Hepatic stellate cells retain the capacity to synthesize retinyl esters and to store neutral lipids in small lipid droplets in the absence of LRAT

Hepatic stellate cells (HSCs) are professional lipid-storing cells and are unique in their property to store most of the retinol (vitamin A) as retinyl esters in large-sized lipid droplets. Hepatic stellate cell activation is a critical step in the development of chronic liver disease, as activated HSCs cause fibrosis. During activation, HSCs lose their lipid droplets containing triacylglycerols, cholesteryl esters, and retinyl esters. Lipidomic analysis revealed that the dynamics of disappearance of these different classes of neutral lipids are, however, very different from each other. Although retinyl esters steadily decrease during HSC activation, triacylglycerols have multiple pools one of which becomes transiently enriched in polyunsaturated fatty acids before disappearing. These observations are consistent with the existence of preexisting “original” lipid droplets with relatively slow turnover and rapidly recycling lipid droplets that transiently appear during activation of HSCs. Elucidation of the molecular machinery involved in the regulation of these distinct lipid droplet pools may open new avenues for the treatment of liver fibrosis.

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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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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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Hepatic stellate cells in the liver of dogs with steroid-induced hepatopathy

Bulletin of the Veterinary Institute in Pulawy ◽

10.2478/bvip-2014-0041 ◽

2014 ◽

Vol 58 (2) ◽

pp. 273-276

Author(s):

Małgorzata Sobczak-Filipiak ◽

Józef Szarek ◽

Michał Czopowicz ◽

Joanna Mieczkowska ◽

Roman Lechowski

Keyword(s):

Electron Microscope ◽

Hepatic Stellate Cells ◽

Lipid Droplets ◽

Stellate Cells ◽

Structure And Function ◽

Surgical Biopsy ◽

Carnoy’S Solution ◽

Short Period ◽

Collagen Accumulation ◽

And Function

Abstract Morphological lesions in hepatic stellate cells caused by the immunosuppressive doses of dexamethasone were investigated in dogs. The archival samples of liver collected during a surgical biopsy were examined. The samples were fixed in 10% buffered formalin or Carnoy’s solution and then stained with routine histochemical methods. The lesions were also investigated under electron microscope. It was demonstrated that the number of stellate cells significantly increased (P = 0.0277), yet the size of cytoplasmic lipid droplets significantly decreased (P = 0.0001). Even though steroid-induced hepatopathy is considered to be a reversible pathology, and the lesions in hepatocytes under the influence of dexamethasone occur in a short period, it was found that hepatic stellate cells proliferated and underwent activation. This resulted in collagen accumulation in the hepatic sinuses. The functional and morphological disturbances in the canine liver in the course of steroid-induced hepatopathy are initially subclinical, but the changes in the structure and function of hepatic stellate cells may become a cause of lesions in the wall of hepatic sinusoidal vessels, which may induce additional functional pathologies unrelated to the damage to hepatocytes.

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Lecithin:Retinol Acyl Transferase (LRAT) induces the formation of lipid droplets

10.1101/733931 ◽

2019 ◽

Cited By ~ 3

Author(s):

Martijn R. Molenaar ◽

Tsjerk A. Wassenaar ◽

Kamlesh K. Yadav ◽

Alexandre Toulmay ◽

Muriel C. Mari ◽

...

Keyword(s):

Mammalian Cells ◽

Lipid Droplets ◽

Neutral Lipids ◽

Yeast Cells ◽

Acyl Transferase ◽

Hydrophobic Core ◽

Retinyl Ester ◽

Steryl Esters ◽

Retinyl Esters

AbstractLipid droplets are unique and nearly ubiquitous organelles that store neutral lipids in a hydrophobic core, surrounded by a monolayer of phospholipids. The primary neutral lipids are triacylglycerols and steryl esters. It is not known whether other classes of neutral lipids can form lipid droplets by themselves. Here we show that production of retinyl esters by lecithin:retinol acyl transferase (LRAT) in yeast cells, incapable of producing triacylglycerols and steryl esters, causes the formation of lipid droplets. By electron microscopy, these lipid droplets are morphologically indistinguishable from those in wild-type cells. In silico and in vitro experiments confirmed the propensity of retinyl esters to segregate from membranes and to form lipid droplets. The hydrophobic N-terminus of LRAT displays preferential interactions with retinyl esters in membranes and promotes the formation of large retinyl ester-containing lipid droplets in mammalian cells. Our combined data indicate that the molecular design of LRAT is optimally suited to allow the formation of characteristic large lipid droplets in retinyl ester-storing cells.

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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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Distribution of vitamin A-storing lipid droplets in hepatic stellate cells in liver lobules?A comparative study

The Anatomical Record ◽

10.1002/ar.a.10036 ◽

2003 ◽

Vol 271A (1) ◽

pp. 240-248 ◽

Cited By ~ 31

Author(s):

Nobuyo Higashi ◽

Haruki Senoo

Keyword(s):

Vitamin A ◽

Comparative Study ◽

Hepatic Stellate Cells ◽

Lipid Droplets ◽

Stellate Cells

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

Pharmaceutics ◽

10.3390/pharmaceutics11120676 ◽

2019 ◽

Vol 11 (12) ◽

pp. 676 ◽

Cited By ~ 2

Author(s):

Gina Valentino ◽

Cristina Zivko ◽

Florian Weber ◽

Lorine Brülisauer ◽

Paola Luciani

Keyword(s):

Hepatic Stellate Cells ◽

Lipid Droplets ◽

Rational Design ◽

Stellate Cells ◽

Cellular Level ◽

Adherent Cells ◽

Cell Membrane Fluidity ◽

Essential Phospholipids ◽

Main Component

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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