Synergy of Phospholipid—Drug Formulations Significantly Deactivates Profibrogenic Human Hepatic Stellate Cells

The pivotal role of hepatic stellate cells (HSCs) in orchestrating the bidirectional process of progression and regression of liver fibrosis makes them an ideal target for exploring new antifibrotic therapies. Essential phospholipids (EPLs), with their polyenylphosphatidylcholine (PPC) fraction, either alone or combined with other hepatoprotective substances such as silymarin, are recommended in hepatic impairment, but a scientific rationale for their use is still lacking. Herein, we compared the ability of EPLs to restore quiescent-like features in HSCs with that of dilinoleoylphosphatidylcholine (DLPC), PPC fraction’s main component. Specifically, we screened at the cellular level the antifibrotic effects of PPC formulations in the presence and absence of silymarin, by using LX-2 cells (pro-fibrogenic HSCs) and by assessing the main biochemical hallmarks of the activated and deactivated states of this cell line. We also proved the formulations’ direct effect on the motional order of cell membranes of adherent cells. LX-2 cells, examined for lipid droplets as a quiescence marker, showed that PPCs led to a more prominent deactivation than DLPC. This result was confirmed by a reduction of collagen and α-SMA expression, and by a profound alteration in the cell membrane fluidity. PPC–silymarin formulations deactivated HSCs with a significant synergistic effect. The remarkable bioactivity of PPCs in deactivating fibrogenic HSCs paves the way for the rational design of new therapeutics aimed at managing hepatic fibrosis.

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Investigating the expression of autophagy genes during the in vitro activation of mouse hepatic stellate cells

Ministry of Science and Technology, Vietnam ◽

10.31276/vjst.63(2).21-26 ◽

2021 ◽

Vol 63 (2) ◽

pp. 21-26

Author(s):

Minh Thanh Dang ◽

◽

Van Trinh Le ◽

Quang Huy Do ◽

Thi Hang Tran ◽

...

Keyword(s):

Hepatic Stellate Cells ◽

Lipid Droplets ◽

Stellate Cells ◽

Beclin 1 ◽

Collagen I ◽

Antifibrotic Therapy ◽

Qrt Pcr ◽

Oil Red O

This study aims to evaluate the expression level of autophagy genes during the activation of mouse hepatic stellate cells (HSCs) in vitro. The HSCs isolated from the mouse liver were cultured in vitro for 7 days. The activation of HSCs was evaluated by their morphology, the storage of lipid droplets by oil red O (ORO) staining, the expression of activation-related genes α-sma, collagen I, and quiescence-related gene lrat by qRT PCR and ICC staining (α-SMA). The expression of autophagy genes lc3b, beclin 1, atg12 were assessed by qRT PCR and ICC staining (LC3). The results showed that the isolated HSCs were activated after 3 days and 7 days of the culture in vitro. The activation was indicated by the morphological change of HSCs to myofibroblast-like cells, loss of lipid droplets, and increased expression of fibrotic genes α-sma and collagen I, decreased expression of lrat. Additionally, the expression of autophagy genes lc3b, beclin 1, and atg12 were significantly increased in the activated HSCs after the culture in vitrofor 3 and 7 days. This study contributes the preliminary results to further studies on the role of autophagy during the activation of HSCs, which may be exploited for the development of the antifibrotic therapy targeting autophagy.

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Faculty Opinions recommendation of Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726326158.793518619 ◽

2016 ◽

Author(s):

Ralf Weiskirchen ◽

Jens Herrmann

Keyword(s):

Hepatic Stellate Cells ◽

Lipid Droplets ◽

Stellate Cells ◽

Perilipin 5 ◽

Activated Hepatic Stellate Cells

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The role of hepatic stellate cells in liver regeneration

Journal of Hepatology ◽

10.1016/j.jhep.2004.04.003 ◽

2004 ◽

Vol 40 (6) ◽

pp. 1023-1026 ◽

Cited By ~ 33

Author(s):

C BALABAUD

Keyword(s):

Liver Regeneration ◽

Hepatic Stellate Cells ◽

Stellate Cells

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Replacement of Retinyl Esters by Polyunsaturated Triacylglycerol Species in Lipid Droplets of Hepatic Stellate Cells during Activation

PLoS ONE ◽

10.1371/journal.pone.0034945 ◽

2012 ◽

Vol 7 (4) ◽

pp. e34945 ◽

Cited By ~ 48

Author(s):

Nicole Testerink ◽

Mokrish Ajat ◽

Martin Houweling ◽

Jos F. Brouwers ◽

Vishnu V. Pully ◽

...

