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Exploring Molecular Mechanisms of Liver Fibrosis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 April 2024) | Viewed by 8860

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Special Issue Editors

Prof. Dr. Tilman Sauerbruch

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Guest Editor

Department of Internal Medicine I, University Hospital of Bonn, 53127 Bonn, Germany
Interests: portal hypertension; bile acids; beta-blockers; NASH; NAFLD; cirrhosis; therapy

Prof. Dr. Ralf Weiskirchen

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Guest Editor

Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany
Interests: liver diseases, biomakrer, cellular signaling, cytokines, chemokines; food products, vitamin A, weight loss, diet, fats, carbohydrates; supplements
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Special Issue Information

Dear Colleagues,

Fibrosis is a double-edged sword. On the one hand, it can be the final state of a healed inflammation as scar tissue; on the other hand, it is frequently associated with a reduction or loss of organ function. Moreover, especially in liver disease, it is a surrogate parameter that indicates a progression of the disease to liver cirrhosis or even hepatocellular carcinoma. This is especially true for non-alcoholic fatty liver disease, a pandemic disorder associated with Western lifestyles and diets. To influence organ fibrosis, it is important to better understand its induction, perpetuation and termination at the molecular level. The induction of liver fibrosis may be metabolic (e.g. alcohol, diet, drugs), infectious (e.g. viruses), autoimmune (e.g. primary biliary cholangitis) or due to monogenetic defects (e.g. increased iron storage). The molecular mechanisms on the way to the final stage fibrosis are very different – dependent on its pathogenesis. It is the aim of this special issue to provide more insight into these processes.

Prof. Dr. Tilman Sauerbruch
Prof. Dr. Ralf Weiskirchen
Guest Editors

Manuscript Submission Information

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Keywords

fibrosis
hepatic stellate cells
portal hypertension
extracellular matrix
cytokines
chemokines
biomarkers
NASH
NAFLD
cirrhosis
hepatocellular carcinoma
therapy
animal models

Published Papers (6 papers)

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Research

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16 pages, 871 KiB

Open AccessArticle

Gut Microbiota and Biomarkers of Endothelial Dysfunction in Cirrhosis

by Irina Efremova, Roman Maslennikov, Elena Poluektova, Oleg Medvedev, Anna Kudryavtseva, George Krasnov, Maria Fedorova, Filipp Romanikhin, Vyacheslav Bakhitov, Salekh Aliev, Natalia Sedova, Tatiana Kuropatkina, Anastasia Ivanova, Maria Zharkova, Ekaterina Pervushova and Vladimir Ivashkin

Int. J. Mol. Sci. 2024, 25(4), 1988; https://doi.org/10.3390/ijms25041988 - 06 Feb 2024

Viewed by 782

Abstract

Our aim was to study the association of endothelial dysfunction biomarkers with cirrhosis manifestations, bacterial translocation, and gut microbiota taxa. The fecal microbiome was assessed using 16S rRNA gene sequencing. Plasma levels of nitrite, big endothelin-1, asymmetric dimethylarginine (ADMA), presepsin, and claudin were measured as biomarkers of endothelial dysfunction, bacterial translocation, and intestinal barrier dysfunction. An echocardiography with simultaneous determination of blood pressure and heart rate was performed to evaluate hemodynamic parameters. Presepsin, claudin 3, nitrite, and ADMA levels were higher in cirrhosis patients than in controls. Elevated nitrite levels were associated with high levels of presepsin and claudin 3, the development of hemodynamic circulation, hypoalbuminemia, grade 2–3 ascites, overt hepatic encephalopathy, high mean pulmonary artery pressure, increased abundance of Proteobacteria and Erysipelatoclostridium, and decreased abundance of Oscillospiraceae, Subdoligranulum, Rikenellaceae, Acidaminococcaceae, Christensenellaceae, and Anaerovoracaceae. Elevated ADMA levels were associated with higher Child–Pugh scores, lower serum sodium levels, hypoalbuminemia, grade 2–3 ascites, milder esophageal varices, overt hepatic encephalopathy, lower mean pulmonary artery pressure, and low abundance of Erysipelotrichia and Erysipelatoclostridiaceae. High big endothelin-1 levels were associated with high levels of presepsin and sodium, low levels of fibrinogen and cholesterol, hypocoagulation, increased Bilophila and Coprobacillus abundances, and decreased Alloprevotella abundance. Full article

(This article belongs to the Special Issue Exploring Molecular Mechanisms of Liver Fibrosis)

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12 pages, 1253 KiB

Open AccessArticle

Saturated Fat-Mediated Upregulation of IL-32 and CCL20 in Hepatocytes Contributes to Higher Expression of These Fibrosis-Driving Molecules in MASLD

by Katharina Schilcher, Rania Dayoub, Marion Kubitza, Jakob Riepl, Kathrin Klein, Christa Buechler, Michael Melter and Thomas S. Weiss

