Bile Acid TCDCA Reverses Obesity-Driven Vascular Damage via a Novel Endothelial Pathway

Obesity dramatically raises cardiovascular disease risk, yet not all obese individuals develop equal vascular damage. Understanding why requires examining early pathological changes—particularly endothelial dysfunction (ED)—before hypertension or overt metabolic disease sets in. This study directly addressed that gap by examining ex vivo arterioles from omental adipose tissue of 213 non-hypertensive obese (NHO) patients, categorized as metabolically healthy obesity (MHO, n=62) or metabolically unhealthy obesity (MUO, n=151).

Using wire myography, the researchers measured endothelium-dependent vasodilation responses to acetylcholine and bradykinin, plus endothelium-independent responses, in all participants. Strikingly, both MHO and MUO groups showed comparable degrees of ED, and neither group's ED correlated reliably with traditional cardiovascular risk factors such as BMI, blood glucose, lipids, or blood pressure. This highlights a significant blind spot in standard risk assessment for obese individuals who appear metabolically healthy.

Targeted serum metabolomics across the cohort identified bile acids (BAs) as the metabolite class most strongly and negatively correlated with ED severity. Among individual BAs, chenodeoxycholic acid (CDCA) emerged as the top candidate biomarker. The team then tested various BA derivatives and found that taurochenodeoxycholic acid (TCDCA)—a taurine-conjugated form of CDCA—potently alleviated obesity-induced ED and delayed hypertension onset across ex vivo human arteriole experiments, diet-induced obese mouse models, and other preclinical systems. Notably, bariatric surgery elevated circulating TCDCA levels, partially explaining its cardiovascular benefits.

Mechanistic investigation revealed that TCDCA acts through the nuclear receptor Farnesoid X receptor (FXR) specifically in endothelial cells. Endothelial-specific FXR deletion worsened obesity-induced ED and hypertension, and abolished the beneficial effects of both bariatric surgery and TCDCA treatment. Within endothelial cells, FXR activation by TCDCA upregulated the transcription factor ATF4. Under obese conditions, the mitochondrial protein PHB1 was found to suppress ATF4 transcription; TCDCA-FXR signaling relieved this suppression. Enhanced ATF4 activity then boosted serine biosynthesis and one-carbon metabolism, key pathways supporting endothelial nitric oxide production and redox balance.

These findings have meaningful translational implications. CDCA could serve as a blood-based biomarker to identify obese individuals with severe ED who are at elevated CVD risk—even among those classified as metabolically healthy. TCDCA represents a pharmacologically actionable target, with a defined signaling axis (TCDCA→FXR→PHB1 suppression relief→ATF4→serine/one-carbon metabolism) offering multiple intervention points. Caveats include the observational nature of the human metabolomics data, the relatively modest cohort size, and the need for prospective trials to validate CDCA as a clinical biomarker and confirm TCDCA's safety and efficacy in humans.