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

Eun Jeong Jung, Sung Won Kwon, Byung Hwa Jung, Seon Hee Oh, Byung Hoon Lee

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Orotic acid (OA), an intermediate in pyrimidine metabolism, has been used for a variety of purposes, such as dietary supplements. Although it is well documented that OA induces fatty liver in a species-specific manner, the precise molecular mechanisms remain unclear. The present study investigated the role of the adenosine monophosphate-activated protein kinase (AMPK)-sterol regulatory element-binding protein-1 (SREBP-1) pathway in the OAinduced fatty liver. Treatment with OA suppressed the phosphorylation of AMPK via proteasomal degradation of upstream kinase LKB1 and induced activation of SREBP-1 in both human hepatoma cell lines and primary rat hepatocytes. OA-induced SREBP-1 transcriptional activity was suppressed by cotreatment with aminoimidazole carboxamide ribonucleotide (AICAR) or metformin, or by overexpression of constitutively active AMPK (CA-AMPK) in the human hepatoma cell line. Importantly, in vivo data corroborated these results. Feeding 1% OA with diet decreased the phosphorylation of AMPK and increased the maturation of SREBP-1 and the expression of SREBP-responsive genes in the rat liver. OA-induced lipid accumulation was also completely inhibited by rapamycin. Mouse hepatocytes and mice were resistant to OA-induced lipogenesis because of little if any response in AMPK and downstream effectors. In conclusion, OA induces hepatic lipogenesis, mediated predominantly by the AMPK/SREBP-1 pathway in rat hepatocytes and human hepatoma cell lines.

Original languageEnglish (US)
Pages (from-to)1617-1625
Number of pages9
JournalJournal of lipid research
Volume52
Issue number9
DOIs
StatePublished - Sep 1 2011

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Keywords

  • Adenosine monophosphate-activated protein kinase
  • Lipids
  • Pharmacology
  • Sterol regulatory element-binding protein-1
  • Toxicology

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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