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NTCP deficiency in mice protects against obesity and hepatosteatosis
Joanne M. Donkers, … , Ronald P.J. Oude Elferink, Stan F.J. van de Graaf
Joanne M. Donkers, … , Ronald P.J. Oude Elferink, Stan F.J. van de Graaf
Published June 25, 2019
Citation Information: JCI Insight. 2019;4(14):e127197. https://doi.org/10.1172/jci.insight.127197.
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Research Article Hepatology Metabolism

NTCP deficiency in mice protects against obesity and hepatosteatosis

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Abstract

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.

Authors

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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Figure 1

NTCP-KO mice have attenuated body weight gain and reduced (hepatic) adiposity when fed a high-fat diet.

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NTCP-KO mice have attenuated body weight gain and reduced (hepatic) adip...
(A) Conjugated and unconjugated plasma bile acid levels, measured by high-performance liquid chromatography (HPLC), of nonfasted, chow-fed NTCP-expressing (+/–) and NTCP-KO mice (n = 8). conj., conjugated; unconj., unconjugated. (B–G) Female wild-type (WT, n = 10) or NTCP-KO (n = 13) mice were fed a low-fat diet (LFD) or high-fat diet (HFD) for 16 weeks. (B) Concentration of the individual conjugated and unconjugated bile acid species in plasma. Plasma was collected after a 4-hour fast, and bile acid concentration and species were measured by HPLC. N.D., not determined. Asterisk indicates significant changes of both HFD groups compared with the WT LFD group; hash tag indicates a significant change between NTCP-KO HFD and WT HFD mice. (C) Body weight change (Δ) and (D) body weight accumulation between the start and end of the experiment. (E) Food intake g/day per animal. Food intake per cage was weekly measured, divided over the number of animals per cage, and averaged for the 16-week period. n = 3 or 4 cages per group, each with 3 or 4 animals per cage. (F) Hepatic triglyceride content by representative images of liver histology by H&E (top) and Oil Red O (ORO, bottom) staining. Digital images were taken by using a ×10 eyepiece and a ×20 objective. (G) Plasma biochemistry displaying levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (Alk. Phos.), and lactate dehydrogenase (LDH). All data are represented as mean ± SEM; each dot represents an individual animal (A–D and G) or cage (E). *P < 0.05, calculated with 2-way ANOVA (Holm-Šídák’s) (A) or 1-way ANOVA (Tukey’s) (B–E and G).

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