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 recently identified as important signalling molecules regulating glucose metabolism, inflammation and energy expenditure. Targeting bile acid signalling is, therefore, appealing to treat metabolic diseases such as diabetes and atherosclerosis. These disorders are potentially affecting >1 billion individuals worldwide and current options to treat them remain insufficient. I postulate 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 signalling by controlling how fast bile acids are removed from serum after a meal. In this proposal I will elucidate the contribution of bile acid dynamics to energy homeostasis and metabolism and identify the molecular mechanisms that regulate NTCP. My aim is to generate novel strategies to reduce hepatic bile acid uptake to prolong bile-acid signalling and increase energy expenditure, improve glucose handling and reduce atherosclerosis.My key objectives are:1. to determine the consequence of NTCP modulation on systemic bile acid dynamics, glucose and energy metabolism in animal models. To this end, I will perform careful metabolic analysis of a unique Slc10a1 knockout model in combination with diet-induced and genetic models for atherosclerosis and diabetes.2. to identify novel means to inhibit NTCP-mediated bile acid uptake. To this end, I will make use of a FRET-based bile acid sensor that I recently developed to characterize the molecular regulation of hepatic bile acid uptake and to identify FDA-approved drugs that inhibit NTCP-mediated bile acid uptake.This will establish my new research line on serum bile acid dynamics and ultimately provide new ways to treat metabolic diseases related to disturbed bile acid, lipid, glucose and energy homeostasis.