Abstract
Liver X receptor-α (LXRα) and its target sterol regulatory element-binding protein-1c (SREBP-1c) play key roles in hepatic lipogenesis. Rimonabant, an inverse agonist of cannabinoid receptor type 1 (CB1), has been studied as an antiobesity drug. In view of the link between CB1 and energy metabolism, this study investigated the effect of rimonabant on LXRα-mediated lipogenesis in hepatocytes and the underlying basis. Rimonabant treatment inhibited CYP7A1-LXRα response element gene transactivation and an increase in LXRα mRNA level by the LXRα agonist N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317) in HepG2 cells. Rimonabant consistently attenuated the activation of SREBP-1c and its target gene induction. The reversal by CB1 agonists on rimonabant's repression of SREBP-1c supported the role of CB1 in this effect. Rimonabant inhibited the activation of SREBP-1c presumably via Gαi/o inhibition, as did pertussis toxin. Adenylyl cyclase activator forskolin or 8-bromo-cAMP treatment mimicked the action of rimonabant, suggesting that Gαi/o inhibition causes repression of SREBP-1c by increasing the cAMP level. Knockdown or chemical inhibition of protein kinase A (PKA) prevented the inhibition of LXRα by rimonabant, supporting the fact that an increase in cAMP content and PKA activation, which catalyzes LXRα inhibitory phosphorylation, might be responsible for the antilipogenic effect. In addition, rimonabant activated liver kinase B1 (LKB1), resulting in the activation of AMP-activated protein kinase responsible for LXRα repression. Moreover, PKA inhibition prevented the activation of LKB1, supporting the fact that PKA regulates LKB1. In conclusion, rimonabant has an antilipogenic effect in hepatocytes by inhibiting LXRα-dependent SREBP-1c induction, as mediated by an increase in PKA activity and PKA-mediated LKB1 activation downstream of CB1-coupled Gαi/o inhibition.
Footnotes
This work was supported by the National Research Foundation of Korea funded by the Korean Ministry of Education, Science and Technology Development [Grant 2011-0001204].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.111.072769.
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ABBREVIATIONS:
- LXRα
- liver X receptor-α
- T090
- T0901317, N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide
- LXRE
- LXRα-response element
- SREBP-1c
- sterol regulatory element binding protein-1c
- FAS
- fatty acid synthase
- ACC
- acetyl-CoA carboxylase
- SCD-1
- stearoyl-CoA desaturase-1
- ABCA1
- ATP-binding cassette transporter A1
- CB1
- cannabinoid receptor type 1
- AMPK
- AMP-activated protein kinase
- PKA
- cAMP-dependent protein kinase A
- LKB1
- liver kinase B1
- Hu 210
- (6aR)-trans-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol
- ACEA
- arachidonyl-2′-chloroethylamide
- PKI
- PKA inhibitor
- CaMKK
- calcium/calmodulin-dependent kinase kinase
- GW3965
- 3-[3-[N-(2-chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino]propyloxy]phenylacetic acid hydrochloride
- 8-Br-cAMP
- 8-bromo-cAMP
- H89
- N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide
- PCR
- polymerase chain reaction
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- siRNA
- small interfering RNA
- PXRE
- pregnane X receptor response element
- AM251
- N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3 carboxamide
- GPCR
- G protein-coupled receptor
- CAB39
- calcium binding protein 39
- STO-609
- 7H-benz[de]benzimidazo[2,1-a]isoquinoline-7-one-3-carboxylic acid acetate
- DN
- dominant-negative
- S6K1
- p70 ribosomal S6 kinase-1.
- Received April 6, 2011.
- Accepted July 27, 2011.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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