Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA.
Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA; Institute of Biosciences & Technology, Texas A&M University, Houston, TX, 77030, USA.
J Nutr Biochem. 2023 Jan;111:109157. doi: 10.1016/j.jnutbio.2022.109157. Epub 2022 Sep 20.
Gata4 is a member of the zinc finger GATA transcription factor family and is required for liver development during the embryonic stage. Gata4 expression is repressed during NAFLD progression, however how it functions in this situation remains unclear. Here, Gata4 was deleted specifically in hepatocytes via Cre recombinase driven by the Alb promoter region. Under a high-fat diet (HFD) or methionine and choline deficient diet (MCD), Gata4 knockout (KO) male, but not female, mice displayed more severe NAFLD or NASH, evidenced by increased steatosis, fibrosis, as well as a higher NAS score and serum ALT level. The Gata4KO male liver exposed to a HFD or MCD had a reduced ratio of pACC/ACC, similar to the Gata4KO hepatocytes treated with palmitic acid. More cell apoptosis, which is associated with activated JNK signaling and inhibited NFκB signaling, was observed in the Gata4KO male liver and isolated hepatocytes. However, the inflammatory status in the Gata4KO male liver was similar to the control liver. Importantly, lower activation of AKT signaling in the liver, which is consistent with de-sensitized insulin signaling in isolated hepatocytes, was found in the Gata4KO male. In summary, our data demonstrated that loss of Gata4 in hepatocytes promoted NAFLD progression in male mice.
Gata4 是锌指 GATA 转录因子家族的成员，在胚胎期的肝脏发育中是必需的。Gata4 的表达在 NAFLD 进展过程中受到抑制，但它在这种情况下如何发挥作用尚不清楚。在这里，通过 Alb 启动子区域驱动的 Cre 重组酶，特异性地在肝细胞中删除了 Gata4。在高脂肪饮食 (HFD) 或蛋氨酸和胆碱缺乏饮食 (MCD) 下，Gata4 敲除 (KO) 雄性而非雌性小鼠表现出更严重的非酒精性脂肪性肝病或 NASH，其证据为脂肪变性、纤维化增加，以及更高的 NAS 评分和血清 ALT 水平。暴露于 HFD 或 MCD 的 Gata4KO 雄性肝脏的 pACC/ACC 比值降低，类似于用棕榈酸处理的 Gata4KO 肝细胞。在 Gata4KO 雄性肝脏和分离的肝细胞中观察到更多的细胞凋亡，这与激活的 JNK 信号和抑制的 NFκB 信号有关。然而，Gata4KO 雄性肝脏的炎症状态与对照肝脏相似。重要的是，在 Gata4KO 雄性肝脏中发现 AKT 信号的激活降低，这与分离的肝细胞中胰岛素信号的脱敏一致。总之，我们的数据表明，肝细胞中 Gata4 的缺失促进了雄性小鼠的非酒精性脂肪性肝病的进展。
