4β-Hydroxycholesterol is a prolipogenic factor that promotes SREBP1c expression and activity through the liver X receptor
| Autor: | Douglas F. Covey, Daniel K. Nomura, Ofer Moldavski, Xuntian Jiang, Mingxing Qian, Ethan J. Weiss, Robert J. van Eijkeren, Andreas Stahl, Peter-James H. Zushin, Charles A. Berdan, Daniel S. Ory, Roberto Zoncu |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
insulin Biochemistry & Molecular Biology 4β-HC 4β-hydroxycholesterol LD lipid droplet mTOR mechanistic Target of Rapamycin Oxysterol lipid droplets LDS lipid-depleted serum QD415-436 DNL de novo lipogenesis Medical Biochemistry and Metabolomics 030204 cardiovascular system & hematology HC hydroxycholesterol Biochemistry 03 medical and health sciences 0302 clinical medicine Endocrinology EtOAc ethyl acetate ent-4HC enantiomer of 4β-HC Lipid droplet Lipid biosynthesis Genetics polycyclic compounds Transcriptional regulation Liver X receptor Transcription factor Chemistry Liver Disease de-novo-lipogenesis liver-X-Receptor PI3K phosphatidylinositol 3-kinase Lipid metabolism DPBS dulbecco’s phosphate buffered saline Cell Biology SREBP1c Cell biology 030104 developmental biology Lipogenesis lipids (amino acids peptides and proteins) NAFLD nonalcoholic fatty liver disease Biochemistry and Cell Biology Digestive Diseases Sterol Regulatory Element Binding Protein 1 oxysterol THF tetrahydrofuran Research Article |
| Zdroj: | Journal of Lipid Research Journal of Lipid Research, Vol 62, Iss, Pp 100051-(2021) |
| ISSN: | 0022-2275 |
| DOI: | 10.1016/j.jlr.2021.100051 |
| Popis: | Oxysterols are oxidized derivatives of cholesterol that play regulatory roles in lipid biosynthesis and homeostasis. How oxysterol signaling coordinates different lipid classes such as sterols and triglycerides remains incompletely understood. Here, we show that 4β-hydroxycholesterol (HC) (4β-HC), a liver and serum abundant oxysterol of poorly defined functions, is a potent and selective inducer of the master lipogenic transcription factor, SREBP1c, but not the related steroidogenic transcription factor SREBP2. By correlating tracing of lipid synthesis with lipogenic gene expression profiling, we found that 4β-HC acts as a putative agonist for the liver X receptor (LXR), a sterol sensor and transcriptional regulator previously linked to SREBP1c activation. Unique among the oxysterol agonists of the LXR, 4β-HC induced expression of the lipogenic program downstream of SREBP1c and triggered de novo lipogenesis both in primary hepatocytes and in the mouse liver. In addition, 4β-HC acted in parallel to insulin-PI3K–dependent signaling to stimulate triglyceride synthesis and lipid-droplet accumulation. Thus, 4β-HC is an endogenous regulator of de novo lipogenesis through the LXR-SREBP1c axis. |
| Databáze: | OpenAIRE |
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