Role of the AMPK/SREBP-1 pathway in the development of orotic acid-induced fatty liver

Abstract

been used as a chemical inducer of fatty liver ( 2, 3 ). Although somewhat inconclusive, the reported mechanisms of OA-induced fatty liver include impairment of fatty acid oxidation, stimulation of lipogenesis, and reduction in lipid transport from the liver ( 4, 5 ). OA-induced fatty liver is species specifi c, and thus far, only the rat has been found to be susceptible. Durschlag and Robinson demonstrated that pharmacokinetic factors determined species specifi city in OA-induced hepatotoxicity ( 6 ). However, the precise molecular mechanism by which OA induces fat accumulation, specifi cally in the rat liver, has remained unclear. Identifi cation of molecular targets of OA effects and susceptibility are of great importance in terms of scientifi c as well as practical aspects. The major source of OA in a typical adult diet is milk and dairy products, which contribute about 0.005% of the total solids, a level at which rats do not show hepatic changes. However, considering the high content of OA in many dietary supplements, vitamin and mineral complexes, and muscle-building products widely sold on the market, we should be wary of possible health effects posed to humans.AMP-activated protein kinase (AMPK), a heterotrimeric enzyme complex, is the key regulator of energy metabolism in cells. The energy-sensing motif of the enzyme monitors the energy status of cells and controls its activity by phosphorylation at T172 ( 7 ). In the liver, activation of AMPK phosphorylates and inactivates the rate-limiting enzymes of lipogenesis, such as acetyl-CoA carboxylase (ACC) ( 8 ). AMPK is classically regulated by various metabolic stresses that cause an increase in the AMP/ATP ratio or Induction of fatty liver in rats by orotic acid (OA; 6-carboxyuracil) administration was fi rst observed in 1955 ( 1 ).

Disruption of uridine homeostasis links liver pyrimidine metabolism to lipid accumulation

“…Consistent with our observation, orotate was reported to induce fatty liver in rodents more than half a century ago ( 41 ), but the precise mechanism has yet to be delineated ( 42 ). Our data suggest that orotate causes fatty liver by impairing hepatic mitochondrial respiration via inhibition of DHODH enzymatic activity.…”

Proliferating effect of orotic acid through mTORC1 activation mediated by negative regulation of AMPK in SK-Hep1 hepatocellular carcinoma cells

“…However, OA treatment to these cells reversed the effects of LKB1, as observed by decreased raptor phosphorylation and increased p70S6K1 phosphorylation. These results are in line with our data, wherein we observed proteasomal degradation of LKB1 and subsequent attenuation of AMPK phosphorylation by OA in LKB1-overexpressed HeLa cells (Jung et al, 2011).…”

“…While many studies have demonstrated the properties of OA as a tumor promoter, few have provided evidence and understanding of the molecular mechanisms of OA-induced cell proliferation. Recently we reported that OA induces fatty liver mediated by mTOR activation (Jung et al, 2011). Based on these results, we hypothesized that OA-induced mTOR activation could contribute to the cell proliferation.…”

“…The expression plasmids of pEGFP-LKB1 were obtained from Dr. J. Ha (Kyung Hee University, Korea). Cells were transfected with appropriate plasmids constructs, CA-AMPK and pEGFP-LKB1, by using the LipofectAMINE 2000 (Invitrogen, Carlsbad, CA, USA) as described previously (Jung et al, 2011).…”

Cinnamamides, Novel Liver X Receptor Antagonists that Inhibit Ligand-Induced Lipogenesis and Fatty Liver

“…For Oil Red-O staining, frozen liver tissues were cut into 7 mm and affixed to microscope slides. Sections were reacted with Oil Red-O solution buffer and counterstained with Harris hematoxylin as described (Jung et al, 2011).…”