Research Article Details
| Article ID: | A07362 |
| PMID: | 32526241 |
| Source: | Eur J Pharmacol |
| Title: | Berbamine induced AMPK activation regulates mTOR/SREBP-1c axis and Nrf2/ARE pathway to allay lipid accumulation and oxidative stress in steatotic HepG2 cells. |
| Abstract: | Non-alcoholic fatty liver disease is emanating as a global cataclysm. This study was designed to investigate the antioxidative, anti-inflammatory and fat metabolism-regulating potential of berbamine (BBM), a natural bis-benzylisoquinoline alkaloid. BBM attenuated intracellular lipid accumulation in oleic-acid exposed HepG2 cells (0.5 mM) by inhibiting fatty acid uptake, lipogenesis, and promoting fatty acid β-oxidation by activating AMP-activated kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR)-α. Berbamine (5 μM) induced AMPK activation (P < 0.001) via LKB1 (Ser-428) and elevated AMP:ATP ratio (P < 0.001). AMPK activation negatively regulated mTOR and also constrained the nuclear translocation of SREBP-1c and inhibited the lipogenic proteins, stearoyl-CoA desaturase-1 (SCD-1) and fatty acid synthase (FAS) (P < 0.001). BBM stimulated nuclear translocation of redox-sensitive nuclear factor erythroid-2-related factor-2 (Nrf2) and increased hepatic expression of Nrf2 responsive enzymes, HO-1 and Nqo-1. BBM treatment reduced the oxidative burst and pro-inflammatory responses by significantly enhancing hepatic antioxidant defenses [SOD (P < 0.001), catalase (P < 0.001) and cellular glutathione (P < 0.01)] and diminishing NF-κB regulated pro-inflammatory cytokines (TNF-α, and IL-6) levels respectively. TEM analysis confirmed the disruption of mitochondrial structure and reduction in mitochondrial size (50.97%, P < 0.001) in steatotic HepG2 cells which was significantly prevented by 5 μM BBM treatment (71.84% as compared to control, P < 0.01). Pre-treatment of Compound C (AMPK inhibitor, 25 μM) greatly repressed the anti-steatotic properties exhibited by BBM confirming the involvement of AMPK signaling pathway. In summary, the results manifest that BBM reduces intracellular lipid accumulation via AMPK/mTOR/SREBP-1c axis mediated regulation of lipid metabolism and upsurged nuclear stability of Nrf2 by promoting AMPK/Nrf2 association to ameliorate oxidative stress/proinflammatory response. |
| DOI: | 10.1016/j.ejphar.2020.173244 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | Details |
| S04 | Anti-oxidative stress | oxidative stress | α-tocopherol: antioxidant | Vitamin E | Details |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T01 | 5'-AMP-activated protein kinase subunit beta-1 | PRKAB1 | activator | Kinase | Q9Y478 | AAKB1_HUMAN | Details |
| T08 | Tumor necrosis factor | TNF | inhibitor | Cytokine | P01375 | TNFA_HUMAN | Details |
| T10 | Caspase-1 | CASP1 | inhibitor | Enzyme | P29466 | CASP1_HUMAN | Details |
| T46 | ATP-citrate synthase | ACLY | inhibitor | Transferase | P53396 | ACLY_HUMAN | Details |
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| T20 | Fatty acid synthase | FASN | inhibitor | Enzyme | P49327 | FAS_HUMAN | Details |
| T22 | Stearoyl-CoA desaturase | SCD | inhibitor | Enzyme | O00767 | SCD_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class |
|---|
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D010 | Amoxicillin | Chemical drug | DB01060 | -- | -- | Under clinical trials | Details |
| D248 | Obeticholic Acid | Chemical drug | DB05990 | NR1H4 activator; NR1H4 agonist; FXR agonist | Enhance lipid metabolism | Approval rejected | Details |
| D158 | Glutathione | Chemical drug | DB00143 | MGST3; HPGDS; GSTM2; GSTM5; GPX7 cofactor; MGST2; GSS; GSTM1; GSTK1; GSTM3; GSTM4; GPX1 cofactor; GPX2 cofactor; GPX3 cofactor | -- | Under clinical trials | Details |