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.


Joanne M. Donkers, Sander Kooijman, Davor Slijepcevic, Roni F. Kunst, Reinout L.P. Roscam Abbing, Lizette Haazen, Dirk R. de Waart, Johannes H.M. Levels, Kristina Schoonjans, Patrick C.N. Rensen, Ronald P.J. Oude Elferink, Stan F.J. van de Graaf


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