Int. J. Mol. Sci. 2023, 24(17), 13222; https://doi.org/10.3390/ijms241713222 - 25 Aug 2023

Cited by 1 | Viewed by 1231

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases, ranging from liver steatosis to metabolic dysfunction-associated steatohepatitis (MASH), increasing the risk of developing cirrhosis and hepatocellular carcinoma (HCC). Fibrosis within MASLD is critical for disease development; therefore, the identification of fibrosis-driving factors is indispensable. We analyzed the expression of interleukin 32 (IL-32) and chemokine CC ligand 20 (CCL20), which are known to be linked with inflammation and fibrosis, and for their expression in MASLD and hepatoma cells. RT-PCR, ELISA and Western blotting analyses were performed in both human liver samples and an in vitro steatosis model. IL-32 and CCL20 mRNA expression was increased in tissues of patients with NASH compared to normal liver tissue. Stratification for patatin-like phospholipase domain-containing protein 3 (PNPLA3) status revealed significance for IL-32 only in patients with I148M (rs738409, CG/GG) carrier status. Furthermore, a positive correlation was observed between IL-32 expression and steatosis grade, and between IL-32 as well as CCL20 expression and fibrosis grade. Treatment with the saturated fatty acid palmitic acid (PA) induced mRNA and protein expression of IL-32 and CCL20 in hepatoma cells. This induction was mitigated by the substitution of PA with monounsaturated oleic acid (OA), suggesting the involvement of oxidative stress. Consequently, analysis of stress-induced signaling pathways showed the activation of Erk1/2 and p38 MAPK, which led to an enhanced expression of IL-32 and CCL20. In conclusion, cellular stress in liver epithelial cells induced by PA enhances the expression of IL-32 and CCL20, both known to trigger inflammation and fibrosis. Full article

(This article belongs to the Special Issue Exploring Molecular Mechanisms of Liver Fibrosis)

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12 pages, 2269 KiB

Open AccessArticle

KLF10 Inhibits TGF-β-Mediated Activation of Hepatic Stellate Cells via Suppression of ATF3 Expression

by Soonjae Hwang, Sangbin Park, Uzma Yaseen, Ho-Jae Lee and Ji-Young Cha

Int. J. Mol. Sci. 2023, 24(16), 12602; https://doi.org/10.3390/ijms241612602 - 09 Aug 2023

Cited by 2 | Viewed by 1419

Abstract

Liver fibrosis is a progressive and debilitating condition characterized by the excessive deposition of extracellular matrix proteins. Stellate cell activation, a major contributor to fibrogenesis, is influenced by Transforming growth factor (TGF-β)/SMAD signaling. Although Krüppel-like-factor (KLF) 10 is an early TGF-β-inducible gene, its specific role in hepatic stellate cell activation remains unclear. Our previous study demonstrated that KLF10 knockout mice develop severe liver fibrosis when fed a high-sucrose diet. Based on these findings, we aimed to identify potential target molecules involved in liver fibrosis and investigate the mechanisms underlying the KLF10 modulation of hepatic stellate cell activation. By RNA sequencing analysis of liver tissues from KLF10 knockout mice with severe liver fibrosis induced by a high-sucrose diet, we identified ATF3 as a potential target gene regulated by KLF10. In LX-2 cells, an immortalized human hepatic stellate cell line, KLF10 expression was induced early after TGF-β treatment, whereas ATF3 expression showed delayed induction. KLF10 knockdown in LX-2 cells enhanced TGF-β-mediated activation, as evidenced by elevated fibrogenic protein levels. Further mechanistic studies revealed that KLF10 knockdown promoted TGF-β signaling and upregulated ATF3 expression. Conversely, KLF10 overexpression suppressed TGF-β-mediated activation and downregulated ATF3 expression. Furthermore, treatment with the chemical chaperone 4-PBA attenuated siKLF10-mediated upregulation of ATF3 and fibrogenic responses in TGF-β-treated LX-2 cells. Collectively, our findings suggest that KLF10 acts as a negative regulator of the TGF-β signaling pathway, exerting suppressive effects on hepatic stellate cell activation and fibrogenesis through modulation of ATF3 expression. These results highlight the potential therapeutic implications of targeting the KLF10-ATF3 axis in liver fibrosis treatment. Full article

(This article belongs to the Special Issue Exploring Molecular Mechanisms of Liver Fibrosis)

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Review

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18 pages, 6630 KiB

Open AccessReview

The Role of SCAP/SREBP as Central Regulators of Lipid Metabolism in Hepatic Steatosis

by Preethi Chandrasekaran and Ralf Weiskirchen

Int. J. Mol. Sci. 2024, 25(2), 1109; https://doi.org/10.3390/ijms25021109 - 16 Jan 2024

