Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea.
Department of Life Science, Ewha Womans University, Seoul, Republic of Korea.
Liver Int. 2021 Dec;41(12):2892-2902. doi: 10.1111/liv.15030. Epub 2021 Aug 16.
Bile acid (BA) dysregulation is related to not only metabolic diseases but also nonalcoholic fatty liver disease (NAFLD). We investigated whether circulating BA levels are altered according to the histological severity of NAFLD independent of metabolic derangements.
Global metabolic profiling and targeted BA analysis using sera collected from biopsy-proven no-NAFLD (n = 67), nonalcoholic fatty liver (NAFL) (n = 99), and nonalcoholic steatohepatitis (NASH, n = 75) subjects were performed sequentially. Circulating metabolome analysis integrated with the hepatic transcriptome was performed to elucidate the mechanistic basis of altered circulating BA profiles after stratification by obesity (body mass index ≤ 25 kg/m ). Circulating BA alterations were also validated in an independent validation cohort (29 no-NAFLD, 70 NAFL and 37 NASH).
Global profiling analysis showed that BA was the metabolite significantly altered in NASH compared to NAFL. Targeted BA analysis demonstrated that glyco-/tauro-conjugated primary BAs were commonly increased in nonobese and obese NASH, while unconjugated primary BAs increased only in nonobese NASH. These characteristic primary BA level changes were maintained even after stratification according to diabetes status and were replicated in the independent validation cohort. Compared to nonobese NAFL patients, nonobese NASH patients exhibited upregulated hepatic expression of CYP8B1.
BA metabolism is dysregulated as the histological severity of NAFLD worsens, independent of obesity and diabetes status; dysregulation is more prominent in nonobese NAFLD patients. Metabolome-driven omics approach provides new insight into our understanding of altered BA metabolism associated with individual phenotypes of NAFLD.
胆汁酸（BA）失调不仅与代谢疾病有关，还与非酒精性脂肪性肝病（NAFLD）有关。我们研究了在不考虑代谢紊乱的情况下，循环 BA 水平是否会根据 NAFLD 的组织学严重程度而改变。
对经活检证实无 NAFLD（n=67）、非酒精性脂肪肝（NAFL，n=99）和非酒精性脂肪性肝炎（NASH，n=75）患者的血清进行了全球代谢谱分析和靶向 BA 分析。对肥胖（BMI≤25kg/m）分层后，对循环代谢组分析与肝转录组进行了整合，以阐明改变循环 BA 谱的机制基础。在独立验证队列（29 例无 NAFLD、70 例 NAFL 和 37 例 NASH）中也验证了循环 BA 的改变。
整体分析显示，与 NAFL 相比，NASH 中 BA 是代谢物显著改变。靶向 BA 分析表明，甘氨/牛磺酸结合的初级 BA 通常在非肥胖和肥胖 NASH 中增加，而未结合的初级 BA 仅在非肥胖 NASH 中增加。即使根据糖尿病状态进行分层，这些特征性的初级 BA 水平变化仍然保持不变，并在独立验证队列中得到复制。与非肥胖 NAFL 患者相比，非肥胖 NASH 患者表现出 CYP8B1 肝表达上调。
BA 代谢在 NAFLD 的组织学严重程度恶化时失调，与肥胖和糖尿病状态无关；在非肥胖的 NAFLD 患者中失调更为明显。代谢组学驱动的组学方法为我们理解与 NAFLD 个体表型相关的改变的 BA 代谢提供了新的见解。
