老化和饮食是代谢性疾病的风险因素。胆汁酸受体法尼索达X受体（FXR）敲除（KO）小鼠随着年龄的增长发展出代谢性肝脏疾病，其进展为癌症，而西方饮食（WD）的摄入加速了病情的发展。当前研究揭示了FXR依赖的饮食和年龄相关代谢性肝疾病发展的分子特征。 雄性野生型（WT）和FXR KO小鼠无论在健康控制饮食（CD）或WD饮食下，分别在5、10或15个月龄时安乐死。对肝脏转录组、肝脏、血清和尿液代谢组学以及微生物组进行了分析。WD摄入促进了WT小鼠的肝脏老化。在FXR依赖性的情况下，增加了炎症并减少了氧化磷酸化是WD和老化影响的主要途径。FXR在调节炎症和B细胞介导的体液免疫中起作用，年龄增大时其增强。此外，FXR还规定了神经元分化、肌肉收缩和细胞骨架组织以及代谢。有654个转录本共同受饮食、年龄和FXR KO影响，其中76个在人肝细胞癌（HCC）和健康肝脏中有差异表达。尿液代谢物可区分不同基因型的饮食效应，而血清代谢物则明显分离了年龄无论饮食。老化和FXR KO共同影响氨基酸代谢和TCA周期。此外，FXR对老龄肠道菌群的定殖至关重要。综合分析揭示了受WD摄入、老化和FXR KO影响的代谢物和细菌与肝脏转录本相关，与HCC患者生存率相关。FXR是防止饮食或年龄相关代谢疾病的靶点。揭示的代谢物和微生物可以作为代谢性疾病的诊断标志物。 ©2023. 作者。

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.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.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.FXR is a target to prevent diet or age-associated metabolic disease. The uncovered metabolites and microbes can be diagnostic markers for metabolic disease.© 2023. The Author(s).