JAB1 promotes palmitate-induced insulin resistance via ERK pathway in hepatocytes
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ORIGINAL ARTICLE
JAB1 promotes palmitate-induced insulin resistance via ERK pathway in hepatocytes Yun Zhao 1 & Suxian Ma 1 & Xingna Hu 1 & Min Feng 1 & Rong Xiang 1 & Min Li 1 & Chenxiao Liu 1 & Ting Lu 1 & Aijie Huang 1 & Jiaqi Chen 1 & Mian Wu 1 & Honghong Lu 1 Received: 25 May 2020 / Accepted: 6 October 2020 # University of Navarra 2020
Abstract Insulin resistance (IR) is the primary pathological mechanism underlying Type 2 diabetes mellitus (T2DM). Many researches have reported the relationship between chronic inflammation and IR, while the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway is rapidly activated in inflammatory conditions. However, the functional role of ERK1/2 in IR remains to be identified. We here reported that C-Jun activation domain-binding protein-1 (JAB1) was upregulated in IR. In addition, we showed that depletion of JAB1 led to recovery of insulin sensitivity. Given the fact that JAB1 played as an activator of ERK1/2, we assumed JAB1 was involved in IR through ERK pathway. So we assessed the effects of JAB1 knockdown in palmitate acid (PA) treated HepG2 cells. Importantly, JAB1 siRNA blocked the effect of PA-induced activation of ERK1/2. Furthermore, silencing of JAB1 could reduce the release of inflammatory factors, facilitate hepatic glucose uptake and improve lipid metabolism. All these data implicated that JAB1 knockdown might alleviate PA-induced IR through ERK pathway in hepatocytes. Keywords Type 2 diabetes . Insulin resistance . JAB1 . ERK pathway
Introduction Type 2 diabetes mellitus (T2DM) is showing the trend of youth and has become a major epidemic disease with various ages [8]. While insulin resistance (IR) is the key feature of T2DM [1, 19], especially in obese people [8]. Elevated plasma free fatty acid (FFA) levels are observed in individuals with IR [9]. The increase in hepatic FFA may induce IR by promoting protein kinase C translocation from the cytosol to the membrane, leading to impaired insulin receptor substrate (IRS) associated phosphatidylinositol 3-kinase (PI3-K) activity [5, 15]. Additionally, elevated FFA derives secretion of proYun Zhao and Suxian Ma contributed equally to this work. Key Points • JAB1 plays a role in chronic inflammation. • JAB1 knockdown has a protective effect on insulin sensitivity. • We associate JAB1, ERK pathway with insulin resistance. • JAB1 may act as a possible target for the treatment of T2DM. * Honghong Lu szsynfm@163.com 1
The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, Jiangsu 215008, People’s Republic of China
inflammatory cytokines including TNF-α and IL-6, which finally results in chronic inflammatory responses [19]. In the situation of chronic inflammation, several pathways are quickly activated in cascade [10, 12]. One of the vital inflammatory signals associated with insulin signaling is the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway [7, 18]. As is known to all, ERK1/2 can phosphorylate proteins on serine residues, thereby inhibiting tyrosine phosphoryl
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