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Biomedicines
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Liver Fibrosis: Molecular Mechanisms, Potential Therapeutic Targets and Clinical Biomarkers
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Liver Fibrosis: Molecular Mechanisms, Potential Therapeutic Targets and Clinical Biomarkers

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 21968

Special Issue Editor

Dr. Takefumi Kimura

E-Mail Website
Guest Editor
Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
Interests: liver disease; including NAFLD; NASH; hepatitis; HCC
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Liver fibrosis is an important pathological condition that directly affects the prognosis of chronic liver diseases, including viral hepatitis and non-alcoholic fatty liver disease (NAFLD). The mechanism of fibrosis formation has long been investigated. Recently, therapies targeting hepatic stellate cells (HSC) activation, fibrosis scar evolution, immunity, and cell death have been proposed. On the other hand, the development of non-invasive fibrosis biomarkers that do not require liver biopsy is underway. Serum markers such as FIB-4 and APRI, as well as US and MRI elastography are gaining recognition. In this Special Issue, we focus on the study of cellular signals and receptors that are altered in liver fibrosis formation. Comprehensive studies summarizing potential therapeutic targets, reports of novel therapeutic targets, and discussions of the development of fibrosis biomarkers that could serve as indicators of fibrosis treatment are welcome.

Dr. Takefumi Kimura
Guest Editor

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Keywords

  • liver
  • fibrosis
  • treatment
  • therapeutic target
  • biomarker
  • hepatitis
  • NAFLD
  • NASH
  • MAFLD
  • HSC
  • GPCR
  • immunity
  • cell death

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Related Special Issue

Published Papers (8 papers)

