Feriod Colleen N, Oliveira Andre Gustavo, Guerra Mateus T, Nguyen Lily, Richards Kisha Mitchell, Jurczak Michael J, Ruan Hai-Bin, Camporez Joao Paulo, Yang Xiaoyong, Shulman Gerald I, Bennett Anton M, Nathanson Michael H, Ehrlich Barbara E
Department of Cellular and Molecular Physiology, Yale University School of Medicine New Haven, CT 06520.
Department of Pharmacology, Yale University School of Medicine New Haven, CT 06520.
Hepatol Commun. 2017 Feb;1(1):23-35. doi: 10.1002/hep4.1012. Epub 2016 Nov 11.
Fatty liver is the most common type of liver disease, affecting nearly one third of the US population and more than half a billion people worldwide. Abnormalities in ER calcium handling and mitochondrial function each have been implicated in abnormal lipid droplet formation. Here we show that the type 1 isoform of the inositol 1,4,5-trisphosphate receptor (InsPR1) specifically links ER calcium release to mitochondrial calcium signaling and lipid droplet formation in hepatocytes. Moreover, liver-specific InsPR1 knockout mice have impaired mitochondrial calcium signaling, decreased hepatic triglycerides, reduced lipid droplet formation and are resistant to development of fatty liver. Patients with non-alcoholic steatohepatitis, the most malignant form of fatty liver, have increased hepatic expression of InsPR1 and the extent of ER-mitochondrial co-localization correlates with the degree of steatosis in human liver biopsies.
InsPR1 plays a central role in lipid droplet formation in hepatocytes and the data suggest that it is involved in the development of human fatty liver disease.
脂肪肝是最常见的肝脏疾病类型，影响着近三分之一的美国人口以及全球超过5亿人。内质网钙处理异常和线粒体功能异常均与异常脂滴形成有关。在此我们表明，肌醇1,4,5-三磷酸受体（InsPR1）的1型异构体特异性地将内质网钙释放与肝细胞中的线粒体钙信号传导及脂滴形成联系起来。此外，肝脏特异性InsPR1基因敲除小鼠的线粒体钙信号传导受损，肝脏甘油三酯减少，脂滴形成减少，并且对脂肪肝的发展具有抗性。非酒精性脂肪性肝炎患者是脂肪肝最恶性的形式，其肝脏中InsPR1的表达增加，并且内质网与线粒体共定位的程度与人肝活检中的脂肪变性程度相关。
InsPR1在肝细胞脂滴形成中起核心作用，数据表明它参与了人类脂肪肝疾病的发展。