Keyword(s):

Hepatic Stellate Cells ◽

Lipid Droplets ◽

Stellate Cells ◽

Retinyl Esters ◽

Triacylglycerol Species

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Role of DDAH/ADMA pathway in TGF-β1-mediated activation of hepatic stellate cells

Molecular Medicine Reports ◽

10.3892/mmr.2017.8107 ◽

2017 ◽

Author(s):

Zhenguo Liu ◽

Juan Wang ◽

Wu Xing ◽

Yingqiong Peng ◽

Yan Huang ◽

...

Keyword(s):

Hepatic Stellate Cells ◽

Stellate Cells ◽

Tgf Β1

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A non-autonomous role of MKL1 in the activation of hepatic stellate cells

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms ◽

10.1016/j.bbagrm.2019.03.001 ◽

2019 ◽

Vol 1862 (6) ◽

pp. 609-618 ◽

Cited By ~ 18

Author(s):

Zilong Li ◽

Ping Li ◽

Yunjie Lu ◽

Donglin Sun ◽

Xiaoying Zhang ◽

...

Keyword(s):

Hepatic Stellate Cells ◽

Stellate Cells

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The Role of Signal Transducer and Activator of Transcription 5 and Transforming Growth Factor-β1 in Hepatic Fibrosis Induced by Chronic Hepatitis C Virus Infection in Egyptian Patients

Medical Principles and Practice ◽

10.1159/000487308 ◽

2018 ◽

Vol 27 (2) ◽

pp. 115-121

Author(s):

Mona A. Abu El Makarem ◽

Ghada M. El-Sagheer ◽

Moustafa A. Abu El-Ella

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C ◽

Liver Fibrosis ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Serum Levels ◽

Signal Transducer ◽

Egyptian Patients ◽

Tgf Β1

Objective: To investigate the possible role of signal transducer and activator of transcription 5 (STAT5) in the pathogenesis of liver fibrosis in Egyptian patients with chronic hepatitis C (CHC) virus infection and its relation to hepatic stellate cells (HSC). Subjects and Methods: Sixty-five patients (46 males and 19 females) were divided into 4 groups based on the severity of fibrosis as detected by Fibroscan as follows: F1, n = 15; F2, n = 21; F3, n = 13; and F4, n = 16. Twenty age- and gender-matched healthy persons volunteered as controls. The serum levels of STAT5, TGF-β1, α-smooth muscle actin (α-SMA), fasting blood sugar, and fasting insulin, as well as homeostasis model assessment of insulin resistance (HOMA-IR), were determined and compared for all groups. The usefulness of the studied serum biomarkers for predicting liver fibrosis was evaluated using a receiver operating characteristic curve. Results: Serum levels of STAT5 were significantly lower in patients compared to controls (9.69 ± 5.62 vs. 14.73 ± 6.52, p ≤ 0.001); on the contrary, TGF-β1, α-SMA, and HOMA-IR were significantly higher in patients compared to controls (mean: 1,796.04 vs. 1,636.94; 14.94 vs. 8.1; and 7.91 vs. 4.18; p ≤ 0.01 and 0.001, respectively). TGF-β1 and α-SMA showed a progressive increase with advancing severity of hepatic fibrosis (mean TGF-β1: 2,058.4 in F1-F2 and 1,583.8 in F3-F4, p ≤ 0.04; mean α-SMA: 13.59 in F1-F2 and 16.62 in F3-F4, p ≤ 0.05). STAT5 had a significant negative correlation with TGF-β1 (p ≤ 0.001), while no correlation was detected with α-SMA (p ≤ 0.8). Conclusions: STAT5 may play a significant role in hepatic fibrogenesis through the induction of TGF-β1 but not through the activation of hepatic stellate cells.

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