{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Lu D"],"funding":["Intramural NIH HHS","National Cancer Institute"],"pagination":["159089"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8864892"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["1867(2)"],"pubmed_abstract":["In addition to maintaining bile acid, cholesterol and glucose homeostasis, farnesoid X receptor (FXR) also regulates fatty acid β-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<sup>fl/fl</sup>), liver-specific Fxr-null (Fxr<sup>ΔHep</sup>) and intestine-specific Fxr-null (Fxr<sup>ΔIE</sup>) 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<sup>fl/fl</sup> mice, resulting in reduced levels of total acylcarnitines and relative accumulation of long/medium chain acylcarnitines and fatty acids in liver. Fxr<sup>ΔHep</sup> mice responded to OCA treatment in a manner similar to Fxr<sup>fl/fl</sup> mice while Fxr<sup>ΔIE</sup> 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 PGC1α 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."],"journal":["Biochimica et biophysica acta. Molecular and cell biology of lipids"],"pubmed_title":["Intestinal farnesoid X receptor signaling controls hepatic fatty acid oxidation."],"pmcid":["PMC8864892"],"funding_grant_id":["Z01 BC005562"],"pubmed_authors":["Krausz KW","Lu D","Yan T","Feng C","Xu J","Xiao P","Liu Y","Wang Q","Luo Y","Xue L","Gonzalez FJ","Zhao J","Xie C"],"additional_accession":[]},"is_claimable":false,"name":"Intestinal farnesoid X receptor signaling controls hepatic fatty acid oxidation.","description":"In addition to maintaining bile acid, cholesterol and glucose homeostasis, farnesoid X receptor (FXR) also regulates fatty acid β-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<sup>fl/fl</sup>), liver-specific Fxr-null (Fxr<sup>ΔHep</sup>) and intestine-specific Fxr-null (Fxr<sup>ΔIE</sup>) 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<sup>fl/fl</sup> mice, resulting in reduced levels of total acylcarnitines and relative accumulation of long/medium chain acylcarnitines and fatty acids in liver. Fxr<sup>ΔHep</sup> mice responded to OCA treatment in a manner similar to Fxr<sup>fl/fl</sup> mice while Fxr<sup>ΔIE</sup> 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 PGC1α 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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Feb","modification":"2025-04-19T17:58:46.769Z","creation":"2025-04-19T17:58:46.769Z"},"accession":"S-EPMC8864892","cross_references":{"pubmed":["34856412"],"doi":["10.1016/j.bbalip.2021.159089"]}}