Hepatic steatosis, often triggered by non-alcoholic fatty liver disease (NAFLD), is a leading cause of liver dysfunction globally, affecting approximately 30% of the population. The progression from steatosis to hepatic fibrosis, which may ultimately lead to cirrhosis, is a significant concern in liver disease management. This review highlights the critical role of solute carrier (SLC) family transporters in both hepatic steatosis and fibrosis. SLC transporters are membrane-bound proteins responsible for transporting a variety of molecules, including fatty acids, amino acids, and nucleotides, across biological membranes. The review aims to explore how these transporters influence the pathophysiological processes underlying liver diseases, focusing on their roles in lipid metabolism, hepatocyte function, and the development of fibrosis.
Role of SLC Transporters in Hepatic Steatosis
SLC transporters contribute to the development of hepatic steatosis by regulating lipid metabolism. Members of the SLC family, such as SLC2A2 (GLUT2), SLC2A4 (GLUT4), and SLC2A5 (GLUT5), are involved in glucose and fatty acid transport into liver cells, affecting processes such as de novo lipogenesis (DNL) and glucose-induced lipid accumulation. Dysregulation of glucose transporters like GLUT2 can exacerbate insulin resistance (IR) and promote lipogenesis in hepatocytes. In contrast, GLUT4's translocation to the cell membrane in response to insulin signaling influences glucose uptake, and abnormal GLUT4 activity can further contribute to steatosis, particularly in response to high-fat diets.
Mechanisms of Action and Impact on Hepatic Fibrosis
As steatosis progresses, hepatic fibrosis can develop as a result of chronic liver injury. The activation of hepatic stellate cells (HSCs), the epithelial-mesenchymal transition (EMT) of hepatocytes, and macrophage polarization are key events in this process. SLC transporters influence these cellular responses. For example, SLC1A5, a glutamine transporter, is upregulated in conditions like non-alcoholic steatohepatitis (NASH), and its inhibition can reduce HSC activation and the subsequent fibrotic response. Transporters like GLUT1, expressed by HSCs, are also implicated in fibrosis by facilitating glucose uptake in activated stellate cells, thereby promoting fibrosis via enhanced glycolysis.
SLC Transporters in Drug-Induced Liver Injury
Beyond their role in lipid metabolism, SLC transporters are also implicated in drug-induced liver injury. For instance, multidrug resistance-associated transporters are critical in mediating the hepatic response to pharmacological agents, such as statins and anti-tuberculosis drugs, which can cause drug-induced hepatic steatosis. SLC transporters regulate the uptake and efflux of these drugs, influencing their effects on liver cells and potentially contributing to hepatic dysfunction.
Conclusion
SLC transporters play pivotal roles in the development and progression of hepatic steatosis and fibrosis through their regulation of lipid and glucose metabolism, cellular responses to injury, and drug interactions. Understanding the molecular mechanisms of these transporters provides valuable insights into liver disease pathophysiology and offers potential therapeutic targets for managing NAFLD, NASH, and hepatic fibrosis. Continued research on SLC transporters, including clinical trials targeting these proteins, could lead to the development of novel therapeutic strategies for liver diseases.
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https://www.xiahepublishing.com/2310-8819/JCTH-2024-00348
The study was recently published in the Journal of Clinical and Translational Hepatology .
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study's novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
