Taurochenodeoxycholic acid alleviates obesity-induced endothelial dysfunction

Area of Science:

• Cardiovascular Research
• Metabolomics
• Endocrinology

Background:

• Obesity significantly increases cardiovascular disease (CVD) risk, with endothelial dysfunction (ED) being an early pathological change.
• Understanding ED heterogeneity in non-hypertensive obese (NHO) individuals is crucial for effective prevention and treatment strategies.
• Metabolic profiling may reveal novel biomarkers and therapeutic targets for obesity-related ED.

Purpose of the Study:

• To characterize ED heterogeneity in NHO individuals.
• To investigate associations between serum metabolites and obesity-induced ED.
• To identify predictive and therapeutic metabolites for obesity-induced ED.

Main Methods:

• Wire myography assessed ex vivo arteriole ED in 213 NHO patients (metabolically healthy obesity [MHO] and metabolically unhealthy obesity [MUO]).
• Targeted metabolomic profiling identified serum metabolites associated with ED.
• Mechanistic studies explored the role of the TCDCA-FXR-PHB1-ATF4 pathway in endothelial cells.

Main Results:

• Obesity-induced ED in NHO patients showed limited correlation with traditional CVD risk factors.
• MHO and MUO groups exhibited similar ED and metabolomic profiles.
• Serum metabolomics identified bile acids (BAs), particularly chenodeoxycholic acid (CDCA), negatively correlated with ED. Taurochenodeoxycholic acid (TCDCA) protected against ED and hypertension, mediated by endothelial FXR activation, PHB1, and ATF4, enhancing serine and one-carbon metabolism.

Conclusions:

• CDCA is a potential biomarker for identifying obesity-induced ED.
• TCDCA demonstrates therapeutic potential for various forms of obesity-induced ED.
• The TCDCA-FXR-PHB1-ATF4 axis offers a novel strategy to delay hypertension and CVD onset by modulating metabolism.