Role of adenosine monophosphate-activated protein kinase-p70 ribosomal S6 kinase-1 pathway in repression of liver X receptor-alpha-dependent lipogenic gene induction and hepatic steatosis by a novel class of dithiolethiones.
Dithiolethiones, a novel class of adenosine monophosphate-activated protein kinase (AMPK) activators, prevent insulin resistance through AMPK-dependent p70 ribosomal S6 kinase-1 (S6K1) inhibition. There is no known effect of S6K1 for liver X receptor-alpha (LXRalpha)-mediated lipogenic gene expression and steatosis, a cause of chronic liver disease. This study investigated the role of S6K1 in LXRalpha activation and the effects of oltipraz (prototype) and other dithiolethiones on LXRalpha-dependent lipogenesis in hepatocytes and high-fat diet animal model. Oltipraz prevented the ability of LXRalpha agonist (T0901317) to activate sterol regulatory element binding protein-1c (SREBP-1c), inhibiting its own mRNA and protein induction. Impaired SREBP-1c activity by oltipraz caused inhibition of LXRalpha-induced transcription of the fatty acid synthase, LXRalpha, acetyl-CoA carboxylase, stearoyl-CoA desaturase-1, and adenosine triphosphate-binding cassette transporter A1 genes. S6K1 activation antagonized the inhibitory effect of oltipraz on SREBP-1c activation, whereas dominant negative (DN) mutant S6K1 and rapamycin inhibited the T0901317-induced SREBP-1c expression. Oltipraz impaired LXRalpha DNA binding activity and LXR agonist-induced CYP7A1-LXRE-luciferase (CYP7A1) transactivation. Moreover, in vitro S6K1 directly phosphorylated LXRalpha at serine residues for gene transactivation, which was antagonized by its DN mutant. S6K1 inhibition antagonized CYP7A1 induction promoted by AMPK inhibition, whereas AMPK activation abrogated S6K1-dependent CYP7A1 induction, supporting the opposing role of S6K1 and AMPK in LXR activity. Finally, oltipraz was found to inhibit hepatic triglyceride accumulation and lipogenic gene induction in mice fed a high-fat diet. Other dithiolethiones also inhibited SREBP-1c induction by T0901317.


CONCLUSIONS
Our findings showing the role of AMPK-S6K1 pathway in LXR activity and S6K1-dependent inhibition of LXRalpha-induced lipogenic gene transactivation by a novel class of dithiolethiones led to the identification of S6K1 as a particularly attractive target for intervention in hepatic steatosis.
Hwahng
Seong Hwan
SH
Innovative Drug Research Center for Metabolic and Inflammatory Disease, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
Ki
Sung Hwan
SH
Bae
Eun Ju
EJ
Kim
Hyun Eun
HE
Kim
Sang Geon
SG
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D005234:Fatty Liver / Q000235:genetics*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors; D011719:Pyrazines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000187:drug effects; D013871:Thiones; D013876:Thiophenes; D015533:Transcriptional Activation / Q000187:drug effects*
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D011719:Pyrazines; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D017868:Cyclic AMP-Dependent Protein Kinases