The essential roles of FXR in diet and age influenced metabolic changes and liver disease development: a multi-omics study

Guiyan Yang; Prasant K Jena; Ying Hu; Lili Sheng; Shin-Yu Chen; Carolyn M Slupsky; Ryan Davis; Clifford G Tepper; Yu-Jui Yvonne Wan

doi:10.1186/s40364-023-00458-9

The essential roles of FXR in diet and age influenced metabolic changes and liver disease development: a multi-omics study

Biomark Res. 2023 Feb 18;11(1):20. doi: 10.1186/s40364-023-00458-9.

Authors

Guiyan Yang¹, Prasant K Jena¹, Ying Hu¹, Lili Sheng¹, Shin-Yu Chen², Carolyn M Slupsky², Ryan Davis¹, Clifford G Tepper³, Yu-Jui Yvonne Wan⁴

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of California, Davis Health. Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA.
² Department of Nutrition, University of California, Davis, CA, USA.
³ Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA, USA.
⁴ Department of Pathology and Laboratory Medicine, University of California, Davis Health. Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA. yjywan@ucdavis.edu.

Abstract

Background: Aging and diet are risks for metabolic diseases. Bile acid receptor farnesoid X receptor (FXR) knockout (KO) mice develop metabolic liver diseases that progress into cancer as they age, which is accelerated by Western diet (WD) intake. The current study uncovers the molecular signatures for diet and age-linked metabolic liver disease development in an FXR-dependent manner.

Methods: Wild-type (WT) and FXR KO male mice, either on a healthy control diet (CD) or a WD, were euthanized at the ages of 5, 10, or 15 months. Hepatic transcriptomics, liver, serum, and urine metabolomics as well as microbiota were profiled.

Results: WD intake facilitated hepatic aging in WT mice. In an FXR-dependent manner, increased inflammation and reduced oxidative phosphorylation were the primary pathways affected by WD and aging. FXR has a role in modulating inflammation and B cell-mediated humoral immunity which was enhanced by aging. Moreover, FXR dictated neuron differentiation, muscle contraction, and cytoskeleton organization in addition to metabolism. There were 654 transcripts commonly altered by diets, ages, and FXR KO, and 76 of them were differentially expressed in human hepatocellular carcinoma (HCC) and healthy livers. Urine metabolites differentiated dietary effects in both genotypes, and serum metabolites clearly separated ages irrespective of diets. Aging and FXR KO commonly affected amino acid metabolism and TCA cycle. Moreover, FXR is essential for colonization of age-related gut microbes. Integrated analyses uncovered metabolites and bacteria linked with hepatic transcripts affected by WD intake, aging, and FXR KO as well as related to HCC patient survival.

Conclusion: FXR is a target to prevent diet or age-associated metabolic disease. The uncovered metabolites and microbes can be diagnostic markers for metabolic disease.

Keywords: Bile acid; Bile acid receptor; Gut microbiota; Hepatocellular carcinoma; Liver; Metabolic disease; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis.

Abstract

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