Jung, Eun-Jeong Kwon, Sung-Won Jung, Byung-Hwa Oh, Seon-Hee Lee, Byung-Hoon 2024-01-20T16:31:19Z 2024-01-20T16:31:19Z 2021-09-05 2011-09 0022-2275 https://pubs.kist.re.kr/handle/201004/130032 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 OA-induced 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.-Jung, E-J., S-W. Kwon, B-H. Jung, S-H. Oh, and B-H. Lee. Role of the AMPK-SREBP-1 pathway in the development of orotic acid-induced fatty liver. J. Lipid Res. 2011. 52: 1617-1625. English AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC ACTIVATED PROTEIN-KINASE HEPATIC STEATOSIS SPECIES-SPECIFICITY LIPID-ACCUMULATION S6 KINASE RAT-LIVER METABOLISM EXPRESSION OXIDATION AMPK Role of the AMPK/SREBP-1 pathway in the development of orotic acid-induced fatty liver Article 10.1194/jlr.M015263 1 JOURNAL OF LIPID RESEARCH, v.52, no.9, pp.1617 - 1625 JOURNAL OF LIPID RESEARCH 52 9 1617 1625 scie scopus 000293827600002 2-s2.0-80051820360 Biochemistry & Molecular Biology Biochemistry & Molecular Biology Article ACTIVATED PROTEIN-KINASE HEPATIC STEATOSIS SPECIES-SPECIFICITY LIPID-ACCUMULATION S6 KINASE RAT-LIVER METABOLISM EXPRESSION OXIDATION AMPK lipids toxicology pharmacology adenosine monophosphate-activated protein kinase sterol regulatory element-binding protein-1