BHF Cardiovascular Centre of Excellence and Centre of Integrative Biomedicine, Cardiovascular Division, King's College London, London, UK.
Institute of Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
Sci Rep. 2017 May 24;7(1):2338. doi: 10.1038/s41598-017-02439-z.
Transient receptor potential canonical 5 (TRPC5), a calcium-permeable, non-selective cation channel is expressed in the periphery, but there is limited knowledge of its regulatory roles in vivo. Endogenous modulators of TRPC5 include a range of phospholipids that have an established role in liver disease, including lysophosphatidylcholine (LPC). Cholestasis is characterized by impairment of excretion of bile acids, leading to elevation of hepatic bile acids. We investigated the contribution of TRPC5 in a murine model of cholestasis. Wild-type (WT) and TRPC5 knock-out (KO) mice were fed a diet supplemented with 0.5% cholic acid (CA) for 21 days. CA-diet supplementation resulted in enlargement of the liver in WT mice, which was ameliorated in TRPC5 KO mice. Hepatic bile acid and lipid content was elevated in WT mice, with a reduction observed in TRPC5 KO mice. Consistently, liver enzymes were significantly increased in cholestatic WT mice and significantly blunted in TRPC5 KO mice. Localized dyslipidaemia, secondary to cholestasis, was investigated utilizing a selected lipid analysis. This revealed significant perturbations in the lipid profile following CA-diet feeding, with increased cholesterol, triglycerides and phospholipids, in WT, but not TRPC5 KO mice. Our results suggest that activation of TRPC5 contributes to the development of cholestasis and associated dyslipidemia. Modulation of TRPC5 activity may present as a novel therapeutic target for liver disease.
瞬时受体电位经典型 5（TRPC5）是一种钙通透性、非选择性阳离子通道，在外周组织中表达，但体内其调节作用的相关知识有限。TRPC5 的内源性调节剂包括一系列在肝病中具有明确作用的磷脂，包括溶血磷脂酰胆碱（LPC）。胆汁淤积的特征是胆汁酸排泄受损，导致肝内胆汁酸升高。我们在胆汁淤积的小鼠模型中研究了 TRPC5 的作用。野生型（WT）和 TRPC5 敲除（KO）小鼠喂食添加 0.5%胆酸（CA）的饮食 21 天。CA 饮食补充导致 WT 小鼠肝脏增大，而 TRPC5 KO 小鼠的肝脏增大得到改善。WT 小鼠肝内胆汁酸和脂质含量升高，TRPC5 KO 小鼠的含量降低。一致的是，胆汁淤积 WT 小鼠的肝酶显著升高，而 TRPC5 KO 小鼠的肝酶显著降低。利用选定的脂质分析研究了继发于胆汁淤积的局部脂血症。这表明 CA 饮食喂养后脂质谱发生显著改变，WT 小鼠的胆固醇、甘油三酯和磷脂增加，但 TRPC5 KO 小鼠没有增加。我们的结果表明，TRPC5 的激活有助于胆汁淤积的发展和相关的脂血症。TRPC5 活性的调节可能成为肝病的一种新的治疗靶点。
