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Ethyl 2-[2,3,4-Trimethoxy-6-(1-Octanoyl)Phenyl] Acetate (TMPA) Ameliorates Lipid Accumulation by Disturbing the Combination of LKB1 with Nur77 and Activating the AMPK Pathway in HepG2 Cells and Mice Primary Hepatocytes
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy ( IF 2.8 ) Pub Date : 2021-10-02 , DOI: 10.2147/dmso.s321246 Xiaoyu Wang 1 , Guangbing Li 1, 2 , Changfa Guo 3 , Jiayao Zhang 1 , Junjie Kong 1, 2 , Jingyi He 1, 2 , Feiyu Li 1 , Yong Liu 1 , Yang Yang 1 , Ziwen Lu 1 , Jun Liu 1, 2
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy ( IF 2.8 ) Pub Date : 2021-10-02 , DOI: 10.2147/dmso.s321246 Xiaoyu Wang 1 , Guangbing Li 1, 2 , Changfa Guo 3 , Jiayao Zhang 1 , Junjie Kong 1, 2 , Jingyi He 1, 2 , Feiyu Li 1 , Yong Liu 1 , Yang Yang 1 , Ziwen Lu 1 , Jun Liu 1, 2
Affiliation
Background: The AMP-activated protein kinase alpha (AMPKα) pathway has widely been considered a key factor in energy metabolism. Ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl] acetate (TMPA) is a novel AMPK agonist, which influences the stability of Nuclear Receptor Subfamily 4, Group A, Member 1 (Nur77)-serine-threonine kinase 11 (LKB1) in the nucleus. A recent study has determined that TMPA can ameliorate the reduction of insulin resistance in type II db/db mice. However, the role of TMPA in hepatocyte lipid metabolism has not been elucidated.
Objective: To investigate whether TMPA could ameliorate liver lipid accumulation under the stimulation of free fatty acids (FFAs) in vitro.
Methods: We evaluated differences of Nur77 and AMPK pathway in mice fed a high-fat diet and those fed a normal diet. In vitro, TMPA was added to HepG2 cells and primary hepatocytes before FFAs stimulation. Oil red O staining, Nile red staining were used to evaluate lipid deposition. Western blot and immunofluorescence were used to quantify related proteins.
Results: Nur77, AMPKα, LKB1, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), acetyl-CoA carboxylase phosphorylation (p-ACC), and carnitine palmitoyltransferase 1 (CPT1A) showed significant differences in vivo. Under the intervention of TMPA, HepG2 cells and primary hepatocytes showed considerable amelioration of lipid deposition and improved the expression of phosphorylated (p)-AMPKα (p-AMPKα), p-LKB1, p-ACC, and CPT1A. Furthermore, Western blotting and immunofluorescence studies indicated that LKB1 dramatically increased expression in the cytoplasm but decreased in the nucleus. Further, AMPKα phosphorylation (p-AMPKα) also showed a higher expression in cytoplasm instead of the nucleus.
Conclusion: TMPA ameliorated lipid accumulation by influencing the stability of Nur77-LKB1 in vitro.
中文翻译：
2-[2,3,4-Trimethoxy-6-(1-Octanoyl)Phenyl] 乙酸乙酯 (TMPA) 通过干扰 LKB1 与 Nur77 的结合并激活 HepG2 细胞和小鼠原代肝细胞中的 AMPK 通路来改善脂质积累
背景： AMP 活化蛋白激酶 α (AMPKα) 途径已被广泛认为是能量代谢的关键因素。2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl] 乙酸乙酯 (TMPA) 是一种新型 AMPK 激动剂，它影响核受体亚科 4、A 组、成员 1 (Nur77)-的稳定性-细胞核中的丝氨酸-苏氨酸激酶 11 (LKB1)。最近的一项研究确定，TMPA 可以改善 II 型 db/db 小鼠的胰岛素抵抗。然而，尚未阐明 TMPA 在肝细胞脂质代谢中的作用。
目的：探讨在体外游离脂肪酸（FFA）刺激下，TMPA是否能改善肝脏脂质积累。
方法：我们评估了喂食高脂肪饮食和喂食正常饮食的小鼠中 Nur77 和 AMPK 通路的差异。在体外，TMPA 在 FFAs 刺激之前被添加到 HepG2 细胞和原代肝细胞中。油红O染色、尼罗红染色用于评价脂质沉积。Western印迹和免疫荧光用于量化相关蛋白质。
结果：Nur77、AMPKα、LKB1、3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）、乙酰辅酶A羧化酶磷酸化（p-ACC）和肉碱棕榈酰转移酶1（CPT1A）在体内表现出显着差异。在 TMPA 的干预下，HepG2 细胞和原代肝细胞的脂质沉积得到显着改善，磷酸化 (p)-AMPKα (p-AMPKα)、p-LKB1、p-ACC 和 CPT1A 的表达得到改善。此外，蛋白质印迹和免疫荧光研究表明，LKB1 在细胞质中的表达显着增加，但在细胞核中的表达减少。此外，AMPKα磷酸化（p-AMPKα）在细胞质而不是细胞核中也显示出更高的表达。
结论： TMPA 通过影响 Nur77-LKB1 在体外的稳定性来改善脂质积累。
更新日期：2021-10-02
Objective: To investigate whether TMPA could ameliorate liver lipid accumulation under the stimulation of free fatty acids (FFAs) in vitro.
