Gα12 overexpression induced by miR16 dysregulation contributes to liver fibrosis by promoting autophagy in hepatic stellate cells

Kyu Min Kim, Chang Yeob Han, Ji Young Kim, Sam Seok Cho, Yun Seok Kim, Ja Hyun Koo, Jung Min Lee, Sung Chul Lim, Keon Wook Kang, Jae Sung Kim, Se-Jin Hwang, Sung Hwan Ki, Sang Geon Kim

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background & aims: Hepatic stellate cells (HSCs) play a role in liver fibrosis. Guanine nucleotide-binding α-subunit12 (Gα 12 ) 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 Gα 12 on HSC trans-differentiation. This study investigated whether Gα 12 is overexpressed in HSCs and, if so, its effect on liver fibrosis and the molecular basis. Methods: Gα 12 expression was assessed by immunostaining, and immunoblot analyses of mouse fibrotic liver tissues and primary HSCs. The role of Gα 12 for liver fibrosis was estimated using toxicant injury mouse model with Gα 12 gene knockout and/or HSC-specific Gα 12 delivery using lentiviral vectors, and primary HSCs and LX-2 cells with microRNA (miR) inhibitor, overexpression vectors, or adenoviruses. miR-16, Gα 12 , and LC3 were examined in fibrosis patient samples. Results: Gα 12 was overexpressed in activated HSCs and fibrotic liver, and was colocalized with desmin. In a CCl 4 -induced fibrosis mouse model, Gα 12 ablation prevented increases in fibrosis and liver injury. This effect was attenuated by HSC-specific lentiviral delivery of Gα 12 . Moreover, Gα 12 activation promoted autophagy accompanying JNK-dependent ATG12-5 conjugation. In addition, we found that miR-16 was a direct inhibitor of de novo synthesis of Gα 12 . Modulations of miR-16 altered autophagy in HSCs. In a fibrosis animal model or patients with severe fibrosis, miR-16 levels were lower than their corresponding controls. Consistently, cirrhotic patient liver tissues showed Gα 12 and LC3 up-regulation in desmin-positive areas. Conclusions: MiR-16 dysregulation in HSCs causes Gα 12 overexpression, which activates HSCs by facilitating autophagy through ATG12-5 formation, implying that Gα 12 and the regulatory molecules may serve targets in the amelioration of liver fibrosis. Lay Summary: Gα 12 is up-regulated in activated HSCs as a consequence of dysregulation of a specific microRNA abundant in HSCs, facilitating the progression of liver fibrosis. This event is mediated by JNK-dependent ATG12-5 formation and promotion of autophagy. We suggest that Gα 12 and associated regulators may serve as new targets in HSCs for treatment of liver fibrosis.

Original languageEnglish
Pages (from-to)493-504
Number of pages12
JournalJournal of Hepatology
Volume68
Issue number3
DOIs
StatePublished - 2018 Mar 1

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Hepatic Stellate Cells
Autophagy
Liver Cirrhosis
MicroRNAs
Fibrosis
Desmin
Liver
Gene Knockout Techniques
Guanine Nucleotides
Wounds and Injuries
G-Protein-Coupled Receptors
Adenoviridae

Keywords

  • G protein
  • Liver fibrosis
  • activated stellate cell
  • lysosomal degradation
  • non-coding RNA

