Hepatic miR-192-3p reactivation alleviates steatosis by targeting glucocorticoid receptor
Background & Aims: The paradox of hepatic insulin resistance describes the inability for liver to respond to bioenergetics hormones in suppressing gluconeogenesis whilst maintaining lipid synthesis. Here, we report the deficiency of miR-192-3p in the livers of mice with diabetes and its role...
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Format: | Article |
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Elsevier
2020-12-01
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Series: | JHEP Reports |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2589555920301130 |
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doaj-73b0b1e43800418cbc94f8979a3a4eaa |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zhangting Wang Kai-Kei Miu Xueyan Zhang Angel Tsz-Yau Wan Gang Lu Hoi-Hung Cheung Heung-Man Lee Alice Pik-Shan Kong Juliana Chung-Ngor Chan Wai-Yee Chan |
spellingShingle |
Zhangting Wang Kai-Kei Miu Xueyan Zhang Angel Tsz-Yau Wan Gang Lu Hoi-Hung Cheung Heung-Man Lee Alice Pik-Shan Kong Juliana Chung-Ngor Chan Wai-Yee Chan Hepatic miR-192-3p reactivation alleviates steatosis by targeting glucocorticoid receptor JHEP Reports Hepatic steatosis Diabetes mellitus MicroRNA Glucocorticoid receptor Transcription repressor High carbohydrate consumption |
author_facet |
Zhangting Wang Kai-Kei Miu Xueyan Zhang Angel Tsz-Yau Wan Gang Lu Hoi-Hung Cheung Heung-Man Lee Alice Pik-Shan Kong Juliana Chung-Ngor Chan Wai-Yee Chan |
author_sort |
Zhangting Wang |
title |
Hepatic miR-192-3p reactivation alleviates steatosis by targeting glucocorticoid receptor |
title_short |
Hepatic miR-192-3p reactivation alleviates steatosis by targeting glucocorticoid receptor |
title_full |
Hepatic miR-192-3p reactivation alleviates steatosis by targeting glucocorticoid receptor |
title_fullStr |
Hepatic miR-192-3p reactivation alleviates steatosis by targeting glucocorticoid receptor |
title_full_unstemmed |
Hepatic miR-192-3p reactivation alleviates steatosis by targeting glucocorticoid receptor |
title_sort |
hepatic mir-192-3p reactivation alleviates steatosis by targeting glucocorticoid receptor |
publisher |
Elsevier |
series |
JHEP Reports |
issn |
2589-5559 |
publishDate |
2020-12-01 |
description |
Background & Aims: The paradox of hepatic insulin resistance describes the inability for liver to respond to bioenergetics hormones in suppressing gluconeogenesis whilst maintaining lipid synthesis. Here, we report the deficiency of miR-192-3p in the livers of mice with diabetes and its role in alleviating hepatic steatosis. Methods: As conventional pre-microRNA (miRNA) stem-loop overexpression only boosts guiding strand (i.e. miR-192-5p) expression, we adopted an artificial AAV(DJ)-directed, RNA Pol III promoter-driven miRNA hairpin construct for star-strand-specific overexpression in the liver. Liver steatosis and insulin resistance markers were evaluated in primary hepatocytes, mice with diabetes, and mice with excessive carbohydrate consumption. Results: Functional loss of miR-192-3p in liver exacerbated hepatic micro-vesicular steatosis and insulin resistance in either mice with diabetes or wild-type mice with excessive fructose consumption. Liver-specific overexpression of miR-192-3p effectively halted hepatic steatosis and ameliorated insulin resistance in these mice models. Likewise, hepatocytes overexpressing miR-192-3p exhibited improved lipid accumulation, accompanied with decreases in lipogenesis and lipid-accumulation-related transcripts. Mechanistically, glucocorticoid receptor (GCR, also known as nuclear receptor subfamily 3, group C, member 1 [NR3C1]) was demonstrated to be negatively regulated by miR-192-3p. The effect of miR-192-3p on mitigating micro-vesicular steatosis was ablated by the reactivation of NR3C1. Conclusions: The star strand miR-192-3p was an undermined glycerolipid regulator involved in controlling fat accumulation and insulin sensitivity in liver through blockade of hepatic GCR signalling; this miRNA may serve as a potential therapeutic option for the common co-mobility of diabetic mellitus and fatty liver disease. Lay summary: The potential regulatory activity of star strand microRNA (miRNA) species has been substantially underestimated. In this study, we investigate the role and mechanism of an overlooked star strand miRNA (miR-192-3p) in regulating hepatic steatosis and insulin signalling in the livers of mice with diabetes and mice under excessive carbohydrate consumption. |
topic |
