Ajoene, a stable garlic by-product, inhibits high fat diet-induced hepatic steatosis and oxidative injury through LKB1-dependent AMPK activation.
Hepatic steatosis, a hepatic component of metabolic syndrome, is common and may progress to steatohepatitis and cirrhosis. The liver X receptor-α (LXRα)-sterol regulatory element binding protein-1c (SREBP-1c) pathway plays a key role in hepatic steatosis. This study investigated the potential of ajoene, a stable garlic by-product, to inhibit high fat diet (HFD)-induced hepatic steatosis and the underlying mechanism. Ajoene treatment attenuated fat accumulation and induction of lipogenic genes in the liver of HFD-fed mice. Blood biochemical analyses and histopathologic examinations showed that ajoene prevented liver injury with the inhibition of oxidative stress, as evidenced by thiobarbituric acid reactive substances formation and nitrotyrosinylation. Moreover, ajoene treatment inhibited LXRα agonist (T0901317)-mediated SREBP-1c activation, and transactivation of the lipogenic target genes in hepatocytes. Ajoene was found to activate AMP-activated protein kinase (AMPK) via LKB1, responsible for the inhibition of p70 ribosomal S6 kinase-1 (S6K1). The ability of ajoene to repress T0901317-induced SREBP-1c expression was antagonized by inhibition of AMPK or activation of S6K1, supporting the role of these kinases in the antisteatotic effect. Our results demonstrate that ajoene has an effect of activating AMPK through LKB1 and inhibit S6K1 activity, contributing to the prevention of SREBP-1c-mediated hepatic lipogenesis via the inhibition of LXRα activity.
Han
Chang Yeob
CY
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
Ki
Sung Hwan
SH
Kim
Young Woo
YW
Noh
Kyoung
K
Lee
Da Yeon
DY
Kang
Bomi
B
Ryu
Jae-Ha
JH
Jeon
Raok
R
Kim
Eun Hyun
EH
Hwang
Se Jin
SJ
Kim
Sang Geon
SG
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004041:Dietary Fats / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005234:Fatty Liver / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D005737:Garlic / Q000737:chemistry*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D018384:Oxidative Stress / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism; D013454:Sulfoxides
D004041:Dietary Fats; D004220:Disulfides; D013454:Sulfoxides; C048980:ajoene; D017346:Protein Serine-Threonine Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases