Hepatic miR-192-3p reactivation alleviates steatosis by targeting glucocorticoid receptor
Open accessAbstract
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: 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.
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Several genes were previously connected with fatty liver disease such as Nr3c1, Nr3c2, Zbtb16, Dnmt1, and Keap1, but most of the top genes had no connections with liver disease or NASH.
“Several genes were previously connected with fatty liver disease such as the glucocorticoid receptor Nr3c128,29, the mineralocorticoid receptor Nr3c230,31, the transcription factor Zbtb1632, the DNA methyltransferase Dnmt133, and the E3 ubiquitin ligase adaptor Keap134,35, but most of the top genes had no connections with liver disease or NASH.”
From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [28]
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- Authors
- Wang, Z., Miu, K.-K., Zhang, X., Wan, A. T.-Y., Lu, G., Cheung, H.-H., Lee, H.-M., Kong, A. P.-S., Chan, J. C.-N., & Chan, W.-Y.
- Affiliations
- Chinese University of Hong Kong (HK)
- Corresponding author
- Chan, Wai-Yee
- ORCID
- Venue
- JHEP Reports
- Publisher
- Elsevier BV
- Published
- 2020-12
- Volume
- 2
- Issue
- 6
- Pages
- 100179
- ISSN
- 2589-5559 (ISSN-L)
- PMC
- PMC7588854
- OpenAlex
- W3083365264
- Cited by
- 22
- References
- 40
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 5 · 2020: 1
- FWCI
- 2.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- JHEP Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Health and Medical Research Fund (06170996)
- Research Grants Council General Research Fund (14103418)
- Ministry of Science and Technology
- Shenzhen Virtue University Park Laboratory Support Special Fund (YFJGJS1.0)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- hepatic steatosis, insulin resistance, glucocorticoid receptor, NR3C1, lipogenesis, diabetes mellitus, lipid accumulation
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