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
  • 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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