Liver Sinusoidal Endothelial Cells in the Regulation of Immune Responses and Fibrosis in Metabolic Dysfunction-Associated Fatty Liver Disease

Abstract

Liver Sinusoidal Endothelial Cells (LSECs) play a crucial role in maintaining liver homeostasis, regulating immune responses, and fibrosis in liver diseases. This review explores the unique functions of LSECs in liver pathology, particularly their roles in immune tolerance, antigen presentation, and the modulation of hepatic stellate cells (HSCs) during fibrosis. LSECs act as key regulators of immune balance in the liver by preventing excessive immune activation while also filtering antigens and interacting with immune cells, including Kupffer cells and T cells. Metabolic Dysfunction-Associated Fatty Liver Disease(MAFLD) is significant because it can lead to advanced liver dysfunction, such as cirrhosis and liver cancer. The prevalence of Metabolic Associated Steatohepatitis (MASH) is increasing globally, particularly in the United States, and is closely linked to rising rates of obesity and type 2 diabetes. Early diagnosis and intervention are vital to prevent severe outcomes, highlighting the importance of studying LSECs in liver disease. However, during chronic liver diseases, LSECs undergo dysfunction, leading to their capillarization, loss of fenestrations, and promotion of pro-fibrotic signaling pathways such as Transforming growth factor-beta (TGF-β), which subsequently activates HSCs and contributes to the progression of liver fibrosis. The review also discusses the dynamic interaction between LSECs, HSCs, and other hepatic cells during the progression of liver diseases, emphasizing how changes in LSEC phenotype contribute to liver scarring and fibrosis. Furthermore, it highlights the potential of LSECs as therapeutic targets for modulating immune responses and preventing fibrosis in liver diseases. By restoring LSECs' function and targeting pathways associated with their dysfunction, novel therapies could be developed to halt or reverse liver disease progression. The findings of this review reinforce the importance of LSECs in liver pathology and suggest that they hold significant promises as targets for future treatment strategies aimed at addressing chronic liver diseases.

Keywords: LSEC dysfunction; LSECs; MAFLD liver disease; MASH; immune regulation; immune tolerance; liver fibrosis; therapeutic targets.

Figure 1

Structural and functional changes in liver LSECs in normal and injured liver. This image illustrates the structural and functional differences in LSECs between a normal liver (A) and an injured liver (B). In the normal liver, hepatocytes are aligned with fenestrated LSECs, allowing for efficient blood flow and interaction with Kupffer cells, macrophages, and NK Cells. Quiscent (q)HSCs are present in the space of Disse. In contrast, the injured liver shows hepatocyte damage, loss of fenestration in LSECs, and the activation of HSCs (aHSCs) into myofibroblasts, leading to extracellular matrix (ECM) deposition and collagen accumulation. This results in the activation of Kupffer cells, macrophages, and the presence of lymphocytes, natural killer cells (NKTs), and neutrophils, indicating an inflammatory response. The figure also highlights the molecular changes in LSECs, such as increased TGF-β expression (red up arrow) and decreased nitric oxide (NO) production (down blue arrow), and their interactions with other hepatic cells during liver injury. This figure also depicts ECM thickening in the space of Disse during fibrosis.

Figure 2

MAFLD progression stages and the role of LSECs in therapeutic strategies. This figure illustrates the progression stages of MAFLD with associated liver phenotypes and the role of LSECs. It highlights the importance of understanding LSECs in these stages to design and develop therapeutic strategies for identifying drug targets. The stages include Healthy Liver, Hepatic Steatosis (Fatty Liver), Steatohepatitis (MASH) (Fat + Inflammation), Advanced MASH (Fibrosis) (Fat + Inflammation + ECM), Cirrhosis, and Hepatocellular Carcinoma (HCC). Each stage is accompanied by visual representations of liver phenotypes, descriptions of LSECs’ roles, and suggested therapeutic strategies, emphasizing the critical role of LSECs in disease progression and potential drug targets.