TY - JOUR AU - Donkers, Joanne M. AU - Kooijman, Sander AU - Slijepcevic, Davor AU - Kunst, Roni F. AU - Roscam Abbing, Reinout L.P. AU - Haazen, Lizette AU - de Waart, Dirk R. AU - Levels, Johannes H.M. AU - Schoonjans, Kristina AU - Rensen, Patrick C.N. AU - Oude Elferink, Ronald P.J. AU - van de Graaf, Stan F.J. T1 - NTCP deficiency in mice protects against obesity and hepatosteatosis PY - 2019/07/25/ AB - Bile acids play a major role in the regulation of lipid and energy metabolism. Here we propose the hepatic bile acid uptake transporter Na+ taurocholate cotransporting polypeptide (NTCP) as a target to prolong postprandial bile acid elevations in plasma. Reducing hepatic clearance of bile acids from plasma by genetic deletion of NTCP moderately increased plasma bile acid levels, reduced diet-induced obesity, attenuated hepatic steatosis, and lowered plasma cholesterol levels. NTCP and G protein–coupled bile acid receptor–double KO (TGR5–double KO) mice were equally protected against diet-induced obesity as NTCP–single KO mice. NTCP-KO mice displayed decreased intestinal fat absorption and a trend toward higher fecal energy output. Furthermore, NTCP deficiency was associated with an increased uncoupled respiration in brown adipose tissue, leading to increased energy expenditure. We conclude that targeting NTCP-mediated bile acid uptake can be a novel approach to treat obesity and obesity-related hepatosteatosis by simultaneously dampening intestinal fat absorption and increasing energy expenditure. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.127197 VL - 4 IS - 14 UR - https://doi.org/10.1172/jci.insight.127197 PB - The American Society for Clinical Investigation ER -