In this paper, we studied the mechanism of the triglyceride (TG)-lowering effect of kaempferol in vitro and in vivo. Kaempferol showed LXR agonistic activities without inducing TGs or the expression of several lipogenic genes in cultured cells. A luciferase and qPCR analysis showed that kaempferol increased the transactivation of PPARα and PPARδ and stimulated gene expression associated with fatty acid oxidation and uptake in hepatocytes. More importantly, kaempferol inhibited protein kinase B (Akt) activity and suppressed SREBP-1 activation via multiple mechanisms, including through increasing Insig-2a expression, reducing SREBP-1 phosphorylation, and increasing GSK-3 phosphorylation. Collectively, these actions inhibited the SREBP-1 activation process. Furthermore, as an Akt/mTOR pathway inhibitor, kaempferol led to the induction of hepatic autophagy and resulted in a decrease in lipid droplet formation in the mouse liver. These findings demonstrate that kaempferol exerts its TG-lowering effect via Akt inhibition and activation of PPARα and PPARδ. PRACTICAL APPLICATIONS: Kaempferol is a major dietary flavonoid in various plant-based foods, and it is used as a valuable ingredient in functional foods, with numerous beneficial properties such as anticancer, antioxidant, and anti-atherosclerotic activities. Kaempferol exerts its TG-lowering effect via Akt inhibition and activation of PPARα and PPARδ. Currently, the number of people with hyperlipidemia is rapidly growing in both developed and developing societies; thus, we propose that kaempferol could be used for therapeutic interventions aimed at the treatment of these individuals.
Keywords: AKT; PPARs; autophagy; kaempferol; triglycerides.
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