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS 1867.2(2022):13.