Immune-metabolic dialogues: how branched-chain amino acids and extracellular vesicles shape chronic liver disease
Immune-metabolic dialogues: how branched-chain amino acids and extracellular vesicles shape chronic liver disease
Chronic liver disease (CLD), affecting 1.5 billion people worldwide, includes viral, metabolic, alcoholic, and autoimmune disorders. This thesis of Lizbeth Martinez Aguilar investigates two understudied areas in CLD: the context-dependent role of branched-chain amino acids (BCAAs) and the potential of extracellular vesicles (EVs) as biomarkers of hepatic decompensation.
BCAAs (leucine, isoleucine, and valine) show opposing patterns across liver -related cells. BCAAs link muscle-liver metabolic crosstalk and may improve nutrition in cirrhosis. In hepatocytes, leucine protects against lipotoxic stress through mTOR-independent mitochondrial remodeling, but only when BCKDH catabolic activity is sufficient. In hepatic stellate cells, BCAAs and their metabolites exhibit antifibrotic effects, with species- and disease-specific differences. BCAAs also emerge as regulators of resident liver macrophages when catabolism is intact where they support anti-inflammatory and antioxidant programs, but impaired catabolism shifts macrophages toward pro-inflammatory metabolic states. Overall, BCAAs are not universally beneficial or harmful; their effects depend critically on cellular catabolic capacity, lipid environment, disease stage, tissue type, and organism.
Chapters 7–9 focus on EVs as diagnostic tools. EVs participate in liver disease pathogenesis and carry molecular signatures reflecting inflammation, fibrosis, and metabolic dysfunction. After optimizing protocols for EV isolation from blood, proteomic profiling identified key EV proteins (HP, CNDP1, and CFHR4) that accurately distinguish decompensated cirrhosis and normalize after transplantation, highlighting their clinical promise.
Overall, the thesis shows that BCAA effects are highly context-dependent and that EV proteomics offers a powerful platform for detecting and understanding hepatic decompensation, advancing precision approaches in CLD.