Abstract
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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is a predominant liver disease with a rapid increase in prevalence worldwide, accounting for the hepatic phenotype of the metabolic syndrome [1]
In vitro experiments showed that hepatic stellate cells (HSCs) lacking chemokine receptor 2 (CCR2) or its downstream mediator p47phox do not exhibit phosphorylation of ERKs or protein kinase B (AKT), chemotaxis, or generation of ROS in response to CC chemokines such as MCP-1 (CCL2), MCP-2 (CCL8), or MCP-3 (CCL7) [44]. These results indicate that CCR2 promotes chemotaxis of HSCs and the development of liver fibrosis
Namodenoson regulated the Wnt/bcatenin pathway and decreased phosphoinositide 3-kinase (PI3K) expression in liver extracts in CCl4-treated mice and LX2-cells. These results indicate that namodenoson exerts a protective effect for non-alcoholic steatohepatitis (NASH) through the regulation of the PI3K/NF-kB/Wnt/bcatenin signaling pathway [50]
Summary
Non-alcoholic fatty liver disease (NAFLD) is a predominant liver disease with a rapid increase in prevalence worldwide, accounting for the hepatic phenotype of the metabolic syndrome [1]. The Gs-coupled dopamine D1 receptor (DRD1) was found to be preferentially expressed in mesenchymal cells of the lung and HSCs in the liver [18]. The use of the adenosine receptor antagonists such as caffeine or ZM241385 reduced liver fibrosis in wild-type mice exposed to CCl4 or thioacetamide in the same study.
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