2. Academic Validation
  3. Intestinal farnesoid X receptor signaling controls hepatic fatty acid oxidation

Intestinal farnesoid X receptor signaling controls hepatic fatty acid oxidation

  • Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Feb;1867(2):159089. doi: 10.1016/j.bbalip.2021.159089.
Dasheng Lu 1,  Yameng Liu 2,  Yuhong Luo 3,  Jie Zhao 3,  Chao Feng 4,  Liming Xue 4,  Jiale Xu 4,  Qiong Wang 3,  Tingting Yan 3,  Ping Xiao 4,  Kristopher W Krausz 3,  Frank J Gonzalez 5,  Cen Xie 6
Affiliations

Affiliations

  • 1 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America; Shanghai Municipal Center for Disease Control and Prevention, State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, Shanghai, PR China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.
  • 3 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America.
  • 4 Shanghai Municipal Center for Disease Control and Prevention, State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, Shanghai, PR China.
  • 5 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America. Electronic address: [email protected].
  • 6 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China. Electronic address: [email protected].
PMID: 34856412 DOI: 10.1016/j.bbalip.2021.159089
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 (FXRfl/fl), liver-specific Fxr-null (FXRΔHep) and intestine-specific Fxr-null (FXRΔIE) 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 FXRfl/fl mice, resulting in reduced levels of total acylcarnitines and relative accumulation of long/medium chain acylcarnitines and fatty acids in liver. FXRΔHep mice responded to OCA treatment in a manner similar to FXRfl/fl mice while FXRΔIE 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.

Keywords

Acylcarnitines; FGF15/19; FXR; Fatty acid oxidation; Metabolomics; PGC1α; Transcriptomics.

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