State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.
Br J Pharmacol. 2022 Mar;179(5):958-978. doi: 10.1111/bph.15369. Epub 2021 Feb 15.
Ilexgenin A is a triterpenoid from ShanLv Cha with beneficial effects on metabolic homeostasis. We investigated whether ilexgenin A could inhibit hepatic de novo fatty acid synthesis via the interfering with SREBP1 maturation.
The effects of Ilexgenin A on CRTC2 translocation and SREBP1 maturation were investigated in the liver of fasted mice and hepatocytes exposed to saturated fatty acids. The effect of Iilexgenin A on hepatic lipid accumulation was also observed in high-fat diet fed mice.
Sec23A and Sec31A are two subunits of COPII complex and their interaction is essential for the processing of SREBP1 maturation. Ilexgenin A activates AMPK by reducing cellular energy and preventing cytoplasmic CRTC2 to compete with Sec23A for binding to Sec31A under nutrient-rich conditions. Consequently, ilexgenin A impaired COPII-dependent SREBP1 maturation via disrupting Sec31A-Sec23A interaction, leading to the inhibition of de novo fatty acid synthesis in the liver. In contrast, mTORC1 phosphorylated Ser136 of CRTC2, facilitating the formation of Sec31A-Sec23A interaction to promote SREBP1 maturation, whereas this action was reversed by ilexgenin A in an AMPK-dependent manner. Ilexgenin A protected CRTC2 function and restrained hepatic lipogenic response in high fat diet-fed mice, providing in vivo evidence to support the beneficial effects of ilexgenin A on lipid metabolism.
Ilexgenin A activated AMPK and restrained CRTC2 to the cytoplasm to prevent SREBP1 maturation via impairing COPII function in the liver. This suggests that CRTC2 might be a potential target for pharmacological intervention to prevent hepatic lipid deposition.
This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.
冬青苷 A 是山绿茶中的一种三萜类化合物，对代谢稳态有益。我们研究了冬青苷 A 是否可以通过干扰 SREBP1 成熟来抑制肝从头脂肪酸合成。
在禁食小鼠的肝脏和暴露于饱和脂肪酸的肝细胞中，研究了冬青苷 A 对 CRTC2 易位和 SREBP1 成熟的影响。还在高脂肪饮食喂养的小鼠中观察了冬青苷 A 对肝脂质积累的影响。
Sec23A 和 Sec31A 是 COPII 复合物的两个亚基，它们的相互作用对于 SREBP1 成熟的加工至关重要。在营养丰富的条件下，冬青苷 A 通过减少细胞能量并防止细胞质 CRTC2 与 Sec31A 竞争结合，激活 AMPK。结果，冬青苷 A 通过破坏 Sec31A-Sec23A 相互作用，损害 COPII 依赖性 SREBP1 成熟，从而抑制肝内从头脂肪酸合成。相比之下，mTORC1 磷酸化 CRTC2 的 Ser136，促进 Sec31A-Sec23A 相互作用的形成，从而促进 SREBP1 成熟，而这一作用被冬青苷 A 以 AMPK 依赖的方式逆转。冬青苷 A 保护 CRTC2 功能并抑制高脂肪饮食喂养的小鼠肝内脂质生成反应，为冬青苷 A 对脂质代谢有益的作用提供了体内证据。
冬青苷 A 通过损害 COPII 功能，激活 AMPK 并将 CRTC2 困在细胞质中，防止 SREBP1 成熟。这表明 CRTC2 可能是预防肝脂质沉积的药理学干预的潜在靶点。
本文是心血管疾病研究临床前模型专题（BJP 第 75 周年）的一部分。要查看本节中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc。
