Department of Pathology, Georgetown University, Washington, DC, 20007, USA.
Department of Medicine, Georgetown University, 4000 Reservoir Rd, NW, Building D, Room 338, Washington, DC, 20007, USA.
Dig Dis Sci. 2020 Jan;65(1):189-203. doi: 10.1007/s10620-019-05722-3. Epub 2019 Jul 11.
Nonalcoholic steatohepatitis (NASH) is a common inflammatory liver condition that may lead to cirrhosis and hepatocellular carcinoma (HCC). Risk factors for NASH include a saturated fat diet, altered lipid metabolism, and genetic and epigenetic factors, including microRNAs. Serum levels of cholecystokinin (CCK) are elevated in mice and humans that consume a high-saturated fat diet. CCK receptors (CCK-Rs) have been reported on fibroblasts which when activated can induce fibrosis; however, their role in hepatic fibrosis remains unknown. We hypothesized that elevated levels of CCK acting on the CCK-Rs play a role in the development of NASH and in NASH-associated HCC.
We performed a NASH Prevention study and Reversal study in mice fed a saturated fat 75% choline-deficient-ethionine-supplemented (CDE) diet for 12 or 18 weeks. In each study, half of the mice received untreated drinking water, while the other half received water supplemented with the CCK-R antagonist proglumide. CCK-R expression was evaluated in mouse liver and murine HCC cells.
CCK receptor antagonist treatment not only prevented NASH but also reversed hepatic inflammation, fibrosis, and steatosis and normalized hepatic transaminases after NASH was established. Thirty-five percent of the mice on the CDE diet developed HCC compared with none in the proglumide-treated group. We found that CCK-BR expression was markedly upregulated in mouse CDE liver and HCC cells compared with normal hepatic parenchymal cells, and this expression was epigenetically regulated by microRNA-148a.
These results support the novel role of CCK receptors in the pathogenesis of NASH and HCC.
非酒精性脂肪性肝炎（NASH）是一种常见的炎症性肝病，可能导致肝硬化和肝细胞癌（HCC）。NASH 的危险因素包括饱和脂肪饮食、脂质代谢改变以及遗传和表观遗传因素，包括 microRNA。在摄入高脂肪饮食的小鼠和人类中，胆囊收缩素（CCK）的血清水平升高。CCK 受体（CCK-Rs）已在成纤维细胞上报道，当被激活时可诱导纤维化；然而，其在肝纤维化中的作用尚不清楚。我们假设，高水平的 CCK 作用于 CCK-Rs 在 NASH 的发展以及 NASH 相关 HCC 中起作用。
我们在喂食 75%饱和脂肪胆碱缺乏蛋氨酸补充（CDE）饮食 12 或 18 周的小鼠中进行了 NASH 预防研究和逆转研究。在每项研究中，一半的小鼠接受未处理的饮用水，而另一半则接受补充 CCK-R 拮抗剂 proglumide 的水。评估了 CCK-R 在小鼠肝脏和鼠 HCC 细胞中的表达。
CCK 受体拮抗剂治疗不仅预防了 NASH，而且在 NASH 确立后还逆转了肝炎症、纤维化和脂肪变性，并使肝转氨酶正常化。与未接受 proglumide 治疗的组相比，35%的 CDE 饮食小鼠发展为 HCC。我们发现，与正常肝实质细胞相比，CCK-BR 在 CDE 小鼠肝和 HCC 细胞中的表达明显上调，这种表达受 microRNA-148a 的表观遗传调控。
这些结果支持 CCK 受体在 NASH 和 HCC 发病机制中的新作用。
