Association between circulating bile acid alterations and nonalcoholic steatohepatitis independent of obesity and diabetes mellitus

Abstract

Background and Aims 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. Methods 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/m2). Circulating BA alterations were also validated in an independent validation cohort (29 no‐NAFLD, 70 NAFL and 37 NASH). Results 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. Conclusions 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.

Bile acids and sphingolipids in non-alcoholic fatty liver disease

“…Consistently, clinical studies have demonstrated that primary and secondary CBAs are tightly associated with NAFLD progression and NASH severity [30,48,49,51,52] . A recent study reported that elevated hepatic taurochenodeoxycholic acid (TCDCA) and taurocholic acid (TCA) in NAFLD patients was associated with symptom onset, disease progression, or death [51] .…”

“…[5,40] In the recent decade, extensive studies from animal models and human patients have found that NAFLD disease progression is closely associated with bile acid dysregulation and sphingolipid homeostasis. [48][49][50][51][52][53][54][55][56][57][58][59][60] Mechanisms linking bile acid metabolism to the development of NAFLD Consistently, clinical studies have demonstrated that primary and secondary CBAs are tightly associated with NAFLD progression and NASH severity. [30,48,49,51,52] A recent study reported that elevated hepatic taurochenodeoxycholic acid (TCDCA) and taurocholic acid (TCA) in NAFLD patients was associated with symptom onset, disease progression, or death.…”

“…[ 51 ] A similar study demonstrated that serum CBA elevations are not observed in NAFL and occur in both non-obese and obese patient cohorts. [ 52 ] Although NAFLD is not correlated to cholestasis, increases in primary CBAs, especially TCA, and a decrease in secondary bile acids, have been observed. [ 48 ] In a similar study where the blood chemistries of 102 NAFLD and 50 healthy patients were monitored, NAFLD patients exhibited highly significant elevations in plasma total, primary, and secondary bile acids.…”

Ilexsaponin A1 Ameliorates Diet-Induced Nonalcoholic Fatty Liver Disease by Regulating Bile Acid Metabolism in Mice

“…Accumulating evidence suggests that BA metabolism is associated with liver disease and may be a potential target for its treatment ( Jung et al, 2021 ). Many natural products have been shown to alleviate or prevent NAFLD by regulating BA metabolism ( Huang et al, 2019 ; Xiong et al, 2021 ).…”

Effect of intravenous ghrelin administration, combined with alcohol, on circulating metabolome in heavy drinking individuals with alcohol use disorder

“…Furthermore, bile acids themselves are capable of influencing metabolic processes, and possibly behavior, through the farnesoid X receptor and Takeda G protein-coupled receptor 5, which are also found in the brain, and by inducing release of glucagon-like peptide 1 and fibroblast growth factor 19 (Huang et al, 2016;Keitel et al, 2010;Maruyama et al, 2002;Mertens et al, 2017). Given that increased bile acid levels have been associated with fatty liver disease, while reduced bile acid levels seem to have a protective effect against fatty liver disease (Bajaj, 2019;Clifford et al, 2021;Jung et al, 2021), future work is needed to shed light on the role of ghrelin-related changes in bile acids, if any, in different alcohol-related outcomes including alcoholassociated liver disease.…”