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

• Published in: Toxicology and applied pharmacology 2015-04, Vol.284 (2), p.113-124
• Main Authors: Seo, Min Suk, Kim, Jung Hwan, Kim, Hye Jung, Chang, Ki Churl, Park, Sang Won
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Acetyl-CoA Carboxylase - metabolism; Adenosine monophosphate-activated protein kinase; AMP; AMP-Activated Protein Kinases - metabolism; Animals; Biphenyl Compounds - pharmacology; CALMODULIN; CARBOXYLASE; CARBOXYLIC ACIDS; Cell Line, Tumor; CONCENTRATION RATIO; DIET; Diet, High-Fat - methods; FATS; Fatty Acid Synthases - metabolism; Fatty Acids, Nonesterified - metabolism; Hep G2 Cells; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - metabolism; Honokiol; Humans; IN VITRO; Lignans - pharmacology; LIPASES; Lipid Metabolism - drug effects; Lipogenesis; Lipogenesis - drug effects; LIVER; Liver - cytology; Liver - drug effects; Liver - metabolism; LIVER CELLS; Liver kinase B1; Magnolia; Male; MICE; Mice, Inbred C57BL; Non-alcoholic steatosis; PHOSPHORYLATION; Phosphorylation - drug effects; Protein-Serine-Threonine Kinases - metabolism; Signal Transduction - drug effects; SIGNALS; Stearoyl-CoA Desaturase - metabolism; Sterol Regulatory Element Binding Protein 1 - metabolism; TRIGLYCERIDES; Triglycerides - metabolism
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2015.02.020

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. [Display omitted] •Honokiol attenuates lipid accumulation induced by free fatty acid in hepatocyte.•Honokiol inhibits the increase in lipogenic enzyme levels induced by free fatty acid.•Honokiol induces the phosphorylation of AMPK and ACC and inhibits SREBP-1c maturation.•LKB1–AMPK signaling pathway mediates anti-lipogenic effect of honokiol in hepatocyte.•Honokiol activates LKB1 and AMPK and inhibits nonalcoholic steatosis in HFD-fed mice.