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Betulinic acid alleviates non-alcoholic fatty liver by inhibiting SREBP1 activity via the AMPK-mTOR-SREBP signaling pathway.
Biochem Pharmacol 2013; 85(9):1330-40BP

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+Show Affiliations

Department of Pharmacology and Clinical Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23435355

Citation

Quan, Hai Yan, et al. "Betulinic Acid Alleviates Non-alcoholic Fatty Liver By Inhibiting SREBP1 Activity Via the AMPK-mTOR-SREBP Signaling Pathway." Biochemical Pharmacology, vol. 85, no. 9, 2013, pp. 1330-40.
Quan HY, Kim DY, Kim SJ, et al. Betulinic acid alleviates non-alcoholic fatty liver by inhibiting SREBP1 activity via the AMPK-mTOR-SREBP signaling pathway. Biochem Pharmacol. 2013;85(9):1330-40.
Quan, H. Y., Kim, D. Y., Kim, S. J., Jo, H. K., Kim, G. W., & Chung, S. H. (2013). Betulinic acid alleviates non-alcoholic fatty liver by inhibiting SREBP1 activity via the AMPK-mTOR-SREBP signaling pathway. Biochemical Pharmacology, 85(9), pp. 1330-40. doi:10.1016/j.bcp.2013.02.007.
Quan HY, et al. Betulinic Acid Alleviates Non-alcoholic Fatty Liver By Inhibiting SREBP1 Activity Via the AMPK-mTOR-SREBP Signaling Pathway. Biochem Pharmacol. 2013 May 1;85(9):1330-40. PubMed PMID: 23435355.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Betulinic acid alleviates non-alcoholic fatty liver by inhibiting SREBP1 activity via the AMPK-mTOR-SREBP signaling pathway. AU - Quan,Hai Yan, AU - Kim,Do Yeon, AU - Kim,Soo Jung, AU - Jo,Hee Kyung, AU - Kim,Go Woon, AU - Chung,Sung Hyun, Y1 - 2013/02/19/ PY - 2013/01/04/received PY - 2013/02/04/revised PY - 2013/02/05/accepted PY - 2013/2/26/entrez PY - 2013/2/26/pubmed PY - 2013/5/23/medline SP - 1330 EP - 40 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 85 IS - 9 N2 - 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. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/23435355/Betulinic_acid_alleviates_non_alcoholic_fatty_liver_by_inhibiting_SREBP1_activity_via_the_AMPK_mTOR_SREBP_signaling_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(13)00093-2 DB - PRIME DP - Unbound Medicine ER -