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A novel role of CRTC2 in promoting nonalcoholic fatty liver disease

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 co-activator (CRTC)...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8689247/
https://www.ncbi.nlm.nih.gov/pubmed/34838715
http://dx.doi.org/10.1016/j.molmet.2021.101402
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author 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
author_facet 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
author_sort Han, Hye-Sook
collection PubMed
description 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 co-activator (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 7–8 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 HFD-induced 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 miR-34a and the subsequent increase in SIRT1-mediated deacetylation processes. We showed that ectopic expression of miR-34a led to the induction of mTORC1 pathway, leading to the hepatic lipid accumulation in part by limiting lipophagy and enhanced lipogenesis. Finally, we found a strong association of CRTC2, miR-34a and mTORC1 activity in the NAFLD patients in humans, demonstrating a conservation of signaling pathways among species. CONCLUSIONS: These data collectively suggest that diet-induced activation of CRTC2 instigates the progression of NAFLD by activating miR-34a-mediated lipid accumulation in the liver via the simultaneous induction of lipogenesis and inhibition of lipid catabolism. Therapeutic approach to specifically inhibit CRTC2 activity in the liver could be beneficial in combating NAFLD in the future.
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spelling pubmed-86892472021-12-30 A novel role of CRTC2 in promoting nonalcoholic fatty liver disease 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 Mol Metab Original Article 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 co-activator (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 7–8 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 HFD-induced 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 miR-34a and the subsequent increase in SIRT1-mediated deacetylation processes. We showed that ectopic expression of miR-34a led to the induction of mTORC1 pathway, leading to the hepatic lipid accumulation in part by limiting lipophagy and enhanced lipogenesis. Finally, we found a strong association of CRTC2, miR-34a and mTORC1 activity in the NAFLD patients in humans, demonstrating a conservation of signaling pathways among species. CONCLUSIONS: These data collectively suggest that diet-induced activation of CRTC2 instigates the progression of NAFLD by activating miR-34a-mediated lipid accumulation in the liver via the simultaneous induction of lipogenesis and inhibition of lipid catabolism. Therapeutic approach to specifically inhibit CRTC2 activity in the liver could be beneficial in combating NAFLD in the future. Elsevier 2021-11-24 /pmc/articles/PMC8689247/ /pubmed/34838715 http://dx.doi.org/10.1016/j.molmet.2021.101402 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
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
A novel role of CRTC2 in promoting nonalcoholic fatty liver disease
title A novel role of CRTC2 in promoting nonalcoholic fatty liver disease
title_full A novel role of CRTC2 in promoting nonalcoholic fatty liver disease
title_fullStr A novel role of CRTC2 in promoting nonalcoholic fatty liver disease
title_full_unstemmed A novel role of CRTC2 in promoting nonalcoholic fatty liver disease
title_short A novel role of CRTC2 in promoting nonalcoholic fatty liver disease
title_sort novel role of crtc2 in promoting nonalcoholic fatty liver disease
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8689247/
https://www.ncbi.nlm.nih.gov/pubmed/34838715
http://dx.doi.org/10.1016/j.molmet.2021.101402
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