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Research

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18 pages, 4927 KiB  
Article
Anti-Fibrotic Efficacy of Apigenin in a Mice Model of Carbon Tetrachloride-Induced Hepatic Fibrosis by Modulation of Oxidative Stress, Inflammation, and Fibrogenesis: A Preclinical Study
by Maryam Melaibari, Huda M. Alkreathy, Ahmed Esmat, Nisreen A. Rajeh, Rasheed A. Shaik, Anwar A. Alghamdi and Aftab Ahmad
Biomedicines 2023, 11(5), 1342; https://doi.org/10.3390/biomedicines11051342 - 2 May 2023
Cited by 5 | Viewed by 2482
Abstract
Background: Hepatic fibrosis is a major health problem all over the world, and there is no effective treatment to cure it. Hence, the current study sought to assess the anti-fibrotic efficacy of apigenin against CCl4-induced hepatic fibrosis in mice. Methods: Forty-eight [...] Read more.
Background: Hepatic fibrosis is a major health problem all over the world, and there is no effective treatment to cure it. Hence, the current study sought to assess the anti-fibrotic efficacy of apigenin against CCl4-induced hepatic fibrosis in mice. Methods: Forty-eight mice were put into six groups. G1: Normal Control, G2: CCl4 Control, G3: Silymarin (100 mg/kg), G4 and G5: Apigenin (2 &20 mg/Kg), G6: Apigenin alone (20 mg/Kg). Groups 2, 3, 4, and 5 were given CCl4 (0.5 mL/kg. i.p.) twice/week for six weeks. The level of AST, ALT, TC, TG, and TB in serum and IL-1β, IL-6, and TNF-α in tissue homogenates were assessed. Histological studies by H&E staining and Immunostaining of liver tissues were also performed. Results: The CCl4-challenged group showed increased serum AST (4-fold), ALT (6-fold), and TB (5-fold). Both silymarin and apigenin treatments significantly improved these hepatic biomarkers. The CCl4-challenged group showed reduced levels of CAT (89%), GSH (53%), and increased MDA (3-fold). Both silymarin and apigenin treatments significantly altered these oxidative markers in tissue homogenates. The CCl4-treated group showed a two-fold increase in IL-1β, IL-6, and TNF-α levels. Silymarin and apigenin treatment considerably decreased the IL-1β, IL-6, and TNF-α levels. Apigenin treatment inhibited angiogenic activity, as evidenced by a decrease in VEGF (vascular endothelial growth factor) expression in liver tissues, and a decline in vascular endothelial cell antigen expression (CD34). Conclusions: Finally, these data collectively imply that apigenin may have antifibrotic properties, which may be explained by its anti-inflammatory, antioxidant, and antiangiogenic activities. Full article
(This article belongs to the Special Issue Liver Fibrosis: Molecular Mechanisms, Potential Therapeutic Targets and Clinical Biomarkers)
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14 pages, 26769 KiB  
Article
A Combination of an Angiotensin II Receptor and a Neprilysin Inhibitor Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation
by Junya Suzuki, Kosuke Kaji, Norihisa Nishimura, Takahiro Kubo, Fumimasa Tomooka, Akihiko Shibamoto, Satoshi Iwai, Yuki Tsuji, Yukihisa Fujinaga, Koh Kitagawa, Tadashi Namisaki, Takemi Akahane and Hitoshi Yoshiji
Biomedicines 2023, 11(5), 1295; https://doi.org/10.3390/biomedicines11051295 - 27 Apr 2023
Cited by 4 | Viewed by 1941
Abstract
The renin–angiotensin–aldosterone system has gained attention due to its role as a mediator of liver fibrosis and hepatic stellate cell (HSC) activation. Meanwhile, the natriuretic peptide (NP) system, including atrial NP (ANP) and C-type NP (CNP), is a counter-regulatory hormone regulated by neprilysin. [...] Read more.
The renin–angiotensin–aldosterone system has gained attention due to its role as a mediator of liver fibrosis and hepatic stellate cell (HSC) activation. Meanwhile, the natriuretic peptide (NP) system, including atrial NP (ANP) and C-type NP (CNP), is a counter-regulatory hormone regulated by neprilysin. Although the combination of an angiotensin receptor and a neprilysin inhibitor (sacubitril/valsartan: SAC/VAL) has shown clinical efficacy in patients with heart failure, its potential effects on hepatic fibrosis have not been clarified. This study assessed the effects of SAC/VAL in carbon tetrachloride (CCl4)-induced murine liver fibrosis as well as the in vitro phenotypes of HSCs. Treatment with SAC and VAL markedly attenuated CCl4-induced liver fibrosis while reducing α-SMA+-HSC expansion and decreasing hepatic hydroxyproline and mRNA levels of pro-fibrogenic markers. Treatment with SAC increased plasma ANP and CNP levels in CCl4-treated mice, and ANP effectively suppressed cell proliferation and TGF-β-stimulated MMP2 and TIMP2 expression in LX-2 cells by activating guanylate cyclase-A/cGMP/protein kinase G signaling. Meanwhile, CNP did not affect the pro-fibrogenic activity of LX-2 cells. Moreover, VAL directly inhibited angiotensin II (AT-II)-stimulated cell proliferation and the expression of TIMP1 and CTGF through the blockade of the AT-II type 1 receptor/protein kinase C pathway. Collectively, SAC/VAL may be a novel therapeutic treatment for liver fibrosis. Full article
(This article belongs to the Special Issue Liver Fibrosis: Molecular Mechanisms, Potential Therapeutic Targets and Clinical Biomarkers)
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17 pages, 2257 KiB  
Article
Development of the Rabbit NASH Model Resembling Human NASH and Atherosclerosis
by Momoko Hayashi, Yoshibumi Kuwabara, Kuniji Ito, Yoshiaki Hojo, Fumiaki Arai, Kazuki Kamijima, Masakazu Takeiri, Xiaojing Wang, Pan Diao, Jun Nakayama and Naoki Tanaka
Biomedicines 2023, 11(2), 384; https://doi.org/10.3390/biomedicines11020384 - 27 Jan 2023
Cited by 5 | Viewed by 2483
Abstract
Non-alcoholic steatohepatitis (NASH) is a chronic liver disease which may progress into liver fibrosis and cancer. Since NASH patients have a high prevalence of atherosclerosis and ensuing cardiovascular diseases, simultaneous management of NASH and atherosclerosis is required. Currently, rodents are the most common [...] Read more.
