Final Report Summary - PROLONGBILESIGNALING (Improving Metabolism via Prolonged Bile Acid Signallingtargeting hepatic bile acid uptake to fight metabolic diseases)
Bile acids play a pivotal role in energy supply as they facilitate the solubilization and absorption of fat in the intestine. Furthermore, bile acids are identified as important signaling molecules regulating glucose metabolism, inflammation and energy expenditure. Targeting bile acid signaling is, therefore, appealing to treat metabolic diseases such as obesity, diabetes and atherosclerosis. These disorders are potentially affecting >1 billion individuals worldwide and current options to treat them remain insufficient. We tested our hypothesis that the hepatic bile acid uptake transporter NTCP (gene name SLC10A1) provides an excellent novel target to improve human health as it determines the duration of bile acid signaling by controlling how fast bile acids are removed from serum after a meal. In this proposal the contribution of bile acid dynamics to energy homeostasis, lipid, cholesterol and glucose metabolism was investigated, as well as novel molecular mechanisms that regulate NTCP. Inhibition of hepatic bile salt uptake lowers body weight in obese mice and increases release of GLP1, a hormone that potentiates glucose clearance. NTCP inhibition further dampens inflammation and leads to lower liver damage in conditions of impaired bile flow (chole-stasis) in mice. Finally, a gut-to-liver signal was identified that reduces hepatic bile salt uptake, protecting the liver against bile salt overload.