G Protein-Coupled Receptor GPR35 Suppresses Lipid Accumulation in Hepatocytes.
G Protein-Coupled Receptor GPR35 Suppresses Lipid Accumulation in Hepatocytes.
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DOI：
10.1021/acsptsci.1c00224
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发表时间：
2021-12-10
影响因子：
--
通讯作者：
Milligan G
中科院分区：
文献类型：
--
作者：
Lin LC;Quon T;Engberg S;Mackenzie AE;Tobin AB;Milligan G
虽然非酒精性脂肪肝很普遍，但目前药物治疗效果不佳。最初，使用人肝细胞系HepG2的野生型和基因组编辑的克隆，我们表明孤儿G蛋白偶联受体GPR35的激活能够并且足以阻断肝脏X受体介导的脂质积聚。对从野生型和GPR35敲除小鼠中分离的肝细胞的研究与GPR35激动剂在这些细胞中的类似作用一致，但由于小鼠和人直系同源物中GPR35激动剂和拮抗剂的药理学显著差异，以及GPR35敲除小鼠肝细胞中基础脂质水平升高，因此无法得出明确结论。为了克服这一点，我们产生并表征了转基因敲入小鼠系，其中相应的人GPR35剪接变体取代了小鼠直向同源物。在来自这些人源化GPR35小鼠的肝细胞中，该受体的激活被证明可以最终阻止并逆转由肝脏X受体刺激诱导的脂质蓄积。这些研究强调了在脂肪肝疾病背景下靶向GPR35的潜力。
Although prevalent, nonalcoholic fatty liver disease is not currently treated effectively with medicines. Initially, using wild-type and genome-edited clones of the human hepatocyte cell line HepG2, we show that activation of the orphan G protein-coupled receptor GPR35 is both able and sufficient to block liver X-receptor-mediated lipid accumulation. Studies on hepatocytes isolated from both wild-type and GPR35 knock-out mice were consistent with a similar effect of GPR35 agonists in these cells, but because of marked differences in the pharmacology of GPR35 agonists and antagonists at the mouse and human orthologues, as well as elevated basal lipid levels in hepatocytes from the GPR35 knock-out mice, no definitive conclusion could be reached. To overcome this, we generated and characterized a transgenic knock-in mouse line in which the corresponding human GPR35 splice variant replaced the mouse orthologue. In hepatocytes from these humanized GPR35 mice, activation of this receptor was shown conclusively to prevent, and also reverse, lipid accumulation induced by liver X-receptor stimulation. These studies highlight the potential to target GPR35 in the context of fatty liver diseases.
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影响因子：
--
作者：
Quon T;Lin LC;Ganguly A;Tobin AB;Milligan G
通讯作者：
Milligan G
影响因子：
3.2
作者：
Divorty N;Milligan G;Graham D;Nicklin SA
通讯作者：
Nicklin SA
影响因子：
7.3
作者：
Deng, Huayun;Hu, Haibei;He, Mingqian;Hu, Jieyu;Niu, Weijun;Ferrie, Ann M.;Fang, Ye
通讯作者：
Fang, Ye
尖端：GPR35/CXCR8是粘膜趋化因子CXCL17的受体。
DOI：
10.4049/jimmunol.1401704
发表时间：
2015-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Maravillas-Montero JL;Burkhardt AM;Hevezi PA;Carnevale CD;Smit MJ;Zlotnik A
通讯作者：
Zlotnik A
影响因子：
7.3
作者：
Park, Soo-Jin;Lee, Seung-Jin;Im, Dong-Soon
通讯作者：
Im, Dong-Soon