The conjugation-resistant bile acid norUDCA cures liver fibrosis but impairs systemic energy metabolism.

Bile acids (BAs) play an important role in systemic metabolic improvements following bariatric surgery. In this study, we found that orally administered norursodeoxycholic acid (norUDCA), a conjugation-resistant C23 derivative of naturally occurring UDCA, accumulated in peripheral organs including heart and brown adipose tissue (BAT). Moreover, norUDCA decreased systemic levels of endogenous conjugated BAs, while increasing unconjugated BAs. Notably, in addition to beneficial effects in a cholestatic liver disease model, norUDCA also lowered plasma glucose and fat mass in mice, suggesting that this BA derivative could be repurposed for treating obesity-associated cardiometabolic diseases. Metabolic energy expenditure studies, however, revealed that norUDCA-treated mice have impaired BAT capacity and developed intolerance to cold stress, a phenotype exacerbated in mice lacking adipose ATGL-dependent lipolysis. Transcriptomic and metabolic analyses demonstrated tissue remodeling in heart and BAT that involved pronounced changes in energy substrate utilization, including enhanced cardiac glucose uptake and higher ketone body utilization in BAT. Importantly, co-administration of a low-carb diet prevented cold stress-induced metabolic deficits. Mechanistic studies in human engineered heart tissue indicated that norUDCA compromised contractile function. In conclusion, these data suggest that conjugation-resistant BA derivatives like norUDCA impair myocardial and BAT energetics by altering glucose, lipid, and energy metabolism, particularly during catabolic cold stress conditions.