Molecular Mechanism of Action for the Geranyl Flavonoid to Counter Dyslipidemia in Diabetic Milieu

This work was to examine the effect of 3’-methyl-4’, 7-dihydroxyflavanone, a geranyl flavonoid (GF), on hepatocellular AMPK activity and lipid levels in HepG2 cells and diabetic mice, and identify molecular mechanism of the GF action on remedying dyslipidemia. The AMPK activation and lipid-lowering effect of the GF in diabetic mice and in HepG2 cells paralleled observations. The GF activated AMPK in HepG2 cells treated with high glucose, and enhance phosphorylation of ACC1 and ACC2, two isoforms of ACC, resulting in decrease in ACC activity and hepatic lipids. As demonstrated in cells overexpressing a dominant-negative AMPK mutant, the effect of GF was shown to be mediated by the activation of AMPK. The AMPK was activated relatively rapidly by GF and well before any potential change in adenosine triphosphate (ATP) level was detected. Thus, both in vivo and in vitro inhibition of AMPK, activation of ACC, and hepatocellular lipid accumulation caused by sustained high glucose levels was effectively counteracted by activating AMPK with treatment of GF. It can be conclude that GF lower lipids both in vivo and in vitro by activating AMPK and inactivating ACC, and consequently down-regulating fatty acid synthesis. The work provides a strong evidence for GF as a new therapeutic agent to definitively remedy dyslipidemia in diabetic milieu.