Honokiol activates the LKB1-AMPK signaling pathway and attenuates the lipid accumulation in hepatocytes.
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.
Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea.
Min Suk
MS
Seo
Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea.
Jung Hwan
JH
Kim
Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea.
Hye Jung
HJ
Kim
Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea.
Ki Churl
KC
Chang
Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea. Electronic address: parksw@gnu.ac.kr.
Sang Won
SW
Park
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D059305:Diet, High-Fat / Q000379:methods; D064429:Fatty Acid Synthases / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects*; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D000498:Allyl Compounds; D010636:Phenols
D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; D001713:Biphenyl Compounds; D064429:Fatty Acid Synthases; D005230:Fatty Acids, Nonesterified; D017705:Lignans; D017346:Protein Serine-Threonine Kinases; D013230:Stearoyl-CoA Desaturase; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols
Adenosine monophosphate-activated protein kinase; Hepatocytes; Honokiol; Lipogenesis; Liver kinase B1; Non-alcoholic steatosis