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J. Hepatol., Available online 2 January 2018 | https://doi.org/10.1016/j.jhep.2017.10.011 Gα12 overexpression induced by miR-16 dysregulation contributes to liver fibrosis by promoting autophagy in hepatic stellate cells

Kyu Min Kim¹, Chang Yeob Han¹, Ji Young Kim², Sam Seok Cho², Yun Seok Kim¹, Ja Hyun Koo¹, Jung Min Lee¹, Sung Chul Lim³, Keon Wook Kang¹, Jae-Sung Kim⁴, Se Jin Hwang⁵, Sung Hwan Ki², Sang Geon Kim^1,*¹ College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea

² College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea

³ College of Medicine, Chosun University, Gwangju 61452, Republic of Korea

⁴ Departments of Surgery University of Florida, Gainesville, FL 32611, USA

⁵ College of Medicine, Hanyang University, Seoul 04763, Republic of Korea

^*Corresponding author.

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.

논문정보

형식Research article
게재일2018년 01월 (BRIC 등록일 2018-01-11)
연구진국내(교신)+국외 연구진
분야 의약학 > 약학

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