Estrogen-related receptor γ controls sterol regulatory element-binding protein-1c expression and alcoholic fatty liver
Although SREBP-1c regulates key enzymes required for hepatic de novo lipogenesis, the mechanisms underlying transcriptional regulation of SREBP-1c in pathogenesis of alcoholic fatty liver is still incompletely understood. In this study, we investigated the role of ERRγ in alcohol-mediated hepatic li...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
December 2019
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| In: |
Biochimica et biophysica acta. Molecular and cell biology of lipids
Year: 2019, Volume: 1864, Issue: 12 |
| ISSN: | 1879-2618 |
| DOI: | 10.1016/j.bbalip.2019.158521 |
| Online Access: | Verlag, Volltext: https://doi.org/10.1016/j.bbalip.2019.158521 Verlag: http://www.sciencedirect.com/science/article/pii/S1388198119301714 
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| Author Notes: | Don-Kyu Kim, Yong-Hoon Kim, Jae-Ho Lee, Yoon Seok Jung, Jina Kim, Rilu Feng, Tae-Il Jeon, In-Kyu Lee, Sung Jin Cho, Seung-Soon Im, Steven Dooley, Timothy F. Osborne, Chul-Ho Lee, Hueng-Sik Choi |
| Summary: | Although SREBP-1c regulates key enzymes required for hepatic de novo lipogenesis, the mechanisms underlying transcriptional regulation of SREBP-1c in pathogenesis of alcoholic fatty liver is still incompletely understood. In this study, we investigated the role of ERRγ in alcohol-mediated hepatic lipogenesis and examined the possibility to ameliorate alcoholic fatty liver through its inverse agonist. Hepatic ERRγ and SREBP-1c expression was increased by alcohol-mediated activation of CB1 receptor signaling. Deletion and mutation analyses of the Srebp-1c gene promoter showed that ERRγ directly regulates Srebp-1c gene transcription via binding to an ERR-response element. Overexpression of ERRγ significantly induced SREBP-1c expression and fat accumulation in liver of mice, which were blocked in Srebp-1c-knockout hepatocytes. Conversely, liver-specific ablation of ERRγ gene expression attenuated alcohol-mediated induction of SREBP-1c expression. Finally, an ERRγ inverse agonist, GSK5182, significantly ameliorates fatty liver disease in chronically alcohol-fed mice through inhibition of SREBP-1c-mediated fat accumulation. ERRγ mediates alcohol-induced hepatic lipogenesis by upregulating SREBP-1c expression, which can be blunted by the inverse agonist for ERRγ, which may be an attractive therapeutic strategy for the treatment of alcoholic fatty liver disease in human. |
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| Item Description: | Gesehen am 19.02.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1879-2618 |
| DOI: | 10.1016/j.bbalip.2019.158521 |