title: Betulinic acid alleviates non-alcoholic fatty liver by inhibiting SREBP1 activity via the AMPK-mTOR-SREBP signaling pathway.
abstract: Non-alcoholic fatty liver disease (NAFLD) is emerging as the most common liver disease in industrialized countries. The discovery of food components that can ameliorate NAFLD is therefore of interest. Betulinic acid (BA) is a triterpenoid with many pharmacological activities, but the effect of BA on fatty liver is as yet unknown. To explore the possible anti-fatty liver effects and their underlying mechanisms, we used insulin-resistant HepG2 cells, primary rat hepatocytes and liver tissue from ICR mice fed a high-fat diet (HFD). Oil Red O staining revealed that BA significantly suppressed excessive triglyceride accumulation in HepG2 cells and in the livers of mice fed a HFD. Ca(+2)-calmodulin dependent protein kinase kinase (CAMKK) and AMP-activated protein kinase (AMPK) were both activated by BA treatment. In contrast, the protein levels of sterol regulatory element-binding protein 1 (SREBP1), mammalian target of rapamycin (mTOR) and S6 kinase (S6K) were all reduced when hepatocytes were treated with BA for up to 24h. We found that BA activates AMPK via phosphorylation, suppresses SREBP1 mRNA expression, nuclear translocation and repressed SREBP1 target gene expression in HepG2 cells and primary hepatocytes, leading to reduced lipogenesis and lipid accumulation. These effects were completely abolished in the presence of STO-609 (a CAMKK inhibitor) or compound C (an AMPK inhibitor), indicating that the BA-induced reduction in hepatic steatosis was mediated via the CAMKK-AMPK-SREBP1 signaling pathway. Taken together, our results suggest that BA effectively ameliorates intracellular lipid accumulation in liver cells and thus is a potential therapeutic agent for the prevention of fatty liver disease.
authors: Department of Pharmacology and Clinical Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors: Hai Yan
authors: HY
authors: Quan
authors: Do Yeon
authors: DY
authors: Kim
authors: Soo Jung
authors: SJ
authors: Kim
authors: Hee Kyung
authors: HK
authors: Jo
authors: Go Woon
authors: GW
authors: Kim
authors: Sung Hyun
authors: SH
authors: Chung
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D020536:Enzyme Activators / Q000494:pharmacology; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D065626:Non-alcoholic Fatty Liver Disease; D053978:Pentacyclic Triterpenes; D021381:Protein Transport; D051381:Rats; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000037:antagonists & inhibitors*; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D000094062:Betulinic Acid
chemical_list: D004041:Dietary Fats; D020536:Enzyme Activators; D053978:Pentacyclic Triterpenes; D051780:Sterol Regulatory Element Binding Protein 1; D051779:Sterol Regulatory Element Binding Proteins; D014280:Triglycerides; D014315:Triterpenes; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; D000094062:Betulinic Acid