TY - JOUR
T1 - Morroniside, a novel GATA3 binding molecule, inhibits hepatic stellate cells activation by enhancing lysosomal acid lipase expression
AU - An, Lin
AU - Zhang, Mi
AU - Lin, Yuefang
AU - Jiang, Ting
AU - Xu, Keyang
AU - Xiao, Shilin
AU - Cai, Liming
AU - Kwan, Hiu Yee
AU - Liu, Zhongqiu
AU - Su, Tao
N1 - Funding Information:
This work was supported by The National Natural Science Foundation of China ( 82104687 , 82074019 ), The Basic and Applied Basic Research Fund Project of Guangdong Province ( 2019A1515110202 ), The China Postdoctoral Science Foundation ( 2021T140145 , 2020M672604 ), the open project of State Key Laboratory of Quality Research in Chinese Medicine ( Macau University of Science and Technology , MUST-SKL-2021-003 , 2R2103 ), Administration of Traditional Chinese Medicine of Guangdong Province ( 20222042 ), Guangdong Basic and Applied Basic Research Foundation (2020B1515130005), Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine (2020B1212030006), Key-Area Research and Development Program of Guangdong Province (2020B1111100004), Research Grant Council of HKSAR (HKBU-22103017-ECS), Innovation & Technology Commission (PRP/015/19FX), National Natural Science Foundation of China ( SCM-2016-NSFC-003 ) and Natural Science Foundation of Guangdong Province ( 2018A0303130122 ).
Publisher Copyright: © 2022 Elsevier GmbH. All rights reserved.
PY - 2022/8
Y1 - 2022/8
N2 - BackgroundLiver fibrosis can be easily developed into irreversible liver cirrhosis or even liver cancer. Lysosomal acid lipase (LAL), encoded by the lipase A (Lipa) gene, is a critical enzyme involved in liver fibrosis development. Morroniside, an iridoid glycoside isolated from Cornus officinalis Sieb. et Zucc., exerts hepatic protective effects. However, the mechanism of action underling the anti-liver fibrosis effects of morroniside have not been fully elucidated. PurposeTo explore whether Lipa served as a biomarker for liver fibrosis and investigate the anti-liver fibrosis effects of morroniside and the underlying action mechanism in liver fibrosis cell models. MethodsLAL expression was examined in the liver tissues of CCl4 and high-fat diet (HFD)-induced liver fibrosis animal models. α-smooth muscle actin (α-SMA) level, collagen and GATA family expressions were analyzed by Real-time PCR and Western blot. Putative transcription factor binding sites in the DNA sequences of Lipa was identified by PROMO-ALGGEN v8.3 online software and ENCODE ChIP-Seq Significance Tool. MD simulation was performed to explore the protein-ligand interaction. ResultsWe found that the expression of hepatic LAL is lower in the liver fibrosis animal models than the control models. The reduced LAL expression is associated with HSCs activation, suggesting LAL is novel liver fibrosis biomarker. More importantly, our data showed that morroniside exerts anti-liver fibrosis effects in vitro. Mechanistic studies reveal that it binds to the hydrophobic sites of GATA3 and also reduces GATA3 expression, which increases LAL expression. ConclusionsThis study, for the first time, suggests LAL is a novel biomarker for liver fibrosis. Besides, morroniside exerts its anti-liver fibrosis effects by targeting GATA3 and LAL and hence inhibits HSC activation. These findings provide strong scientific evidence to support the development of morroniside as novel alternative or complementary therapeutics for liver injury prevention and treatment.
AB - BackgroundLiver fibrosis can be easily developed into irreversible liver cirrhosis or even liver cancer. Lysosomal acid lipase (LAL), encoded by the lipase A (Lipa) gene, is a critical enzyme involved in liver fibrosis development. Morroniside, an iridoid glycoside isolated from Cornus officinalis Sieb. et Zucc., exerts hepatic protective effects. However, the mechanism of action underling the anti-liver fibrosis effects of morroniside have not been fully elucidated. PurposeTo explore whether Lipa served as a biomarker for liver fibrosis and investigate the anti-liver fibrosis effects of morroniside and the underlying action mechanism in liver fibrosis cell models. MethodsLAL expression was examined in the liver tissues of CCl4 and high-fat diet (HFD)-induced liver fibrosis animal models. α-smooth muscle actin (α-SMA) level, collagen and GATA family expressions were analyzed by Real-time PCR and Western blot. Putative transcription factor binding sites in the DNA sequences of Lipa was identified by PROMO-ALGGEN v8.3 online software and ENCODE ChIP-Seq Significance Tool. MD simulation was performed to explore the protein-ligand interaction. ResultsWe found that the expression of hepatic LAL is lower in the liver fibrosis animal models than the control models. The reduced LAL expression is associated with HSCs activation, suggesting LAL is novel liver fibrosis biomarker. More importantly, our data showed that morroniside exerts anti-liver fibrosis effects in vitro. Mechanistic studies reveal that it binds to the hydrophobic sites of GATA3 and also reduces GATA3 expression, which increases LAL expression. ConclusionsThis study, for the first time, suggests LAL is a novel biomarker for liver fibrosis. Besides, morroniside exerts its anti-liver fibrosis effects by targeting GATA3 and LAL and hence inhibits HSC activation. These findings provide strong scientific evidence to support the development of morroniside as novel alternative or complementary therapeutics for liver injury prevention and treatment.
KW - GATA3
KW - Liver fibrosis
KW - Lysosomal acid lipase
KW - Morroniside
UR - http://www.scopus.com/inward/record.url?scp=85131752697&partnerID=8YFLogxK
U2 - 10.1016/j.phymed.2022.154199
DO - 10.1016/j.phymed.2022.154199
M3 - Journal article
C2 - 35679793
SN - 0944-7113
VL - 103
JO - Phytomedicine
JF - Phytomedicine
M1 - 154199
ER -
