Ilexgenin A restrains CRTC2 in the cytoplasm to prevent SREBP1 maturation via AMPK activation in the liver.
Ilexgenin A (Ile-A) is a triterpenoid from ShanLv Cha with beneficial effects on metabolic homeostasis. This study investigated whether Ile-A could inhibit hepatic de novo fatty acid synthesis via the intervention of the processing of SREBP1 maturation.The effects of Ile-A on CRTC2 translocation and SREBP1 maturation were investigated in the liver of fasted-refed mice and hepatocytes exposed to saturated fatty acids. The effect of Ile-A on hepatic lipid accumulation was also observed in high fat diet (HFD)-fed mice.Sec23A and Sec31A are two subunits of COPII complex, and their interaction is essential for the processing of SREBP1 maturation. Ile-A activated AMPK by reducing cellular energy and restrained CRTC2 in the cytoplasm to compete with Sec23A for binding to Sec31A under nutrient-rich conditions. Consequently, Ile-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 Ile-A in an AMPK dependent manner. Ile-A protected CRTC2 function and restrained hepatic lipogenic response in HFD-fed mice, providing in vivo evidence to support the beneficial effects of Ile-A on lipid metabolism.Ile-A activated AMPK and restrained CRTC2 in the cytoplasm to prevent SREBP1 maturation via impairing COPII function in the liver. This finding suggests that CRTC2 might be a potential node for pharmacological intervention to prevent hepatic lipid deposition.