c‐Jun acts downstream of PI3K/AKT signaling to mediate the effect of leptin on methionine adenosyltransferase 2B in hepatic stellate cells in vitro and in vivo

Abstract

Obese patients, often accompanied by hyperleptinemia, are prone to develop liver fibrosis. A large body of data including the results from human studies suggested the promotion role of leptin, an adipocyte-derived hormone, in liver fibrosis. Hepatic stellate cell (HSC) activation, a crucial step in liver fibrogenesis, requires global reprogramming of gene expression which is regulated by multiple mechanisms including epigenetic regulation such as methylation of DNA. S-Adenosylmethionine is a principal biological methyl donor and its biosynthesis is catalyzed by a methionine adenosyltransferase (MAT) such as MATII. MATII consists of the catalytic subunit MAT2A and regulatory subunit MAT2B which are essential for HSC activation. The present research investigated the effect of leptin on the expression of Mat2b in HSCs in vitro and in a leptin-deficient mouse model. Results demonstrated that leptin significantly increased Mat2b expression. Leptin-induced Mat2b expression required the PI3K/AKT signaling pathway. c-Jun, a component of activator protein (AP1), was phosphorylated by leptin-induced PI3K/AKT signaling and thus potentiated its binding to the element around −964 bp in the Mat2b promoter. MAT2B was involved in leptininduced HSC activation and liver fibrosis in a leptin-deficient mouse model. These results might broaden understanding of the mechanisms underlying the liver fibrogenesis in obese patients with hyperleptinemia.

Paeoniflorin Ameliorates Colonic Fibrosis In Rats With Post-Infectious Irritable Bowel Syndrome By Inhibiting The Leptin/Leprb Pathway

“…Previous studies reported that the binding of leptin to LepRb resulted in the suppression of the glycogen synthase kinase 3β (GSK3β)/β-catenin signaling, which was characterized by the increased phosphorylation of PI3K and AKT and expression of BDNF [36][37][38] . Hence, we also attempted to determine the role of the leptinmediated PI3K/AKT pathway in the PI-IBS rat model.…”

Lack of Mof reduces acute liver injury by enhancing transcriptional activation of Igf1

“…Additionally, the liver is a major site of IGF‐1 synthesis (Postic et al, 2004). The IGF‐1 receptor is activated after IGF‐1 binding, which promotes the phosphorylation activation of downstream AKT and activates the transcription of corresponding downstream genes, such as Myc and Jun (Aleem et al, 2011; Xu et al, 2019; Zhu et al, 2020). There is also evidence that liver regeneration is controlled by IGF‐1R activation and signal transduction (Desbois‐Mouthon et al, 2006).…”

“…Additionally, the liver is a major site of IGF-1 synthesis (Postic et al, 2004). The IGF-1 receptor is activated after IGF-1 binding, Aleem et al, 2011;Xu et al, 2019;Zhu et al, 2020). There is also evidence that liver regeneration is controlled by IGF-1R activation and signal transduction (Desbois-Mouthon et al, 2006).…”

Early‐immediate gene Egr1 is associated with TGFβ1 regulation of epigenetic reader Bromodomain‐containing protein 4 via the canonical Smad3 signaling in hepatic stellate cells in vitro and in vivo

“…The intensity of the bands was quantified by ImageJ software (NIH, Bethesda, MD, USA). Quantitative real‐time PCR (RT‐qPCR) was performed with QuantiNova SYBR Green PCR kit (Qiagen GmbH, Hilden, German) according to the procedure we described 14 . The Ct values were normalized against cyclophilin and analyzed using the 2 −ΔΔCt method.…”