Hepatic steatosis Diabetes mellitus MicroRNA Glucocorticoid receptor Transcription repressor High carbohydrate consumption |
url |
http://www.sciencedirect.com/science/article/pii/S2589555920301130 |
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doaj-73b0b1e43800418cbc94f8979a3a4eaa2020-11-25T03:09:36ZengElsevierJHEP Reports2589-55592020-12-0126100179Hepatic miR-192-3p reactivation alleviates steatosis by targeting glucocorticoid receptorZhangting Wang0Kai-Kei Miu1Xueyan Zhang2Angel Tsz-Yau Wan3Gang Lu4Hoi-Hung Cheung5Heung-Man Lee6Alice Pik-Shan Kong7Juliana Chung-Ngor Chan8Wai-Yee Chan9School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong Special Administrative Region, ChinaSchool of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong Special Administrative Region, ChinaSchool of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Zhejiang, ChinaSchool of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong Special Administrative Region, ChinaSchool of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong Special Administrative Region, ChinaSchool of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong Special Administrative Region, ChinaDepartment of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, ChinaDepartment of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China; Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, Hong Kong Special Administrative Region, China; Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong Special Administrative Region, ChinaDepartment of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, China; Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, Hong Kong Special Administrative Region, China; Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong Special Administrative Region, ChinaSchool of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; CUHK_GDL Advanced Institute for Regenerative Medicine, Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China; Corresponding author. Address: Room 123A, Lo Kwee-Seong Integrated Biomedical Sciences Building, Area 39, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China. Tel.: +852 3943 1383; fax: +852 2603 7902.Background & Aims: The paradox of hepatic insulin resistance describes the inability for liver to respond to bioenergetics hormones in suppressing gluconeogenesis whilst maintaining lipid synthesis. Here, we report the deficiency of miR-192-3p in the livers of mice with diabetes and its role in alleviating hepatic steatosis. Methods: As conventional pre-microRNA (miRNA) stem-loop overexpression only boosts guiding strand (i.e. miR-192-5p) expression, we adopted an artificial AAV(DJ)-directed, RNA Pol III promoter-driven miRNA hairpin construct for star-strand-specific overexpression in the liver. Liver steatosis and insulin resistance markers were evaluated in primary hepatocytes, mice with diabetes, and mice with excessive carbohydrate consumption. Results: Functional loss of miR-192-3p in liver exacerbated hepatic micro-vesicular steatosis and insulin resistance in either mice with diabetes or wild-type mice with excessive fructose consumption. Liver-specific overexpression of miR-192-3p effectively halted hepatic steatosis and ameliorated insulin resistance in these mice models. Likewise, hepatocytes overexpressing miR-192-3p exhibited improved lipid accumulation, accompanied with decreases in lipogenesis and lipid-accumulation-related transcripts. Mechanistically, glucocorticoid receptor (GCR, also known as nuclear receptor subfamily 3, group C, member 1 [NR3C1]) was demonstrated to be negatively regulated by miR-192-3p. The effect of miR-192-3p on mitigating micro-vesicular steatosis was ablated by the reactivation of NR3C1. Conclusions: The star strand miR-192-3p was an undermined glycerolipid regulator involved in controlling fat accumulation and insulin sensitivity in liver through blockade of hepatic GCR signalling; this miRNA may serve as a potential therapeutic option for the common co-mobility of diabetic mellitus and fatty liver disease. Lay summary: The potential regulatory activity of star strand microRNA (miRNA) species has been substantially underestimated. In this study, we investigate the role and mechanism of an overlooked star strand miRNA (miR-192-3p) in regulating hepatic steatosis and insulin signalling in the livers of mice with diabetes and mice under excessive carbohydrate consumption.http://www.sciencedirect.com/science/article/pii/S2589555920301130Hepatic steatosisDiabetes mellitusMicroRNAGlucocorticoid receptorTranscription repressorHigh carbohydrate consumption |