Department of Physiology, CIMUS, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Madrid, Spain.
Cell Mol Life Sci. 2024 Nov 28;81(1):468. doi: 10.1007/s00018-024-05507-6.
The use of incretin agonists for managing metabolic dysfunction-associated steatohepatitis (MASH) is currently experiencing considerable interest. However, whether these compounds have a direct action on MASH is still under debate. This study aims to investigate whether GLP-1R/GIPR agonists act directly in hepatocytes and hepatic stellate cells (HSCs). For this, human hepatocyte and HSCs lines, as well as primary human hepatocytes and HSCs treated with Liraglutide, Acyl-GIP or the GLP-1/GIP dual agonist (MAR709) were used. We show that the concentrations of each compound, which were effective in insulin release, did not induce discernible alterations in either hepatocytes or HSCs. In hepatocytes displaying elevated fatty acid content after the treatment with oleic acid and palmitic acid, none of the three compounds reduced lipid concentration. Similarly, in HSCs activated with transforming growth factor-β (TGFb), Liraglutide, Acyl-GIP and MAR709 failed to ameliorate the elevated expression of fibrotic markers. The three compounds were also ineffective in phosphorylating CREB, which mediates insulinotropic actions, in both hepatocytes and HSCs. These findings indicate that incretin agonists have no direct actions in human hepatocytes or hepatic stellate cells, suggesting that their beneficial effects in patients with MASH are likely mediated indirectly, potentially through improvements in body weight, insulin resistance and glycemic control.
目前，人们对使用肠促胰岛素激动剂治疗代谢相关脂肪性肝炎（MASH）产生了浓厚的兴趣。然而，这些化合物是否对 MASH 有直接作用仍存在争议。本研究旨在探讨 GLP-1R/GIPR 激动剂是否直接作用于肝细胞和肝星状细胞（HSCs）。为此，我们使用了人肝细胞和 HSCs 系，以及用利拉鲁肽、酰化 GIP 或 GLP-1/GIP 双重激动剂（MAR709）处理的原代人肝细胞和 HSCs。我们发现，在胰岛素释放方面有效的每种化合物的浓度，既没有在肝细胞或 HSCs 中引起明显的变化。在经油酸和棕榈酸处理后，肝细胞中脂肪酸含量升高的情况下，三种化合物均不能降低脂质浓度。同样，在转化生长因子-β（TGFb）激活的 HSCs 中，利拉鲁肽、酰化 GIP 和 MAR709 也未能改善纤维化标志物的高表达。在肝细胞和 HSCs 中，这三种化合物也不能磷酸化 CREB，而 CREB 介导胰岛素促分泌作用。这些发现表明，肠促胰岛素激动剂对人肝细胞或肝星状细胞没有直接作用，这表明它们在 MASH 患者中的有益作用可能是间接介导的，可能是通过改善体重、胰岛素抵抗和血糖控制。
