Dimethyloxalylglycine Suppresses SREBP1c and Lipogenic Gene Expressions in Hepatocytes Independently of HIF1A
Dimethyloxalylglycine (DMOG) is a representative inhibitor of the prolyl hydroxylase domain (PHD), which mediates the degradation of hypoxia-inducible factor-1-alpha (HIF1A). DMOG exerts its pharmacological effects via the canonical pathway that involves PHD inhibition; however, it remains unclear w...
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MDPI AG
2024-03-01
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| Series: | Current Issues in Molecular Biology |
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| Online Access: | https://www.mdpi.com/1467-3045/46/3/151 |
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| author | Yong Seong Kwon Ye Eun Cho Yeonsoo Kim Minseob Koh Seonghwan Hwang |
| author_facet | Yong Seong Kwon Ye Eun Cho Yeonsoo Kim Minseob Koh Seonghwan Hwang |
| author_sort | Yong Seong Kwon |
| collection | DOAJ |
| description | Dimethyloxalylglycine (DMOG) is a representative inhibitor of the prolyl hydroxylase domain (PHD), which mediates the degradation of hypoxia-inducible factor-1-alpha (HIF1A). DMOG exerts its pharmacological effects via the canonical pathway that involves PHD inhibition; however, it remains unclear whether DMOG affects lipogenic gene expression in hepatocytes. We aimed to elucidate the effects of DMOG on sterol regulatory element-binding protein-1c (SREBP1c), a master regulator of fatty acid synthesis in hepatocytes. DMOG treatment inhibited SREBP1c mRNA and protein expression in HepG2 and AML12 hepatocytes and reduced the transcript levels of SREBP1c-regulated lipogenic genes. A luciferase reporter assay revealed that DMOG inhibited the transcriptional activity of SREBP1c. Moreover, DMOG suppressed SREBP1c expression in mice liver. Mechanistically, treatment with DMOG enhanced the expression of HIF1A and insulin-induced gene 2 (INSIG2), which inhibits the activation of SREBP1c. However, <i>HIF1A</i> or <i>INSIG2</i> knockdown failed to reverse the inhibitory effect of DMOG on SREBP1c expression, suggesting a redundant role of HIF1A and INSIG2 in terms of repressing SREBP1c. DMOG did not function through the canonical pathway involving inhibition of SREBP1c by PHD, highlighting the presence of non-canonical pathways that mediate its anti-lipogenic effect. |
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| issn | 1467-3037 1467-3045 |
| language | English |
| last_indexed | 2024-04-24T18:25:46Z |
| publishDate | 2024-03-01 |
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| series | Current Issues in Molecular Biology |
| spelling | doaj.art-81d5ffc86ca24d5f9b3ce768204fde2a2024-03-27T13:31:27ZengMDPI AGCurrent Issues in Molecular Biology1467-30371467-30452024-03-014632386239710.3390/cimb46030151Dimethyloxalylglycine Suppresses SREBP1c and Lipogenic Gene Expressions in Hepatocytes Independently of HIF1AYong Seong Kwon0Ye Eun Cho1Yeonsoo Kim2Minseob Koh3Seonghwan Hwang4College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of KoreaCollege of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of KoreaCollege of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of KoreaDepartment of Chemistry, Pusan National University, Busan 46241, Republic of KoreaCollege of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of KoreaDimethyloxalylglycine (DMOG) is a representative inhibitor of the prolyl hydroxylase domain (PHD), which mediates the degradation of hypoxia-inducible factor-1-alpha (HIF1A). DMOG exerts its pharmacological effects via the canonical pathway that involves PHD inhibition; however, it remains unclear whether DMOG affects lipogenic gene expression in hepatocytes. We aimed to elucidate the effects of DMOG on sterol regulatory element-binding protein-1c (SREBP1c), a master regulator of fatty acid synthesis in hepatocytes. DMOG treatment inhibited SREBP1c mRNA and protein expression in HepG2 and AML12 hepatocytes and reduced the transcript levels of SREBP1c-regulated lipogenic genes. A luciferase reporter assay revealed that DMOG inhibited the transcriptional activity of SREBP1c. Moreover, DMOG suppressed SREBP1c expression in mice liver. Mechanistically, treatment with DMOG enhanced the expression of HIF1A and insulin-induced gene 2 (INSIG2), which inhibits the activation of SREBP1c. However, <i>HIF1A</i> or <i>INSIG2</i> knockdown failed to reverse the inhibitory effect of DMOG on SREBP1c expression, suggesting a redundant role of HIF1A and INSIG2 in terms of repressing SREBP1c. DMOG did not function through the canonical pathway involving inhibition of SREBP1c by PHD, highlighting the presence of non-canonical pathways that mediate its anti-lipogenic effect.https://www.mdpi.com/1467-3045/46/3/151dimethyloxalylglycineprolyl hydroxylase domainhypoxia-inducible factor-1-alphafatty liverfatty acid synthesissterol regulatory element-binding protein-1c |
| spellingShingle | Yong Seong Kwon Ye Eun Cho Yeonsoo Kim Minseob Koh Seonghwan Hwang Dimethyloxalylglycine Suppresses SREBP1c and Lipogenic Gene Expressions in Hepatocytes Independently of HIF1A Current Issues in Molecular Biology dimethyloxalylglycine prolyl hydroxylase domain hypoxia-inducible factor-1-alpha fatty liver fatty acid synthesis sterol regulatory element-binding protein-1c |
| title | Dimethyloxalylglycine Suppresses SREBP1c and Lipogenic Gene Expressions in Hepatocytes Independently of HIF1A |
| title_full | Dimethyloxalylglycine Suppresses SREBP1c and Lipogenic Gene Expressions in Hepatocytes Independently of HIF1A |
| title_fullStr | Dimethyloxalylglycine Suppresses SREBP1c and Lipogenic Gene Expressions in Hepatocytes Independently of HIF1A |
| title_full_unstemmed | Dimethyloxalylglycine Suppresses SREBP1c and Lipogenic Gene Expressions in Hepatocytes Independently of HIF1A |
| title_short | Dimethyloxalylglycine Suppresses SREBP1c and Lipogenic Gene Expressions in Hepatocytes Independently of HIF1A |
| title_sort | dimethyloxalylglycine suppresses srebp1c and lipogenic gene expressions in hepatocytes independently of hif1a |
| topic | dimethyloxalylglycine prolyl hydroxylase domain hypoxia-inducible factor-1-alpha fatty liver fatty acid synthesis sterol regulatory element-binding protein-1c |
| url | https://www.mdpi.com/1467-3045/46/3/151 |
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