Methods: We evaluated differences of Nur77 and AMPK pathway in mice fed a high-fat diet and those fed a normal diet. In vitro, TMPA was added to HepG2 cells and primary hepatocytes before FFAs stimulation. Oil red O staining, Nile red staining were used to evaluate lipid deposition. Western blot and immunofluorescence were used to quantify related proteins.
Results: Nur77, AMPKα, LKB1, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), acetyl-CoA carboxylase phosphorylation (p-ACC), and carnitine palmitoyltransferase 1 (CPT1A) showed significant differences in vivo. Under the intervention of TMPA, HepG2 cells and primary hepatocytes showed considerable amelioration of lipid deposition and improved the expression of phosphorylated (p)-AMPKα (p-AMPKα), p-LKB1, p-ACC, and CPT1A. Furthermore, Western blotting and immunofluorescence studies indicated that LKB1 dramatically increased expression in the cytoplasm but decreased in the nucleus. Further, AMPKα phosphorylation (p-AMPKα) also showed a higher expression in cytoplasm instead of the nucleus.
Conclusion: TMPA ameliorated lipid accumulation by influencing the stability of Nur77-LKB1 in vitro.
中文翻译：
2-[2,3,4-Trimethoxy-6-(1-Octanoyl)Phenyl] 乙酸乙酯 (TMPA) 通过干扰 LKB1 与 Nur77 的结合并激活 HepG2 细胞和小鼠原代肝细胞中的 AMPK 通路来改善脂质积累
背景： AMP 活化蛋白激酶 α (AMPKα) 途径已被广泛认为是能量代谢的关键因素。2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl] 乙酸乙酯 (TMPA) 是一种新型 AMPK 激动剂，它影响核受体亚科 4、A 组、成员 1 (Nur77)-的稳定性-细胞核中的丝氨酸-苏氨酸激酶 11 (LKB1)。最近的一项研究确定，TMPA 可以改善 II 型 db/db 小鼠的胰岛素抵抗。然而，尚未阐明 TMPA 在肝细胞脂质代谢中的作用。
目的：探讨在体外游离脂肪酸（FFA）刺激下，TMPA是否能改善肝脏脂质积累。
方法：我们评估了喂食高脂肪饮食和喂食正常饮食的小鼠中 Nur77 和 AMPK 通路的差异。在体外，TMPA 在 FFAs 刺激之前被添加到 HepG2 细胞和原代肝细胞中。油红O染色、尼罗红染色用于评价脂质沉积。Western印迹和免疫荧光用于量化相关蛋白质。
结果：Nur77、AMPKα、LKB1、3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）、乙酰辅酶A羧化酶磷酸化（p-ACC）和肉碱棕榈酰转移酶1（CPT1A）在体内表现出显着差异。在 TMPA 的干预下，HepG2 细胞和原代肝细胞的脂质沉积得到显着改善，磷酸化 (p)-AMPKα (p-AMPKα)、p-LKB1、p-ACC 和 CPT1A 的表达得到改善。此外，蛋白质印迹和免疫荧光研究表明，LKB1 在细胞质中的表达显着增加，但在细胞核中的表达减少。此外，AMPKα磷酸化（p-AMPKα）在细胞质而不是细胞核中也显示出更高的表达。
结论： TMPA 通过影响 Nur77-LKB1 在体外的稳定性来改善脂质积累。
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