Academic Journal
A novel role of CRTC2 in promoting nonalcoholic fatty liver disease
| العنوان: | A novel role of CRTC2 in promoting nonalcoholic fatty liver disease |
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| المؤلفون: | Han, Hye-Sook, Kim, Sang Gyune, Kim, Young Seok, Jang, Si-Hyong, Kwon, Yongmin, Choi, Dahee, Huh, Tom, Moon, Eunyoung, Ahn, Eunyong, Seong, Je Kyung, Kweon, Hee-Seok, Hwang, Geum-Sook, Lee, Dae Ho, Cho, Kae Won, Koo, Seung-Hoi |
| المساهمون: | Seong, Je Kyung |
| بيانات النشر: | Elsevier GmbH |
| سنة النشر: | 2022 |
| المجموعة: | Seoul National University: S-Space |
| مصطلحات موضوعية: | CREB, MTORC1, INHIBITION, AUTOPHAGY, MICRORNA-34A, METABOLISM, PATHWAY, OBESITY, GROWTH, Keywords CRTC2, Nonalcoholic fatty liver disease, miR-34a, Lipophagy, Lipogenesis, mammalian target of rapamycin complex, TSC, tuberous sclerosis complex, NCD, normal chow diet, DIO, diet-induced obesity |
| الوصف: | Objective: Diet-induced obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which instigates severe metabolic disorders, including cirrhosis, hepatocellular carcinoma, and type 2 diabetes. We have shown that hepatic depletion of CREB regulated transcription coactivator (CRTC) 2 protects mice from the progression of diet-induced fatty liver phenotype, although the exact mechanism by which CRTC2 modulates this process is elusive to date. Here, we investigated the role of hepatic CRTC2 in the instigation of NAFLD in mammals. Methods: Crtc2 liver-specific knockout (Crtc2 LKO) mice and Crtc2 flox/flox (Crtc2 f/f) mice were fed a high fat diet (HFD) for 7e8 weeks. Body weight, liver weight, hepatic lipid contents, and plasma triacylglycerol (TG) levels were determined. Western blot analysis was performed to determine Sirtuin (SIRT) 1, tuberous sclerosis complex (TSC) 2, and mammalian target of rapamycin complex (mTORC) 1 activity in the liver. Effects of Crtc2 depletion on lipogenesis was determined by measuring lipogenic gene expression (western blot analysis and qRT-PCR) in the liver as well as Oil red O staining in hepatocytes. Effects of miR-34a on mTORC1 activity and hepatic lipid accumulation was assessed by AAV-miR-34a virus in mice and Ad-miR-34a virus and Ad-anti-miR-34a virus in hepatocytes. Autophagic flux was assessed by western blot analysis after leupeptin injection in mice and bafilomycin treatment in hepatocytes. Lipophagy was assessed by transmission electron microscopy and confocal microscopy. Expression of CRTC2 and p-S6K1 in livers of human NAFLD patients was assessed by immunohistochemistry. Results: We found that expression of CRTC2 in the liver is highly induced upon HFD-feeding in mice. Hepatic depletion of Crtc2 ameliorated HFDinduced fatty liver disease phenotypes, with a pronounced inhibition of the mTORC1 pathway in the liver. Mechanistically, we found that expression of TSC2, a potent mTORC1 inhibitor, was enhanced in Crtc2 LKO mice due to the decreased expression of ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| تدمد: | 2212-8778 |
| Relation: | Molecular Metabolism, Vol.55, p. 101402; https://hdl.handle.net/10371/205549; 000734121800003; 2-s2.0-85121223130; 153455 |
| DOI: | 10.1016/j.molmet.2021.101402 |
| الاتاحة: | https://hdl.handle.net/10371/205549 https://doi.org/10.1016/j.molmet.2021.101402 |
| رقم الانضمام: | edsbas.E3B8B522 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 22128778 |
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| DOI: | 10.1016/j.molmet.2021.101402 |