FoxO3 通过调节固醇调节元件结合蛋白 1c 的表达来调节肝脏甘油三酯代谢。
FoxO3 regulates hepatic triglyceride metabolism via modulation of the expression of sterol regulatory-element binding protein 1c.
机构信息
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Fudan Institute for Metabolic Disease, Fudan University, Shanghai, 200032, China.
出版信息
Lipids Health Dis. 2019 Nov 15;18(1):197. doi: 10.1186/s12944-019-1132-2.
BACKGROUND
Excessive intrahepatic lipid accumulation is the major characteristic of nonalcoholic fatty liver disease (NAFLD). We sought to identify the mechanisms involved in hepatic triglyceride (TG) homeostasis. Forkhead box class O (FoxO) transcription factors have been shown to play an important role in hepatic metabolism. However, little is known about the effect of FoxO3 on hepatic TG metabolism.
METHODS
Liver biopsy samples from patients with NALFD and liver tissues from high glucose and high sucrose (HFHS) fed mice, ob/ob mice and db/db mice were collected for protein and mRNA analysis. HepG2 cells were transfected with small interfering RNA to mediate FoxO3 knockdown, or adenovirus and plasmid to mediate FoxO3 overexpression. FoxO3-cDNA was delivered by adenovirus to the liver of C57BL/6 J male mice on a chow diet or on a high-fat diet, followed by determination of hepatic lipid metabolism. Sterol regulatory element-binding protein 1c (SREBP1c) luciferase reporter gene plasmid was co-transfected into HepG2 cells with FoxO3 overexpression plasmid.
RESULTS
FoxO3 expression was increased in the livers of HFHS mice, ob/ob mice, db/db mice and patients with NAFLD. Knockdown of FoxO3 reduced whereas overexpression of FoxO3 increased cellular TG concentrations in HepG2 cells. FoxO3 gain-of-function caused hepatic TG deposition in C57BL/6 J mice on a chow diet and aggravated hepatic steatosis when fed a high-fat diet. Analysis of the transcripts established the increased expression of genes related to TG synthesis, including SREBP1c, SCD1, FAS, ACC1, GPAM and DGAT2 in mouse liver. Mechanistically, overexpression of FoxO3 stimulated the expression of SREBP1c, whereas knockdown of FoxO3 inhibited the expression of SREBP1c. Luciferase reporter assays showed that SREBP1c regulated the transcriptional activity of the SREBP1c promoter.
CONCLUSIONS
FoxO3 promotes the transcriptional activity of the SREBP1c promoter, thus leading to increased TG synthesis and hepatic TG accumulation.
背景
非酒精性脂肪性肝病（NAFLD）的主要特征是肝内脂质过度堆积。我们试图确定参与肝甘油三酯（TG）稳态的机制。叉头框 O（FoxO）转录因子已被证明在肝代谢中发挥重要作用。然而，关于 FoxO3 对肝 TG 代谢的影响知之甚少。
方法
收集 NAFLD 患者的肝活检样本和高糖高蔗糖（HFHS）喂养的小鼠、ob/ob 小鼠和 db/db 小鼠的肝组织进行蛋白质和 mRNA 分析。用小干扰 RNA 转染 HepG2 细胞以介导 FoxO3 敲低，或用腺病毒和质粒介导 FoxO3 过表达。将 FoxO3-cDNA 通过腺病毒递送至正常饮食或高脂肪饮食的 C57BL/6J 雄性小鼠肝脏，然后测定肝脂质代谢。将固醇调节元件结合蛋白 1c（SREBP1c）荧光素酶报告基因质粒与 FoxO3 过表达质粒共转染入 HepG2 细胞。
结果
HFHS 小鼠、ob/ob 小鼠、db/db 小鼠和 NAFLD 患者肝组织中 FoxO3 表达增加。FoxO3 敲低降低了 HepG2 细胞中细胞内 TG 浓度，而过表达 FoxO3 则增加了细胞内 TG 浓度。FoxO3 功能获得导致正常饮食的 C57BL/6J 小鼠肝内 TG 沉积，并在高脂饮食时加重肝脂肪变性。分析转录本确定了与 TG 合成相关的基因表达增加，包括小鼠肝中的 SREBP1c、SCD1、FAS、ACC1、GPAM 和 DGAT2。在机制上，FoxO3 过表达刺激 SREBP1c 的表达，而 FoxO3 敲低抑制 SREBP1c 的表达。荧光素酶报告基因检测表明 SREBP1c 调节 SREBP1c 启动子的转录活性。
结论
FoxO3 促进 SREBP1c 启动子的转录活性，从而导致 TG 合成增加和肝内 TG 积累。
Zotero 插件