Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States; Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Japan; Research Center for Agricultural Food Industry, Shinshu University, Matsumoto, Japan.
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
Biochim Biophys Acta Mol Basis Dis. 2017 Dec;1863(12):3170-3182. doi: 10.1016/j.bbadis.2017.08.017. Epub 2017 Aug 24.
Growth arrest and DNA damage-inducible 45 α (Gadd45α) is a stress-inducible protein that plays an important role in cell survival/death and DNA repair, but its contribution to the development of nonalcoholic steatohepatitis (NASH) has not been investigated. C57BL/6 Gadd45a-null and wild-type (WT) mice were treated with a methionine and choline-deficient diet (MCD) for eight weeks and phenotypic changes examined. Gadd45a-null mice had more severe hepatic inflammation and fibrosis, higher levels of mRNAs encoding pro-inflammatory, pro-fibrotic, and pro-apoptotic proteins, and greater oxidative and endoplasmic reticulum (ER) stress compared with WT mice. Indeed, Gadd45a mRNA was induced in response to ER stress in primary hepatocytes. Lipidomic analysis of NASH livers demonstrated decreased triacylglycerol (TG) in MCD-treated Gadd45a-null mice, which was associated with increased mRNAs encoding phospholipase D (Pld1/2), phosphatidic acid phosphatase type 2A, and choline/ethanolamine phosphotransferase 1 (Cept1), involved in the phosphatidylcholine-phosphatidic acid-diacylglycerol cycle, and decreased mRNAs encoding fatty acid (FA)-binding protein 1 (Fabp1) and FA transport protein 5. Treatment of cultured primary hepatocytes with tumor necrosis factor α, transforming growth factor β, and hydrogen peroxide led to the corresponding induction of Fabp1, Pld1/2, and Cept1 mRNAs. Collectively, Gadd45α plays protective roles against MCD-induced NASH likely due to attenuating cellular stress and ensuing inflammatory signaling. These results also suggest an interconnection between hepatocyte injury, inflammation and disrupted glycerophospholipid/FA metabolism that yields a possible mechanism for decreased TG accumulation with NASH progression (i.e., "burned-out" NASH).
生长停滞和 DNA 损伤诱导蛋白 45α（Gadd45α）是一种应激诱导蛋白，在细胞存活/死亡和 DNA 修复中发挥重要作用，但它对非酒精性脂肪性肝炎（NASH）的发展的贡献尚未被研究。用蛋氨酸和胆碱缺乏饮食（MCD）处理 8 周后，检查 C57BL/6 Gadd45a 基因敲除和野生型（WT）小鼠的表型变化。与 WT 小鼠相比，Gadd45a 基因敲除小鼠的肝炎症和纤维化更严重，促炎、促纤维化和促凋亡蛋白的 mRNA 水平更高，氧化和内质网（ER）应激更大。事实上，Gadd45a mRNA 是对 ER 应激在原代肝细胞中诱导的。NASH 肝脏的脂质组学分析表明，MCD 处理的 Gadd45a 基因敲除小鼠的三酰甘油（TG）减少，这与编码磷脂酶 D（Pld1/2）、磷酸酶酸磷酸酶 2A 和胆碱/乙醇胺磷酸转移酶 1（Cept1）的 mRNA 增加有关，涉及磷脂酰胆碱-磷酸酸-二酰基甘油循环，编码脂肪酸（FA）结合蛋白 1（Fabp1）和 FA 转运蛋白 5 的 mRNA 减少。用肿瘤坏死因子-α、转化生长因子-β 和过氧化氢处理培养的原代肝细胞，导致 Fabp1、Pld1/2 和 Cept1 mRNA 的相应诱导。总之，Gadd45α 对 MCD 诱导的 NASH 具有保护作用，可能是由于减轻细胞应激和随之而来的炎症信号。这些结果还表明肝细胞损伤、炎症和甘油磷脂/FA 代谢紊乱之间存在联系，这为 NASH 进展时 TG 积累减少提供了一个可能的机制（即“枯竭”的 NASH）。
