Betulinic acid alleviates non-alcoholic fatty liver by inhibiting SREBP1 activity via the AMPK-mTOR-SREBP signaling pathway
| Autor: | Soo Jung Kim, Do Yeon Kim, Hee Kyung Jo, Sung Hyun Chung, Hai Yan Quan, Go Woon Kim |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
Enzyme Activators P70-S6 Kinase 1 Calcium-Calmodulin-Dependent Protein Kinase Kinase Biology AMP-Activated Protein Kinases Biochemistry Liver disease Mice Non-alcoholic Fatty Liver Disease Internal medicine Cell Line Tumor medicine Animals Humans Betulinic Acid Protein kinase A PI3K/AKT/mTOR pathway Triglycerides Pharmacology Cell Nucleus Sterol Regulatory Element Binding Proteins Mice Inbred ICR Ribosomal Protein S6 Kinases TOR Serine-Threonine Kinases Fatty liver AMPK medicine.disease Lipid Metabolism Dietary Fats Triterpenes Sterol regulatory element-binding protein Rats Fatty Liver Protein Transport Endocrinology Liver Lipogenesis Hepatocytes Pentacyclic Triterpenes Sterol Regulatory Element Binding Protein 1 Signal Transduction |
| Zdroj: | Biochemical pharmacology. 85(9) |
| ISSN: | 1873-2968 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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