Honokiol activates the LKB1–AMPK signaling pathway and attenuates the lipid accumulation in hepatocytes

Mar 5, 2015Toxicology and applied pharmacology

Honokiol activates a key energy control pathway and reduces fat buildup in liver cells

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Abstract

Honokiol (10 mg/kg/day) significantly reduced triglyceride accumulation in the livers of mice fed a high-fat diet for 28 days.

Honokiol reduced fat overloading and triglyceride levels in liver cells exposed to free fatty acids.
The effects of honokiol were blocked by an inhibitor of AMP-activated protein kinase (AMPK).
Honokiol inhibited the maturation of a protein that regulates fat synthesis and the production of lipogenic proteins in liver cells.
AMPK activation was linked to honokiol-induced phosphorylation of another protein involved in fat metabolism.
Genetic deletion of a protein that activates AMPK blocked the effects of honokiol on fat synthesis regulation.

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Honokiol is a bioactive neolignan compound isolated from the species of Magnolia. This study was designed to elucidate the cellular mechanism by which honokiol alleviates the development of non-alcoholic steatosis. HepG2 cells were treated with honokiol for 1h, and then exposed to 1mM free fatty acid (FFA) for 24h to simulate non-alcoholic steatosis in vitro. C57BL/6 mice were fed with a high-fat diet for 28days, and honokiol (10mg/kg/day) was daily treated. Honokiol concentration-dependently attenuated intracellular fat overloading and triglyceride (TG) accumulation in FFA-exposed HepG2 cells. These effects were blocked by pretreatment with an AMP-activated protein kinase (AMPK) inhibitor. Honokiol significantly inhibited sterol regulatory element-binding protein-1c (SREBP-1c) maturation and the induction of lipogenic proteins, stearoyl-CoA desaturase-1 (SCD-1) and fatty acid synthase (FAS) in FFA-exposed HepG2 cells, but these effects were blocked by pretreatment of an AMPK inhibitor. Honokiol induced AMPK phosphorylation and subsequent acetyl-CoA carboxylase (ACC) phosphorylation, which were inhibited by genetic deletion of liver kinase B1 (LKB1). Honokiol stimulated LKB1 phosphorylation, and genetic deletion of LKB1 blocked the effect of honokiol on SREBP-1c maturation and the induction of SCD-1 and FAS proteins in FFA-exposed HepG2 cells. Honokiol attenuated the increases in hepatic TG and lipogenic protein levels and fat accumulation in the mice fed with high-fat diet, while significantly induced LKB1 and AMPK phosphorylation. Taken together, our findings suggest that honokiol has an anti-lipogenic effect in hepatocytes, and this effect may be mediated by the LKB1-AMPK signaling pathway, which induces ACC phosphorylation and inhibits SREBP-1c maturation in hepatocytes.

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Honokiol activates the LKB1–AMPK signaling pathway and attenuates the lipid accumulation in hepatocytes

Abstract

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