Delta-like homolog1/GATA binding protein 2 axis mediates leptin inhibition of PPARγ2 expression in hepatic stellate cells in vitro

Aims: Peroxisome-proliferator activated receptor gamma (PPAR gamma) plays a pivotal role in inhibition of hepatic stellate cell (HSC) activation, a key step for liver fibrogenesis. Adipocyte-derived hormone leptin has been shown to promote liver fibrosis in murine and human. PPAR gamma includes two subtypes, PPAR gamma 1 and PPAR gamma 2. Our previous study indicated that leptin down-regulated PPAR gamma 1 expression in HSCs. The aim of this study was to investigate the effect of leptin on PPAR gamma 2 expression and the underlying mechanisms in HSCs. Main methods: Real-time PCR and western blot analyses were used to examine gene expression. The promoter activities were detected by luciferase assay. Key findings: Leptin reduced PPAR gamma 2 expressions at promoter level, mRNA level, and protein level in HSCs, which required beta-catenin, p38 mitogen-activated protein kinase, and delta-like homolog1 (DLK1) signaling pathways. Leptin induced GATA binding protein 2 (GATA2) expression through DLK1 pathway and GATA2 reduced PPAR gamma 2 expression. Ectopic expression of PPAR gamma 2 reduced the protein levels of alpha-smooth muscle actin and alpha 1(I) collagen in HSCs. Significance: Since obese patients, often accompanied by hyperleptinemia, are more prone to liver fibrosis, the data from this study might have potential implications for clarifying the mechanisms for liver fibrogenesis in obese patients with hyperleptinemia.