Background and Purpose
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.
Experimental Approach
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.
Key Results
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.
Conclusions and Implications
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.
LINKED ARTICLES
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