UCLA researchers from the Cardiovascular Theme in the Departments of Anesthesiology, Physiology and Medicine have discovered new pathways and potential treatment options for heart failure, obesity, and diabetes
Heart failure is a leading cause of mortality and hospitalization, and effective therapies remain elusive.Alterations in cardiac and systemic metabolism are hallmarks of the changes in the failing heart and metabolic disorders, including diabetes and obesity.Studies over the past several decades mostly centered on fatty acid and glucose metabolism and their regulation and dysfunction as the underlying mechanisms and therapeutic targets. However, recent genetic and metabolic analysis in both human clinic cohorts and animal models revealed unexpected involvement of other metabolic pathways involving amino acids as a significant contributor the pathogenesis of heart failure and diabetes.
UCLA researchers led by Prof. Yibin Wang employed unbiased systems approaches to discover relevant metabolic pathways and genes related to heart failure and metabolic disorders. Unexpectedly, they have identified defective branched-chain amino acid (BCAA) catabolic pathway is a hallmark and pathogenic contributor to heart failure, obesity and diabetes. Using both genetic tools and small molecule compound, they demonstrated that molecular defects of BCAA catabolic genes are the underlying basis for BCAA catabolic defects observed in diseased hearts or obese tissues.They further demonstrated that pharmacological inhibition of a key regulator for BCAA catabolic activities can restore functional defects in BCAA catabolic flux, leading to significant amelioration of heart failure, diabetes and obesity in clinically relevant disease models. These findings revealed a novel paradigm for disease diagnosis and therapeutic intervention.
heart failure, branched chain amino acids, BCAA, catabolism, cardiac failure, diabetes, obesity, catabolic defect, amino acid catabolism, cardiac metabolism, heart metabolism