232-LB: Chronic Adrenergic Stimulation of Human Brown and White Adipose Tissue Increases Bile Acid Synthesis Enzyme Expression and Plasma Bile Acid Levels

Abstract

Beyond enabling digestion of fats, bile acids (BA) are now known to be receptor ligands that improve glucose and lipoprotein metabolism. Classically, regulation of BA synthesis has thought to be exclusively hepatic, but emerging evidence in rodents indicates that BA production is influenced by sympathetic activation of brown and white adipose tissue (BAT and WAT). We recently showed that chronic activation of BAT and WAT in adult women with the β3-adrenergic receptor (AR) agonist mirabegron increased HDL cholesterol, insulin sensitivity, and total plasma BA. The largest increases were with the primary unconjugated cholic and chenodeoxycholic acids. We hypothesized that chronic adrenergic stimulation increased BA synthesis enzymes in adipose tissue, thus increasing flux through these pathways. We therefore measured expression levels of BA synthesis enzymes from patients undergoing elective surgery in the following tissues: subcutaneous WAT (scWAT), and from pheochromocytoma (pheo) patients who have chronic adrenergic activation, scWAT (PhW) and peri-renal BAT (PhB). These were compared to cadaveric liver. Liver had higher expression levels of BAAT, which conjugates BA. However, expression levels among liver, scWAT, PhW, and PhB were similar for the enzymes initiating BA synthesis (CYP7A1) and other intermediate enzymes (CYP7B1, AKR1D1, AMCAR). Furthermore, pheo patients had higher levels of CYP27A1, which initiates the acidic/alternative BA synthesis pathway. These data suggest that regulation of plasma BA is not exclusive to the liver. Rather, human BAT and WAT likely contribute to the BA pool, and chronic adrenergic activation may shift the equilibrium toward primary unconjugated species to improve glucose and lipoprotein metabolism. Disclosure K.Y. Zhu: None. H.J. Lea: None. C. Cero: None. A.M. Cypess: None.