Agonist of RORA Attenuates Nonalcoholic Fatty Liver Progression in Mice via Up-regulation of MicroRNA 122
| Autor: | Oren Tirosh, Chofit Chai, Maytal Gefen, A. Salhab, Devora Gross, Michal Hahn, Tali Lanton, Jonathan Citrin, Anna Permyakova, Ibon Martínez-Arranz, Haixing Liao, Franck Amblard, Eithan Galun, Bryan Cox, Zahira Tber, Henrike Link, Mirna Tannous, Zohar Shemuelian, Johnny Amer, Cristina Alonso, Raymond F. Schinazi, Nofar Rosenberg, Amit Korach, Seema Mengshetti, Dayana Yaish, Hilla Giladi, Gunes Ozhan, Jonathan H. Axelrod, Enara Arretxe, Rifaat Safadi, Pablo Ortiz Betes, Joseph Tam |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Agonist medicine.medical_specialty Hepatology Normal diet medicine.drug_class business.industry Fatty liver Gastroenterology Adipose tissue White adipose tissue medicine.disease Article 3. Good health 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Endocrinology Insulin resistance Lipotoxicity Internal medicine Nonalcoholic fatty liver disease medicine 030211 gastroenterology & hepatology business |
| Zdroj: | Gastroenterology |
| Popis: | Background & Aims Development of nonalcoholic steatohepatitis (NASH) is associated with reductions in hepatic microRNA122 (MIR122); the RAR related orphan receptor A (RORA) promotes expression of MIR122. Increasing expression of RORA in livers of mice increases expression of MIR122 and reduces lipotoxicity. We investigated the effects of a RORA agonist in mouse models of NASH. Methods We screened a chemical library to identify agonists of RORA and tested their effects on a human hepatocellular carcinoma cell line (Huh7). C57BL/6 mice were fed a chow or high-fat diet (HFD) for 4 weeks to induce fatty liver. Mice were given hydrodynamic tail vein injections of a MIR122 antagonist (antagomiR-122) or a control antagomiR once each week for 3 weeks while still on the HFD or chow diet, or intraperitoneal injections of the RORA agonist RS-2982 or vehicle, twice each week for 3 weeks. Livers, gonad white adipose, and skeletal muscle were collected and analyzed by reverse-transcription polymerase chain reaction, histology, and immunohistochemistry. A separate group of mice were fed an atherogenic diet, with or without injections of RS-2982 for 3 weeks; livers were analyzed by immunohistochemistry, and plasma was analyzed for levels of aminotransferases. We analyzed data from liver tissues from patients with NASH included in the RNA-sequencing databases GSE33814 and GSE89632. Results Injection of mice with antagomiR-122 significantly reduced levels of MIR122 in plasma, liver, and white adipose tissue; in mice on an HFD, antagomiR-122 injections increased fat droplets and total triglyceride content in liver and reduced β-oxidation and energy expenditure, resulting in significantly more weight gain than in mice given the control microRNA. We identified RS-2982 as an agonist of RORA and found it to increase expression of MIR122 promoter activity in Huh7 cells. In mice fed an HFD or atherogenic diet, injections of RS-2982 increased hepatic levels of MIR122 precursors and reduced hepatic synthesis of triglycerides by reducing expression of biosynthesis enzymes. In these mice, RS-2982 significantly reduced hepatic lipotoxicity, reduced liver fibrosis, increased insulin resistance, and reduced body weight compared with mice injected with vehicle. Patients who underwent cardiovascular surgery had increased levels of plasma MIR122 compared to its levels before surgery; increased expression of plasma MIR122 was associated with increased levels of plasma free fatty acids and levels of RORA. Conclusions We identified the compound RS-2982 as an agonist of RORA that increases expression of MIR122 in cell lines and livers of mice. Mice fed an HFD or atherogenic diet given injections of RS-2982 had reduced hepatic lipotoxicity, liver fibrosis, and body weight compared with mice given the vehicle. Agonists of RORA might be developed for treatment of NASH. |
| Databáze: | OpenAIRE |
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