SUN-668 - Human White and Brown Adipose Tissues Are Sites of Bile Acid Metabolism

Bile acids (BAs) are cholesterol derivatives that function as amphipathic surfactants, emulsifying dietary lipids to facilitate their digestion and absorption. As systemic endocrine hormones, BAs are also involved in glucose metabolism. While de novo BA synthesis was once thought to occur exclusively in hepatocytes, recent evidence supports extrahepatic origins as well. In two clinical trials of healthy women and men, we showed that mirabegron, a β3-adrenergic receptor (AR) agonist, acutely decreased plasma total bile acid levels. Given the lack of β3-AR in hepatocytes, we hypothesized that human adipose tissues may also play a role in plasma BA synthesis. Here, we used three model systems to determine the roles of human white (WAT) and brown adipose tissue (BAT) in human BA physiology.

Healthy adult women (n=14, 27.5 ± 1.1y, 25.4 ± 1.2 kg*m-2) were treated for 28 days with 100 mg mirabegron each day, and plasma cholestenoic and bile acids were measured on Days 1 and 28 via LC-MS/MS. To model mirabegron’s chronic adrenergic stimulation, we collected paired subcutaneous (pheoWAT) and perirenal adipose (pheoBAT) tissues patients with pheochromocytoma, a syndrome associated with excess plasma catecholamines (9F/7M, 46.6 ± 15.9y, 27.4 ± 6.8 kg*m-2). For tissue controls, we collected subcutaneous white adipose tissues (scWAT) from patients without pheochromocytomas (n=8) as well as liver and skeletal muscles from cadaveric donors (n=13). The final model consisted of human white and brown preadipocytes differentiated over 30 days into functional adipocytes that were treated for up to 12-hours with the catecholamine norepinephrine (NE). Transcription was measured by qPCR and protein levels via immunoblot.

Chronic mirabegron treatment increased all of the principal plasma BA species, including cholic acid, cholestenoic acid, and deoxycholic acid, without affecting hepatic BA synthesis. Both WAT and BAT expressed key enzymes involved in BA synthesis at levels comparable to that seen in the liver. This included CYP7A1, which controls the rate-determining step of BA synthesis and had been considered liver specific. In addition, a key enzyme regulating the acidic pathway of BA synthesis, CYP7B1, was equally expressed in pheoWAT and scWAT as in the liver. Finally, differentiated white and brown adipocytes each responded to NE treatment with a time-dependent upregulation of BA synthesis enzymes along with an uptake of bile acid precursors.

These results demonstrate new physiological roles for human BAT and WAT – the regulation of BA metabolism. As a result, this opens up new avenues for exploring how human WAT and BAT can be targeted to treat cardiometabolic diseases.

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