NTCP deficiency in mice protects against obesity and hepatosteatosis
NTCP deficiency in mice protects against obesity and hepatosteatosis
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DOI：
10.1172/jci.insight.127197
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发表时间：
2019-07-25
期刊：
影响因子：
8
通讯作者：
van de Graaf, Stan F. J.
中科院分区：
文献类型：
--
作者：
Donkers, Joanne M.;Kooijman, Sander;van de Graaf, Stan F. J.
胆汁酸在调节脂质和能量代谢中起主要作用。在这里，我们建议肝胆汁酸摄取转运蛋白Na+牛磺胆酸盐共转运多肽（NTCP）作为延长血浆中餐后胆汁酸升高的靶点。通过基因缺失NTCP减少胆汁酸从血浆中的肝脏清除，适度增加血浆胆汁酸水平，减少饮食诱导的肥胖，减弱肝脂肪变性，并降低血浆胆固醇水平。NTCP和G蛋白偶联胆汁酸受体双KO（TGR 5-双KO）小鼠与NTCP-单KO小鼠一样，对饮食诱导的肥胖具有同等的保护作用。NTCP-KO小鼠表现出肠道脂肪吸收减少和粪便能量输出增加的趋势。此外，NTCP缺乏与棕色脂肪组织的非偶联呼吸增加有关，导致能量消耗增加。我们的结论是，靶向NTCP介导的胆汁酸摄取可以是一种新的方法来治疗肥胖和肥胖相关的脂肪肝，同时抑制肠道脂肪吸收和增加能量消耗。
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.