Peroxisome proliferator-activated receptors gama ameliorates liver fibrosis in non-alcoholic fatty liver disease by inhibiting TGF-β/Smad signaling activation

Abstract

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is a chronic condition characterized by a progressive decline in liver function, leading to disruptions in liver integrity and metabolic function, resulting in lipid deposition and excessive accumulation of extracellular matrix (ECM). The pathogenesis of NAFLD is complex and not yet fully understood, contributing to the absence of specific therapeutic strategies. Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor pivotal in regulating lipid and glucose metabolism. However, the impacts of PPARγ on NAFLD remains insufficiently explored. Thus, this study aimed to investigate the role of PPARγ in NAFLD and its underlying molecular mechanisms. Methods Chemical detection kits were utilized to quantify collagen content, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) level variations. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to assess alterations in extracellular matrix-related genes and inflammatory response genes in liver tissue and HepG2 cells, while western blotting was conducted to analyze the levels of both PPARγ and the TGF-β/Smad signaling pathway. Results Our findings unveiled significantly reduced PPARγ expression in a rat model of NAFLD, leading to subsequent activation of the TGF-β/Smad signaling pathway. Furthermore, PPARγ activation effectively mitigated NAFLD progression by inhibiting inflammation and fibrosis-related gene expression and collagen production. On a cellular level, PPARγ activation was found to inhibit the expression of extracellular matrix-related genes such as matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9), along with inflammatory response genes interleukin (IL)-1β and IL-6. Additionally, PPARγ activation led to a significant decrease in the levels of ALT and AST. At the molecular level, PPARγ notably down-regulated the TGF-β/Smad signaling pathway, which is known to promote liver fibrosis. Conclusion These groundbreaking findings underscore PPARγ activation as a promising therapeutic approach to delay NAFLD progression by targeting the TGF-β/Smad signaling pathway in hepatic cells. This highlights the potential of PPARγ as a promising therapeutic target for NAFLD management in clinical settings.