Cite this

Kim, Kyu Min ; Han, Chang Yeob ; Kim, Ji Young ; Cho, Sam Seok ; Kim, Yun Seok ; Koo, Ja Hyun ; Lee, Jung Min ; Lim, Sung Chul ; Kang, Keon Wook ; Kim, Jae Sung ; Hwang, Se-Jin ; Ki, Sung Hwan ; Kim, Sang Geon. / Gα12 overexpression induced by miR16 dysregulation contributes to liver fibrosis by promoting autophagy in hepatic stellate cells. In: Journal of Hepatology. 2018 ; Vol. 68, No. 3. pp. 493-504.
@article{0bdd8717adc04eb3a01711b51cfaa2b4,
title = "Gα12 overexpression induced by miR16 dysregulation contributes to liver fibrosis by promoting autophagy in hepatic stellate cells",
abstract = "Background & aims: Hepatic stellate cells (HSCs) play a role in liver fibrosis. Guanine nucleotide-binding α-subunit12 (Gα 12 ) 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 Gα 12 on HSC trans-differentiation. This study investigated whether Gα 12 is overexpressed in HSCs and, if so, its effect on liver fibrosis and the molecular basis. Methods: Gα 12 expression was assessed by immunostaining, and immunoblot analyses of mouse fibrotic liver tissues and primary HSCs. The role of Gα 12 for liver fibrosis was estimated using toxicant injury mouse model with Gα 12 gene knockout and/or HSC-specific Gα 12 delivery using lentiviral vectors, and primary HSCs and LX-2 cells with microRNA (miR) inhibitor, overexpression vectors, or adenoviruses. miR-16, Gα 12 , and LC3 were examined in fibrosis patient samples. Results: Gα 12 was overexpressed in activated HSCs and fibrotic liver, and was colocalized with desmin. In a CCl 4 -induced fibrosis mouse model, Gα 12 ablation prevented increases in fibrosis and liver injury. This effect was attenuated by HSC-specific lentiviral delivery of Gα 12 . Moreover, Gα 12 activation promoted autophagy accompanying JNK-dependent ATG12-5 conjugation. In addition, we found that miR-16 was a direct inhibitor of de novo synthesis of Gα 12 . Modulations of miR-16 altered autophagy in HSCs. In a fibrosis animal model or patients with severe fibrosis, miR-16 levels were lower than their corresponding controls. Consistently, cirrhotic patient liver tissues showed Gα 12 and LC3 up-regulation in desmin-positive areas. Conclusions: MiR-16 dysregulation in HSCs causes Gα 12 overexpression, which activates HSCs by facilitating autophagy through ATG12-5 formation, implying that Gα 12 and the regulatory molecules may serve targets in the amelioration of liver fibrosis. Lay Summary: Gα 12 is up-regulated in activated HSCs as a consequence of dysregulation of a specific microRNA abundant in HSCs, facilitating the progression of liver fibrosis. This event is mediated by JNK-dependent ATG12-5 formation and promotion of autophagy. We suggest that Gα 12 and associated regulators may serve as new targets in HSCs for treatment of liver fibrosis.",
keywords = "G protein, Liver fibrosis, activated stellate cell, lysosomal degradation, non-coding RNA",
author = "Kim, {Kyu Min} and Han, {Chang Yeob} and Kim, {Ji Young} and Cho, {Sam Seok} and Kim, {Yun Seok} and Koo, {Ja Hyun} and Lee, {Jung Min} and Lim, {Sung Chul} and Kang, {Keon Wook} and Kim, {Jae Sung} and Se-Jin Hwang and Ki, {Sung Hwan} and Kim, {Sang Geon}",
year = "2018",
month = "3",
day = "1",
doi = "10.1016/j.jhep.2017.10.011",
language = "English",
volume = "68",
pages = "493--504",
journal = "Journal of Hepatology",
issn = "0168-8278",
number = "3",

}

Kim, KM, Han, CY, Kim, JY, Cho, SS, Kim, YS, Koo, JH, Lee, JM, Lim, SC, Kang, KW, Kim, JS, Hwang, S-J, Ki, SH & Kim, SG 2018, 'Gα12 overexpression induced by miR16 dysregulation contributes to liver fibrosis by promoting autophagy in hepatic stellate cells', Journal of Hepatology, vol. 68, no. 3, pp. 493-504. https://doi.org/10.1016/j.jhep.2017.10.011

Gα12 overexpression induced by miR16 dysregulation contributes to liver fibrosis by promoting autophagy in hepatic stellate cells. / Kim, Kyu Min; Han, Chang Yeob; Kim, Ji Young; Cho, Sam Seok; Kim, Yun Seok; Koo, Ja Hyun; Lee, Jung Min; Lim, Sung Chul; Kang, Keon Wook; Kim, Jae Sung; Hwang, Se-Jin; Ki, Sung Hwan; Kim, Sang Geon.

In: Journal of Hepatology, Vol. 68, No. 3, 01.03.2018, p. 493-504.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Gα12 overexpression induced by miR16 dysregulation contributes to liver fibrosis by promoting autophagy in hepatic stellate cells

