Ultrastructural Changes of Hepatic Stellate Cells in the Space of Disse in Alcoholic Fatty Liver

Abstract Myeloid differentiation primary response gene 88 (MyD88), an adaptor protein in the TLRs signaling pathway, is expressed in various liver cells including hepatocytes, Kupffer cells and hepatic stellate cells (HSCs). However, the specific role of MyD88 in HSCs in alcoholic fatty liver (AFL) has not been well investigated. Here, to study the role of MyD88 in HSCs in the development of AFL and its related molecular mechanism, chronic-binge ethanol mice models were established in mice with specific MyD88 knockout in quiescent (MyD88GFAP−KO) and activated HSCs (MyD88SMA−KO), respectively. The results showed that the expression of MyD88 in HSCs was significantly increased in ethanol-induced liver tissues of wild-type mice. MyD88 deficiency in quiescent HSCs inhibited inflammation and lipogenesis, but in activated HSCs it only inhibited inflammation under the ethanol feeding condition. Further mechanism studies found that MyD88 promoted the osteopontin (OPN) secretion of HSCs, which further activated the AKT signaling pathway of hepatocytes and upregulated lipogenic gene expression to promote fat accumulation. In addition, OPN also promotes inflammation by activating p-STAT1. Thus, MyD88 may represent a potential candidate target for the prevention and targeted therapy in AFL, and MyD88 inhibitor can be also applied in inhibiting adipogenesis.

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Hepatic stellate cells: current state and open questions

Biological Chemistry ◽

10.1515/hsz-2021-0180 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Claus Kordes ◽

Hans H. Bock ◽

Doreen Reichert ◽

Petra May ◽

Dieter Häussinger

Keyword(s):

Hepatic Stellate Cells ◽

Stellate Cells ◽

Essential Elements ◽

Future Research ◽

Heinrich Heine ◽

Current State ◽

Open Questions ◽

Sinusoidal Endothelium ◽

Cell Niche ◽

Space Of Disse

Abstract This review article summarizes 20 years of our research on hepatic stellate cells within the framework of two collaborative research centers CRC575 and CRC974 at the Heinrich Heine University. Over this period, stellate cells were identified for the first time as mesenchymal stem cells of the liver, and important functions of these cells in the context of liver regeneration were discovered. Furthermore, it was determined that the space of Disse – bounded by the sinusoidal endothelium and hepatocytes – functions as a stem cell niche for stellate cells. Essential elements of this niche that control the maintenance of hepatic stellate cells have been identified alongside their impairment with age. This article aims to highlight previous studies on stellate cells and critically examine and identify open questions and future research directions.

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Network Pharmacological Analysis and Experimental Validation of the Mechanisms of Action of Si-Ni-San Against Liver Fibrosis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.656115 ◽

2021 ◽

Vol 12 ◽

Author(s):

Siliang Wang ◽

Cheng Tang ◽

Heng Zhao ◽

Peiliang Shen ◽

Chao Lin ◽

...

Keyword(s):

Liver Fibrosis ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Mechanisms Of Action ◽

