TY - JOUR
T1 - NTCP deficiency in mice protects against obesity and hepatosteatosis
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.
PY - 2019
Y1 - 2019
N2 - 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.
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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85070659696&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31237863
U2 - https://doi.org/10.1172/jci.insight.127197
DO - https://doi.org/10.1172/jci.insight.127197
M3 - Article
C2 - 31237863
SN - 2379-3708
VL - 4
JO - JCI Insight
JF - JCI Insight
IS - 14
M1 - :e127197
ER -