AU - Kim, Kyu Min

AU - Han, Chang Yeob

AU - Kim, Ji Young

AU - Cho, Sam Seok

AU - Kim, Yun Seok

AU - Koo, Ja Hyun

AU - Lee, Jung Min

AU - Lim, Sung Chul

AU - Kang, Keon Wook

AU - Kim, Jae Sung

AU - Hwang, Se-Jin

AU - Ki, Sung Hwan

AU - Kim, Sang Geon

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Background & aims: Hepatic stellate cells (HSCs) play a role in liver fibrosis. Guanine nucleotide-binding α-subunit12 (Gα 12 ) 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 Gα 12 on HSC trans-differentiation. This study investigated whether Gα 12 is overexpressed in HSCs and, if so, its effect on liver fibrosis and the molecular basis. Methods: Gα 12 expression was assessed by immunostaining, and immunoblot analyses of mouse fibrotic liver tissues and primary HSCs. The role of Gα 12 for liver fibrosis was estimated using toxicant injury mouse model with Gα 12 gene knockout and/or HSC-specific Gα 12 delivery using lentiviral vectors, and primary HSCs and LX-2 cells with microRNA (miR) inhibitor, overexpression vectors, or adenoviruses. miR-16, Gα 12 , and LC3 were examined in fibrosis patient samples. Results: Gα 12 was overexpressed in activated HSCs and fibrotic liver, and was colocalized with desmin. In a CCl 4 -induced fibrosis mouse model, Gα 12 ablation prevented increases in fibrosis and liver injury. This effect was attenuated by HSC-specific lentiviral delivery of Gα 12 . Moreover, Gα 12 activation promoted autophagy accompanying JNK-dependent ATG12-5 conjugation. In addition, we found that miR-16 was a direct inhibitor of de novo synthesis of Gα 12 . Modulations of miR-16 altered autophagy in HSCs. In a fibrosis animal model or patients with severe fibrosis, miR-16 levels were lower than their corresponding controls. Consistently, cirrhotic patient liver tissues showed Gα 12 and LC3 up-regulation in desmin-positive areas. Conclusions: MiR-16 dysregulation in HSCs causes Gα 12 overexpression, which activates HSCs by facilitating autophagy through ATG12-5 formation, implying that Gα 12 and the regulatory molecules may serve targets in the amelioration of liver fibrosis. Lay Summary: Gα 12 is up-regulated in activated HSCs as a consequence of dysregulation of a specific microRNA abundant in HSCs, facilitating the progression of liver fibrosis. This event is mediated by JNK-dependent ATG12-5 formation and promotion of autophagy. We suggest that Gα 12 and associated regulators may serve as new targets in HSCs for treatment of liver fibrosis.

AB - Background & aims: Hepatic stellate cells (HSCs) play a role in liver fibrosis. Guanine nucleotide-binding α-subunit12 (Gα 12 ) 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 Gα 12 on HSC trans-differentiation. This study investigated whether Gα 12 is overexpressed in HSCs and, if so, its effect on liver fibrosis and the molecular basis. Methods: Gα 12 expression was assessed by immunostaining, and immunoblot analyses of mouse fibrotic liver tissues and primary HSCs. The role of Gα 12 for liver fibrosis was estimated using toxicant injury mouse model with Gα 12 gene knockout and/or HSC-specific Gα 12 delivery using lentiviral vectors, and primary HSCs and LX-2 cells with microRNA (miR) inhibitor, overexpression vectors, or adenoviruses. miR-16, Gα 12 , and LC3 were examined in fibrosis patient samples. Results: Gα 12 was overexpressed in activated HSCs and fibrotic liver, and was colocalized with desmin. In a CCl 4 -induced fibrosis mouse model, Gα 12 ablation prevented increases in fibrosis and liver injury. This effect was attenuated by HSC-specific lentiviral delivery of Gα 12 . Moreover, Gα 12 activation promoted autophagy accompanying JNK-dependent ATG12-5 conjugation. In addition, we found that miR-16 was a direct inhibitor of de novo synthesis of Gα 12 . Modulations of miR-16 altered autophagy in HSCs. In a fibrosis animal model or patients with severe fibrosis, miR-16 levels were lower than their corresponding controls. Consistently, cirrhotic patient liver tissues showed Gα 12 and LC3 up-regulation in desmin-positive areas. Conclusions: MiR-16 dysregulation in HSCs causes Gα 12 overexpression, which activates HSCs by facilitating autophagy through ATG12-5 formation, implying that Gα 12 and the regulatory molecules may serve targets in the amelioration of liver fibrosis. Lay Summary: Gα 12 is up-regulated in activated HSCs as a consequence of dysregulation of a specific microRNA abundant in HSCs, facilitating the progression of liver fibrosis. This event is mediated by JNK-dependent ATG12-5 formation and promotion of autophagy. We suggest that Gα 12 and associated regulators may serve as new targets in HSCs for treatment of liver fibrosis.

KW - G protein

KW - Liver fibrosis

KW - activated stellate cell

KW - lysosomal degradation

KW - non-coding RNA

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U2 - 10.1016/j.jhep.2017.10.011

DO - 10.1016/j.jhep.2017.10.011

M3 - Article

C2 - 29080810

AN - SCOPUS:85039788966

VL - 68

SP - 493

EP - 504

JO - Journal of Hepatology

JF - Journal of Hepatology

SN - 0168-8278

IS - 3

ER -