Network Pharmacology ◽

Related Factor ◽

Alcoholic Fatty Liver ◽

Ppar Γ ◽

Liver Tissues

Background: Si-Ni-San (SNS), a commonly used traditional Chinese medicine (TCM) formula, has potency against liver diseases, such as hepatitis and non-alcoholic fatty liver disease (NAFLD). However, the therapeutic efficacy and pharmacological mechanisms of action of SNS against liver fibrosis remain largely unclear.Methods: A carbon tetrachloride (CCl4)-induced liver fibrosis mouse model was adopted for the first time to investigate the beneficial effects of SNS on liver fibrosis. The potential mechanisms of action of SNS were explored using the network pharmacology-based strategy and validated with the aid of diverse assays.Results: SNS treatment reduced collagen and ECM deposition, downregulated fibrosis-related factor (hyaluronic acid and laminin) contents in serum, maintained the morphological structure of liver tissue, and improved liver function in the liver fibrosis model. Based on network pharmacology results, apoptosis, inflammation and angiogenesis, together with the associated pathways (including VEGF, TNF, caspase, PPAR-γ and NF-κB), were identified as the mechanisms underlying the effects of SNS on liver fibrosis. Further in vivo experiments validated the significant mitigatory effects of SNS on inflammatory infiltration and pro-inflammatory cytokine contents (IFNγ, IL-1β and TGF-β1) in liver tissues of mice with liver fibrosis. SNS suppressed pathologic neovascularization as well as levels of VEGFR1, VEGF and VEGFR2 in liver tissues. SNS treatment additionally inhibited hepatic parenchyma cell apoptosis in liver tissues of mice with liver fibrosis and regulated apoptin expression while protecting L02 cells against apoptosis induced by TNF-α and Act D in vitro. Activation of hepatic stellate cells was suppressed and the balance between MMP13 and TIMP1 maintained in vitro by SNS. These activities may be associated with SNS-induced NF-κB suppression and PPAR-γ activation.Conclusion: SNS effectively impedes liver fibrosis progression through alleviating inflammation, ECM accumulation, aberrant angiogenesis and apoptosis of hepatic parenchymal cells along with inhibiting activation of hepatic stellate cells through effects on multiple targets and may thus serve as a novel therapeutic regimen for this condition.

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Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

Cells ◽

10.3390/cells9010024 ◽

2019 ◽

Vol 9 (1) ◽

pp. 24 ◽

Cited By ~ 7

Author(s):

Olga Khomich ◽

Alexander V. Ivanov ◽

Birke Bartosch

Keyword(s):

Liver Disease ◽

Liver Fibrosis ◽

Hepatic Stellate Cells ◽

Current Knowledge ◽

Stellate Cells ◽

Central Carbon Metabolism ◽

Regenerative Process ◽

Therapeutic Interventions ◽

Alcoholic Fatty Liver ◽

Liver Functions

Liver fibrosis is a regenerative process that occurs after injury. It is characterized by the deposition of connective tissue by specialized fibroblasts and concomitant proliferative responses. Chronic damage that stimulates fibrogenic processes in the long-term may result in the deposition of excess matrix tissue and impairment of liver functions. End-stage fibrosis is referred to as cirrhosis and predisposes strongly to the loss of liver functions (decompensation) and hepatocellular carcinoma. Liver fibrosis is a pathology common to a number of different chronic liver diseases, including alcoholic liver disease, non-alcoholic fatty liver disease, and viral hepatitis. The predominant cell type responsible for fibrogenesis is hepatic stellate cells (HSCs). In response to inflammatory stimuli or hepatocyte death, HSCs undergo trans-differentiation to myofibroblast-like cells. Recent evidence shows that metabolic alterations in HSCs are important for the trans-differentiation process and thus offer new possibilities for therapeutic interventions. The aim of this review is to summarize current knowledge of the metabolic changes that occur during HSC activation with a particular focus on the retinol and lipid metabolism, the central carbon metabolism, and associated redox or stress-related signaling pathways.

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Proteomic Changes of Activated Hepatic Stellate Cells

International Journal of Molecular Sciences ◽

10.3390/ijms222312782 ◽

2021 ◽

Vol 22 (23) ◽

pp. 12782

Author(s):

Maximilian Schinagl ◽

Tamara Tomin ◽

Juergen Gindlhuber ◽

Sophie Honeder ◽

Raphael Pfleger ◽

...

Keyword(s):

