Bile Acid Signaling Dysregulation in MASLD: Linking Serum Profiles, FXR/TGR5 Activity, and Hepatic Lipid Accumulation
Researchers examine bile acid signaling in metabolic-associated steatotic liver disease. They focus on dysregulation. Moreover, they correlate key elements in human patients.
Bile acids act as signaling molecules. They regulate metabolism through receptors. FXR and TGR5 serve as primary targets. When signaling fails, lipid buildup increases in the liver.
Scientists collect serum from MASLD cohorts. They use targeted metabolomics. This measures primary and secondary bile acids accurately. Profiles differ between healthy controls and patients.
In MASLD, total bile acid levels often rise. Conjugated bile acids dominate. Secondary bile acids such as deoxycholic acid decrease. These shifts disrupt normal signaling.
FXR activity declines in affected livers. Researchers assess pathway activity through transcriptomics. They measure FXR target genes like SHP, BSEP, and FGF19. Downregulation appears consistently.
TGR5 signaling also weakens. It normally promotes energy expenditure and reduces inflammation. Reduced TGR5 expression links to worse steatosis.
Hepatic lipid accumulation correlates strongly. Higher serum hydrophobic bile acids associate with greater triglyceride content. Liver biopsies confirm steatosis grades.
Targeted metabolomics reveals specific patterns. Elevated chenodeoxycholic acid ties to severe MASLD. Lower lithocholic acid links to milder cases.
Transcriptomics data supports these findings. FXR suppression correlates with upregulated lipogenic genes. SREBP-1c and FAS expression rises. This drives fat synthesis.
Furthermore, pathway analysis shows inflammation links. Dysregulated bile acids promote pro-inflammatory cytokines. This worsens disease progression.
Human cohort studies highlight variability. Some patients maintain partial FXR activity. Others show near-complete loss. These differences predict disease severity.
Overall, bile acid signaling dysregulation drives MASLD. Altered serum profiles disrupt FXR and TGR5. Consequently, hepatic lipid accumulation accelerates. Targeted metabolomics and transcriptomics provide clear evidence. This work opens doors for receptor agonists as therapy.