Cited by 3 | Viewed by 1561

Abstract

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly increasing worldwide at an alarming pace, due to an increase in obesity, sedentary and unhealthy lifestyles, and unbalanced dietary habits. MASLD is a unique, multi-factorial condition with several phases of progression including steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Sterol element binding protein 1c (SREBP1c) is the main transcription factor involved in regulating hepatic de novo lipogenesis. This transcription factor is synthesized as an inactive precursor, and its proteolytic maturation is initiated in the membrane of the endoplasmic reticulum upon stimulation by insulin. SREBP cleavage activating protein (SCAP) is required as a chaperon protein to escort SREBP from the endoplasmic reticulum and to facilitate the proteolytic release of the N-terminal domain of SREBP into the Golgi. SCAP inhibition prevents activation of SREBP and inhibits the expression of genes involved in triglyceride and fatty acid synthesis, resulting in the inhibition of de novo lipogenesis. In line, previous studies have shown that SCAP inhibition can resolve hepatic steatosis in animal models and intensive research is going on to understand the effects of SCAP in the pathogenesis of human disease. This review focuses on the versatile roles of SCAP/SREBP regulation in de novo lipogenesis and the structure and molecular features of SCAP/SREBP in the progression of hepatic steatosis. In addition, recent studies that attempt to target the SCAP/SREBP axis as a therapeutic option to interfere with MASLD are discussed. Full article

(This article belongs to the Special Issue Exploring Molecular Mechanisms of Liver Fibrosis)

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14 pages, 685 KiB

Open AccessReview

Gut Microbiota and Bacterial Translocation in the Pathogenesis of Liver Fibrosis

by Roman Maslennikov, Elena Poluektova, Oxana Zolnikova, Alla Sedova, Anastasia Kurbatova, Yulia Shulpekova, Natyia Dzhakhaya, Svetlana Kardasheva, Maria Nadinskaia, Elena Bueverova, Vladimir Nechaev, Anna Karchevskaya and Vladimir Ivashkin

Int. J. Mol. Sci. 2023, 24(22), 16502; https://doi.org/10.3390/ijms242216502 - 19 Nov 2023

Cited by 1 | Viewed by 1322

Abstract

Cirrhosis is the end result of liver fibrosis in chronic liver diseases. Studying the mechanisms of its development and developing measures to slow down and regress it based on this knowledge seem to be important tasks for medicine. Currently, disorders of the gut–liver axis have great importance in the pathogenesis of cirrhosis. However, gut dysbiosis, which manifests as increased proportions in the gut microbiota of Bacilli and Proteobacteria that are capable of bacterial translocation and a decreased proportion of Clostridia that strengthen the intestinal barrier, occurs even at the pre-cirrhotic stage of chronic liver disease. This leads to the development of bacterial translocation, a process by which those microbes enter the blood of the portal vein and then the liver tissue, where they activate Kupffer cells through Toll-like receptor 4. In response, the Kupffer cells produce profibrogenic cytokines, which activate hepatic stellate cells, stimulating their transformation into myofibroblasts that produce collagen and other elements of the extracellular matrix. Blocking bacterial translocation with antibiotics, probiotics, synbiotics, and other methods could slow down the progression of liver fibrosis. This was shown in a number of animal models but requires further verification in long-term randomized controlled trials with humans. Full article

(This article belongs to the Special Issue Exploring Molecular Mechanisms of Liver Fibrosis)

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12 pages, 1882 KiB

Open AccessReview

Interleukin-13 (IL-13)—A Pleiotropic Cytokine Involved in Wound Healing and Fibrosis

by Elke Roeb

Int. J. Mol. Sci. 2023, 24(16), 12884; https://doi.org/10.3390/ijms241612884 - 17 Aug 2023

Cited by 4 | Viewed by 1500

Abstract

The liver, as a central metabolic organ, is systemically linked to metabolic–inflammatory diseases. In the pathogenesis of the metabolic syndrome, inflammatory and metabolic interactions between the intestine, liver, and adipose tissue lead to the progression of hepatic steatosis to metabolic-dysfunction-associated steatohepatitis (MASH) and consecutive MASH-induced fibrosis. Clinical and animal studies revealed that IL-13 might be protective in the development of MASH through both the preservation of metabolic functions and Th2-polarized inflammation in the liver and the adipose tissue. In contrast, IL-13-associated loss of mucosal gut barrier function and IL-13-associated enhanced hepatic fibrosis may contribute to the progression of MASH. However, there are only a few publications on the effect of IL-13 on metabolic diseases and possible therapies to influence them. In this review article, different aspects of IL-13-associated effects on the liver and metabolic liver diseases, which are partly contradictory, are summarized and discussed on the basis of the recent literature. Full article

(This article belongs to the Special Issue Exploring Molecular Mechanisms of Liver Fibrosis)

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