Hepatic Stellate Cells ◽

Ribosomal Proteins ◽

Fatty Acid Biosynthesis ◽

Cell Cycle Control ◽

Stellate Cells ◽

Alcoholic Fatty Liver ◽

Cellular Processes ◽

Reliable Model ◽

Activation Data ◽

And Migration

Hepatic stellate cells (HSC) are the major cellular drivers of liver fibrosis. Upon liver inflammation caused by a broad range of insults including non-alcoholic fatty liver, HSC transform from a quiescent into a proliferating, fibrotic phenotype. Although much is known about the pathophysiology of this process, exact cellular processes which occur in HSC and enable this transformation remain yet to be elucidated. In order to investigate this HSC transformation, we employed a simple, yet reliable model of HSC activation via an increase in growth medium serum concentration (serum activation). For that purpose, immortalized human LX-2 HSC were exposed to either 1% or 10% fetal bovine serum (FBS). Resulting quiescent (1% FBS) and activated (10% FBS) LX-2 cells were then subjected to in-depth mass spectrometry-based proteomics analysis as well as comprehensive phenotyping. Protein network analysis of activated LX-2 cells revealed an increase in the production of ribosomal proteins and proteins related to cell cycle control and migration, resulting in higher proliferation and faster migration phenotypes. Interestingly, we also observed a decrease in the expression of cholesterol and fatty acid biosynthesis proteins in accordance with a concomitant loss of cytosolic lipid droplets during activation. Overall, this work provides an update on HSC activation characteristics using contemporary proteomic and bioinformatic analyses and presents an accessible model for HSC activation. Data are available via ProteomeXchange with identifier PXD029121.

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Ultrastructural changes in perfusion-fixed human non-alcoholic fatty liver disease biopsies

Journal of Hepatology ◽

10.1016/s0168-8278(20)31816-x ◽

2020 ◽

Vol 73 ◽

pp. S677

Author(s):

Pauline Verhaegh ◽

Eddie Wisse ◽

Toon De Munck ◽

Jan W. Greve ◽

Joanne Verheij ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Ultrastructural Changes ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

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2119-P: AKR1B10 Is Upregulated in Nonalcoholic Fatty Liver Disease and Is Regulated by Fatty Acid Loading in Hepatocytes and Hepatic Stellate Cells

Diabetes ◽

10.2337/db19-2119-p ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 2119-P

Author(s):

BETHANY DAVIS ◽

DANIELLE M. WILHELMSEN ◽

AMANDA HANSON ◽

JOHANNA DISTEFANO

Keyword(s):

Fatty Acid ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Hepatic Stellate Cells ◽

Fatty Liver Disease ◽

Stellate Cells ◽

Nonalcoholic Fatty Liver ◽

Acid Loading

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Hepatic stellate cells and fibrosis progression in patients with nonalcoholic fatty liver disease

Clinical Gastroenterology and Hepatology ◽

10.1016/s1542-3565(04)00616-0 ◽

2005 ◽

Vol 3 (4) ◽

pp. 384-389 ◽

Cited By ~ 34

Author(s):

Ariel E. Feldstein ◽

Bettina G. Papouchado ◽

Paul Angulo ◽

Schyler Sanderson ◽

Leon Adams ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Hepatic Stellate Cells ◽

Fatty Liver Disease ◽

Stellate Cells ◽

Nonalcoholic Fatty Liver ◽

Fibrosis Progression

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Playing Jekyll and Hyde—The Dual Role of Lipids in Fatty Liver Disease

Cells ◽

10.3390/cells9102244 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2244

Author(s):

Martijn R. Molenaar ◽

Louis C. Penning ◽

J. Bernd Helms

Keyword(s):

Lipid Metabolism ◽

Liver Disease ◽

Fatty Liver ◽

Hepatic Fibrosis ◽

Lipid Accumulation ◽

Fatty Liver Disease ◽

Molecular Mechanisms ◽

Stellate Cells ◽

Alcoholic Fatty Liver ◽

Hepatic Lipid Accumulation

Lipids play Jekyll and Hyde in the liver. On the one hand, the lipid-laden status of hepatic stellate cells is a hallmark of healthy liver. On the other hand, the opposite is true for lipid-laden hepatocytes—they obstruct liver function. Neglected lipid accumulation in hepatocytes can progress into hepatic fibrosis, a condition induced by the activation of stellate cells. In their resting state, these cells store substantial quantities of fat-soluble vitamin A (retinyl esters) in large lipid droplets. During activation, these lipid organelles are gradually degraded. Hence, treatment of fatty liver disease is treading a tightrope—unsophisticated targeting of hepatic lipid accumulation might trigger problematic side effects on stellate cells. Therefore, it is of great importance to gain more insight into the highly dynamic lipid metabolism of hepatocytes and stellate cells in both quiescent and activated states. In this review, part of the special issue entitled “Cellular and Molecular Mechanisms underlying the Pathogenesis of Hepatic Fibrosis 2020”, we discuss current and highly versatile aspects of neutral lipid metabolism in the pathogenesis of non-alcoholic fatty liver disease (NAFLD).

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