Abstract:
BACKGROUND & AIMS:Hepatic stellate cells (HSCs) have a role in liver fibrosis. Guanine nucleotide-binding α-subunit 12 (Gα12) converges signals from G-protein-coupled receptors whose ligand levels are elevated in the environment during liver fibrosis; however, information is lacking on the effect of Gα12 on HSC trans-differentiation. This study investigated the expression of Gα12 in HSCs and the molecular basis of the effects of its expression on liver fibrosis. METHODS:Gα12 expression was assessed by immunostaining, and immunoblot analyses of mouse fibrotic liver tissues and primary HSCs. The role of Gα12 in liver fibrosis was estimated using a toxicant injury mouse model with Gα12 gene knockout and/or HSC-specific Gα12 delivery using lentiviral vectors, in addition to primary HSCs and LX-2 cells using microRNA (miR) inhibitors, overexpression vectors, or adenoviruses. miR-16, Gα12, and LC3 were also examined in samples from patients with fibrosis. RESULTS:Gα12 was overexpressed in activated HSCs and fibrotic liver, and was colocalised with desmin. In a carbon tetrachloride-induced fibrosis mouse model, Gα12 ablation prevented increases in fibrosis and liver injury. This effect was attenuated by HSC-specific lentiviral delivery of Gα12. Moreover, Gα12 activation promoted autophagy accompanying c-Jun N-terminal kinase-dependent ATG12-5 conjugation. In addition, miR-16 was found to be a direct inhibitor of the de novo synthesis of Gα12. Modulations of miR-16 altered autophagy in HSCs. In a fibrosis animal model or patients with severe fibrosis, miR-16 levels were lower than in their corresponding controls. Consistently, cirrhotic patient liver tissues showed Gα12 and LC3 upregulation in desmin-positive areas. CONCLUSIONS:miR-16 dysregulation in HSCs results in Gα12 overexpression, which activates HSCs by facilitating autophagy through ATG12-5 formation. This suggests that Gα12 and its regulatory molecules could serve as targets for the amelioration of liver fibrosis. LAY SUMMARY:Guanine nucleotide-binding α-subunit 12 (Gα12) is upregulated in activated hepatic stellate cells (HSCs) as a consequence of the dysregulation of a specific microRNA that is abundant in HSCs, facilitating the progression of liver fibrosis. This event is mediated by c-Jun N-terminal kinase-dependent ATG12-5 formation and the promotion of autophagy. We suggest that Gα12 and its associated regulators could serve as new targets in HSCs for the treatment of liver fibrosis.
journal_name
J Hepatoljournal_title
Journal of hepatologyauthors
Kim KM,Han CY,Kim JY,Cho SS,Kim YS,Koo JH,Lee JM,Lim SC,Kang KW,Kim JS,Hwang SJ,Ki SH,Kim SGdoi
10.1016/j.jhep.2017.10.011subject
Has Abstractpub_date
2018-03-01 00:00:00pages
493-504issue
3eissn
0168-8278issn
1600-0641pii
S0168-8278(17)32388-7journal_volume
68pub_type
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abstract:BACKGROUND & AIMS:IL28B polymorphisms, jaundice, decline in HCV-RNA, IP-10, and gender have been proposed to be indicative of spontaneous clearance of acute hepatitis C virus infection. The aim of this study was to define a score enabling the discrimination of patients with spontaneous clearance of HCV from those with ...
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journal_title:Journal of hepatology
pub_type: 杂志文章,评审
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(85)80745-5
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2013.01.042
更新日期:2013-06-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2014.11.025
更新日期:2015-04-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章,评审
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(00)80153-1
更新日期:2000-07-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2008.01.011
更新日期:2008-01-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:2004-03-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:2011-10-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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pub_type: 杂志文章
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