Ajoene, A Stable Garlic By-Product, Inhibits High Fat Diet-Induced Hepatic Steatosis and Oxidative Injury Through LKB1-Dependent AMPK Activation

Abstract

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.

Rimonabant, a Cannabinoid Receptor Type 1 Inverse Agonist, Inhibits Hepatocyte Lipogenesis by Activating Liver Kinase B1 and AMP-Activated Protein Kinase Axis Downstream of Gαi/oInhibition

“…LKB1-dependent AMPK activation by a natural product, ajoene, contributed to treating high-fat diet-induced hepatic steatosis (Han et al, 2011). The present finding also showed that LKB1 was necessary for the activation of AMPK by rimonabant, which was verified by the reversal of this effect by LKB1 knockdown.…”

Commonly used fertility drugs, a diet supplement, and stress force AMPK-dependent block of stemness and development in cultured mammalian embryos

“…The following food groups and food extracts have high AMPKactivating capacity: resveratrol (red grape skin extract) [114][115][116][117][118], nootkatone (grapefruit extract) [119], ajoene (garlic extract) [120], BDIM (cruciferous vegetable extract) [19,121], and many others [122]. Medicines activate AMPK including Asa [16], Met [35], phenformin [123,124], rosiglitazone, and phenobarbital [125,126], and there may be others.…”

PRMT3 Regulates Hepatic Lipogenesis Through Direct Interaction With LXRα

“…Recent studies have revealed that high-fat diets increase the expression of lipogenic proteins via LXRa in the liver (26,29,30). In the current study, we also confirmed that PA treatment increases not only LXRa expression, but also lipid accumulation in HepG2 cells, which is consistent with the finding of Kuang et al (31) that PA stimulates LXR activities.…”