Ma Xiao-Jun, Xing Hai-Zhou, Ren Gao-Fei, Rao Xiao-Juan, Li Zhi-Zhen
Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Rd., Zhengzhou 450052, China.
Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Rd., Zhengzhou 450052, China.
Biochem Biophys Res Commun. 2018 Mar 11;497(3):819-826. doi: 10.1016/j.bbrc.2018.01.178. Epub 2018 Feb 16.
Multiple pathways contribute to nonalcoholic fatty liver disease (NAFLD) in response to high fat diets (HFD). A homolog of mammalian JNK-interacting protein 3 (JIP3), also known as JSAP-1, activates different components in various signaling pathways to modulate cellular processes. The purpose of this study was to examine the role of JIP3 in obesity-related pathologies pathway. Wild-type (WT) C57BL/6 and JIP3-knockout (JIP3) mice were randomized to chow or HFD. HFD-fed WT mice increased hepatic JIP3 expression. Mice lacking JIP3 exhibited reduced weight gain, hepatic steatosis, insulin resistance, lipid accumulation, oxidative stress and inflammatory response in mice fed a HFD, which were, importantly, dependent on various signaling pathways. Lipogenesis-linked pathway was inhibited in JIP3 mice after HFD, while PPARα/γ were increased. Additionally, JIP3 inhibited hepatic oxidative stress, evidenced by down-regulation of total reactive oxygen species (ROS), HO, O, malondialdehyde (MDA), xanthine oxidase (XO), inducible nitric oxide synthase (iNOS), and up-regulation of superoxide dismutase (SOD) and total antioxidant capacity (TAC) in mice after HFD feeding, which might be related to nuclear respiratory factor 2 (Nrf-2) pathway activation. Further, inflammatory response was blocked in JIP3 mice fed with HFD. The process might be attributed to the suppression of toll-like receptors (TLRs), p-nuclear factor kappa B (NF-κB) and p-c-Jun-N-terminal kinase (JNK). Thus, JIP3 absence is associated with decreased lipogenesis, oxidative stress and inflammation, supplying a new target for NAFLD treatment.
多种途径参与了高脂饮食（HFD）引发的非酒精性脂肪性肝病（NAFLD）。哺乳动物JNK相互作用蛋白3（JIP3）的同源物，也称为JSAP-1，可激活各种信号通路中的不同成分以调节细胞过程。本研究的目的是探讨JIP3在肥胖相关病理通路中的作用。将野生型（WT）C57BL/6和JIP3基因敲除（JIP3-/-）小鼠随机分为正常饮食或高脂饮食组。高脂饮食喂养的野生型小鼠肝脏JIP3表达增加。缺乏JIP3的小鼠在高脂饮食喂养后体重增加减少、肝脂肪变性、胰岛素抵抗、脂质蓄积、氧化应激和炎症反应减轻，重要的是，这些都依赖于各种信号通路。高脂饮食后JIP3-/-小鼠中与脂肪生成相关的通路受到抑制，而PPARα/γ增加。此外，JIP3抑制肝脏氧化应激，高脂饮食喂养的小鼠中总活性氧（ROS）、HO、O、丙二醛（MDA）、黄嘌呤氧化酶（XO）、诱导型一氧化氮合酶（iNOS）下调，超氧化物歧化酶（SOD）和总抗氧化能力（TAC）上调证明了这一点，这可能与核呼吸因子2（Nrf-2）通路激活有关。此外，高脂饮食喂养的JIP3-/-小鼠炎症反应受到阻断。这个过程可能归因于Toll样受体（TLRs）、磷酸化核因子κB（NF-κB）和磷酸化c-Jun氨基末端激酶（JNK）的抑制。因此，JIP3缺失与脂肪生成减少、氧化应激和炎症减轻有关，为NAFLD治疗提供了一个新靶点。
