Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States.
Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
Front Endocrinol (Lausanne). 2021 Dec 6;12:773432. doi: 10.3389/fendo.2021.773432. eCollection 2021.
The prevalence of non-alcoholic fatty liver disease (NAFLD) is globally increasing. Gaining control over disease-related events in non-alcoholic steatohepatitis (NASH), an advanced form of NAFLD, is currently an unmet medical need. Hepatic fibrosis is a critical prognostic factor in NAFLD/NASH. Therefore, a better understanding of the pathophysiology of hepatic fibrosis and the development of related therapies are of great importance. G protein-coupled receptors (GPCRs) are cell surface receptors that mediate the function of a great variety of extracellular ligands. GPCRs represent major drug targets, as indicated by the fact that about 40% of all drugs currently used in clinical practice mediate their therapeutic effects by acting on GPCRs. Like many other organs, various GPCRs play a role in regulating liver function. It is predicted that more than 50 GPCRs are expressed in the liver. However, our knowledge of how GPCRs regulate liver metabolism and fibrosis in the different cell types of the liver is very limited. In particular, a better understanding of the role of GPCRs in hepatic stellate cells (HSCs), the primary cells that regulate liver fibrosis, may lead to the development of drugs that can improve hepatic fibrosis in NAFLD/NASH. In this review, we describe the functions of multiple GPCRs expressed in HSCs, their roles in liver fibrogenesis, and finally speculate on the development of novel treatments for NAFLD/NASH.
非酒精性脂肪性肝病（NAFLD）的患病率在全球范围内呈上升趋势。目前，非酒精性脂肪性肝炎（NASH）是一种更为严重的 NAFLD 形式，人们尚未能有效控制其疾病相关事件。肝纤维化是非酒精性脂肪性肝病/脂肪性肝炎（NAFLD/NASH）的一个关键预后因素。因此，更好地了解肝纤维化的病理生理学以及开发相关治疗方法非常重要。G 蛋白偶联受体（GPCR）是一种细胞表面受体，可介导多种细胞外配体的功能。GPCR 是主要的药物靶点，这一点可从目前在临床实践中使用的约 40%的所有药物通过作用于 GPCR 来发挥其治疗作用这一事实得到证实。与许多其他器官一样，各种 GPCR 也在调节肝功能方面发挥作用。据预测，肝脏中表达的 GPCR 超过 50 种。然而，我们对于 GPCR 如何调节肝脏代谢和纤维化在肝脏的不同细胞类型中的作用知之甚少。特别是，更好地了解 GPCR 在肝星状细胞（HSCs）中的作用，HSCs 是调节肝纤维化的主要细胞，可能会导致开发出可改善 NAFLD/NASH 肝纤维化的药物。在这篇综述中，我们描述了在 HSCs 中表达的多种 GPCR 的功能、它们在肝纤维化形成中的作用，最后对 NAFLD/NASH 的新型治疗方法的开发进行了推测。
