Liver-Specific Deletion of Mouse CTCF Leads to Hepatic Steatosis via Augmented PPARγ SignalingSummary

Background & Aims: The liver is the major organ for metabolizing lipids, and malfunction of the liver leads to various diseases. Nonalcoholic fatty liver disease is rapidly becoming a major health concern worldwide and is characterized by abnormal retention of excess lipids in the liver. CCC...

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Autores principales:	Yeeun Choi, Min-Ji Song, Woong-Jae Jung, Haengdueng Jeong, Seokjae Park, Bobae Yang, Eun-Chong Lee, Jung-Sik Joo, Dahee Choi, Seung-Hoi Koo, Eun-Kyoung Kim, Ki Taek Nam, Hyoung-Pyo Kim
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Liver Steatosis CTCF PPARγ CD36 Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/a2fe8b241c40454ab82a0f2c5a7e47ac
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spelling	oai:doaj.org-article:a2fe8b241c40454ab82a0f2c5a7e47ac2021-11-12T04:39:23ZLiver-Specific Deletion of Mouse CTCF Leads to Hepatic Steatosis via Augmented PPARγ SignalingSummary2352-345X10.1016/j.jcmgh.2021.07.016https://doaj.org/article/a2fe8b241c40454ab82a0f2c5a7e47ac2021-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X21001624https://doaj.org/toc/2352-345XBackground & Aims: The liver is the major organ for metabolizing lipids, and malfunction of the liver leads to various diseases. Nonalcoholic fatty liver disease is rapidly becoming a major health concern worldwide and is characterized by abnormal retention of excess lipids in the liver. CCCTC-binding factor (CTCF) is a highly conserved zinc finger protein that regulates higher-order chromatin organization and is involved in various gene regulation processes. Here, we sought to determine the physiological role of CTCF in hepatic lipid metabolism. Methods: We generated liver-specific, CTCF-ablated and/or CD36 whole-body knockout mice. Overexpression or knockdown of peroxisome proliferator-activated receptor (PPAR)γ in the liver was achieved using adenovirus. Mice were examined for development of hepatic steatosis and inflammation. RNA sequencing was performed to identify genes affected by CTCF depletion. Genome-wide occupancy of H3K27 acetylation, PPARγ, and CTCF were analyzed by chromatin immunoprecipitation sequencing. Genome-wide chromatin interactions were analyzed by in situ Hi-C. Results: Liver-specific, CTCF-deficient mice developed hepatic steatosis and inflammation when fed a standard chow diet. Global analysis of the transcriptome and enhancer landscape revealed that CTCF-depleted liver showed enhanced accumulation of PPARγ in the nucleus, which leads to increased expression of its downstream target genes, including fat storage-related gene CD36, which is involved in the lipid metabolic process. Hepatic steatosis developed in liver-specific, CTCF-deficient mice was ameliorated by repression of PPARγ via pharmacologic blockade or adenovirus-mediated knockdown, but hardly rescued by additional knockout of CD36. Conclusions: Our data indicate that liver-specific deletion of CTCF leads to hepatosteatosis through augmented PPARγ DNA-binding activity, which up-regulates its downstream target genes associated with the lipid metabolic process.Yeeun ChoiMin-Ji SongWoong-Jae JungHaengdueng JeongSeokjae ParkBobae YangEun-Chong LeeJung-Sik JooDahee ChoiSeung-Hoi KooEun-Kyoung KimKi Taek NamHyoung-Pyo KimElsevierarticleLiver SteatosisCTCFPPARγCD36Diseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 5, Pp 1761-1787 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Liver Steatosis CTCF PPARγ CD36 Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	Liver Steatosis CTCF PPARγ CD36 Diseases of the digestive system. Gastroenterology RC799-869 Yeeun Choi Min-Ji Song Woong-Jae Jung Haengdueng Jeong Seokjae Park Bobae Yang Eun-Chong Lee Jung-Sik Joo Dahee Choi Seung-Hoi Koo Eun-Kyoung Kim Ki Taek Nam Hyoung-Pyo Kim Liver-Specific Deletion of Mouse CTCF Leads to Hepatic Steatosis via Augmented PPARγ SignalingSummary
description	Background & Aims: The liver is the major organ for metabolizing lipids, and malfunction of the liver leads to various diseases. Nonalcoholic fatty liver disease is rapidly becoming a major health concern worldwide and is characterized by abnormal retention of excess lipids in the liver. CCCTC-binding factor (CTCF) is a highly conserved zinc finger protein that regulates higher-order chromatin organization and is involved in various gene regulation processes. Here, we sought to determine the physiological role of CTCF in hepatic lipid metabolism. Methods: We generated liver-specific, CTCF-ablated and/or CD36 whole-body knockout mice. Overexpression or knockdown of peroxisome proliferator-activated receptor (PPAR)γ in the liver was achieved using adenovirus. Mice were examined for development of hepatic steatosis and inflammation. RNA sequencing was performed to identify genes affected by CTCF depletion. Genome-wide occupancy of H3K27 acetylation, PPARγ, and CTCF were analyzed by chromatin immunoprecipitation sequencing. Genome-wide chromatin interactions were analyzed by in situ Hi-C. Results: Liver-specific, CTCF-deficient mice developed hepatic steatosis and inflammation when fed a standard chow diet. Global analysis of the transcriptome and enhancer landscape revealed that CTCF-depleted liver showed enhanced accumulation of PPARγ in the nucleus, which leads to increased expression of its downstream target genes, including fat storage-related gene CD36, which is involved in the lipid metabolic process. Hepatic steatosis developed in liver-specific, CTCF-deficient mice was ameliorated by repression of PPARγ via pharmacologic blockade or adenovirus-mediated knockdown, but hardly rescued by additional knockout of CD36. Conclusions: Our data indicate that liver-specific deletion of CTCF leads to hepatosteatosis through augmented PPARγ DNA-binding activity, which up-regulates its downstream target genes associated with the lipid metabolic process.
format	article
author	Yeeun Choi Min-Ji Song Woong-Jae Jung Haengdueng Jeong Seokjae Park Bobae Yang Eun-Chong Lee Jung-Sik Joo Dahee Choi Seung-Hoi Koo Eun-Kyoung Kim Ki Taek Nam Hyoung-Pyo Kim
author_facet	Yeeun Choi Min-Ji Song Woong-Jae Jung Haengdueng Jeong Seokjae Park Bobae Yang Eun-Chong Lee Jung-Sik Joo Dahee Choi Seung-Hoi Koo Eun-Kyoung Kim Ki Taek Nam Hyoung-Pyo Kim
author_sort	Yeeun Choi
title	Liver-Specific Deletion of Mouse CTCF Leads to Hepatic Steatosis via Augmented PPARγ SignalingSummary
title_short	Liver-Specific Deletion of Mouse CTCF Leads to Hepatic Steatosis via Augmented PPARγ SignalingSummary
title_full	Liver-Specific Deletion of Mouse CTCF Leads to Hepatic Steatosis via Augmented PPARγ SignalingSummary
title_fullStr	Liver-Specific Deletion of Mouse CTCF Leads to Hepatic Steatosis via Augmented PPARγ SignalingSummary
title_full_unstemmed	Liver-Specific Deletion of Mouse CTCF Leads to Hepatic Steatosis via Augmented PPARγ SignalingSummary
title_sort	liver-specific deletion of mouse ctcf leads to hepatic steatosis via augmented pparγ signalingsummary
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/a2fe8b241c40454ab82a0f2c5a7e47ac
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Liver-Specific Deletion of Mouse CTCF Leads to Hepatic Steatosis via Augmented PPARγ SignalingSummary

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