Non-alcoholic steatohepatitis (NASH) is a chronic liver disease which may progress into liver fibrosis and cancer. Since NASH patients have a high prevalence of atherosclerosis and ensuing cardiovascular diseases, simultaneous management of NASH and atherosclerosis is required. Currently, rodents are the most common animal models for NASH and accompanying liver fibrosis, but there are great differences in lipoprotein profiles between rodents and humans, which makes it difficult to reproduce the pathology of NASH patients with atherosclerosis. Rabbits can be a promising candidate for assessing NASH and atherosclerosis because lipoprotein metabolism is more similar to humans compared with rodents. To develop the NASH model using rabbits, we treated the Japanese White rabbit with a newly developed high-fat high-cholesterol diet (HFHCD) containing palm oil 7.5%, cholesterol 0.5%, and ferrous citrate 0.5% for 16 weeks. HFHCD-fed rabbits exhibited NASH at 8 weeks after commencing the treatment and developed advanced fibrosis by the 14th week of treatment. In addition to hypercholesterolemia, atherosclerotic lesion developed in the aorta after 8 weeks. Therefore, this rabbit NASH model might contribute to exploring the concurrent treatment options for human NASH and atherosclerosis. Full article
(This article belongs to the Special Issue Liver Fibrosis: Molecular Mechanisms, Potential Therapeutic Targets and Clinical Biomarkers)
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12 pages, 2465 KiB  
Article
Higher Responsiveness for Women, High Transaminase Levels, and Fat Percentage to Pemafibrate Treatment for NAFLD
by Takanobu Iwadare, Takefumi Kimura, Hideo Kunimoto, Naoki Tanaka, Shun-ichi Wakabayashi, Tomoo Yamazaki, Taiki Okumura, Hiroyuki Kobayashi, Yuki Yamashita, Ayumi Sugiura, Satoru Joshita and Takeji Umemura
Biomedicines 2022, 10(11), 2806; https://doi.org/10.3390/biomedicines10112806 - 4 Nov 2022
Cited by 4 | Viewed by 2229
Abstract
Aim: Pemafibrate (PEM) is a novel selective peroxisome proliferator-activated receptor alpha modulator that is effective for hypertriglyceridemia accompanying non-alcoholic fatty liver disease (HTG-NAFLD). This study aimed to identify the predictors of PEM efficacy for HTG-NAFLD in clinical practice. Methods: We retrospectively enrolled 88 [...] Read more.
Aim: Pemafibrate (PEM) is a novel selective peroxisome proliferator-activated receptor alpha modulator that is effective for hypertriglyceridemia accompanying non-alcoholic fatty liver disease (HTG-NAFLD). This study aimed to identify the predictors of PEM efficacy for HTG-NAFLD in clinical practice. Methods: We retrospectively enrolled 88 HTG-NAFLD patients treated with PEM for 6 months for the analysis of routine blood and body composition testing. A PEM response was defined as a decrease in serum alanine aminotransferase (ALT) of >30% compared with pre-treatment level. The clinical features related to PEM responsiveness were statistically tested between responders and non-responders. Results: All 88 patients completed the 6 month drug regimen without any adverse effects. PEM treatment significantly decreased liver enzymes, triglycerides, and total cholesterol levels, without any detectable impact on body weight or body composition. Comparisons of baseline clinical features revealed female and greater aspartate aminotransferase (AST), ALT, and fat mass % levels to be significantly associated with a PEM response. The optimal cut-off values to predict responders as determined by receiver operating characteristic analysis were AST 45 U/L, ALT 60 U/L, and fat mass 37%. Conclusions: Female HTG-NAFLD patients with higher transaminase and fat mass % levels may be preferentially indicated for PEM treatment. Additional large-scale prospective studies are warranted to verify our results. Full article
(This article belongs to the Special Issue Liver Fibrosis: Molecular Mechanisms, Potential Therapeutic Targets and Clinical Biomarkers)
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18 pages, 4791 KiB  
Article
Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice
by Zhe Zhang, Pan Diao, Xuguang Zhang, Takero Nakajima, Takefumi Kimura and Naoki Tanaka
Biomedicines 2022, 10(7), 1667; https://doi.org/10.3390/biomedicines10071667 - 11 Jul 2022
Cited by 11 | Viewed by 2923
Abstract
Pemafibrate (PEM) is a novel lipid-lowering drug classified as a selective peroxisome proliferator-activated receptor α (PPARα) modulator whose binding efficiency to PPARα is superior to that of fibrates. This agent is also useful for non-alcoholic fatty liver disease and primary biliary cholangitis with [...] Read more.
Pemafibrate (PEM) is a novel lipid-lowering drug classified as a selective peroxisome proliferator-activated receptor α (PPARα) modulator whose binding efficiency to PPARα is superior to that of fibrates. This agent is also useful for non-alcoholic fatty liver disease and primary biliary cholangitis with dyslipidemia. The dose of PEM used in some previous mouse experiments is often much higher than the clinical dose in humans; however, the precise mechanism of reduced serum triglyceride (TG) for the clinical dose of PEM has not been fully evaluated. To address this issue, PEM at a clinically relevant dose (0.1 mg/kg/day) or relatively high dose (0.3 mg/kg/day) was administered to male C57BL/6J mice for 14 days. Clinical dose PEM sufficiently lowered circulating TG levels without apparent hepatotoxicity in mice, likely due to hepatic PPARα stimulation and the enhancement of fatty acid uptake and β-oxidation. Interestingly, PPARα was activated only in the liver by PEM and not in other tissues. The clinical dose of PEM also increased serum/hepatic fibroblast growth factor 21 (FGF21) without enhancing hepatic lipid peroxide 4-hydroxynonenal or inflammatory signaling. In conclusion, a clinically relevant dose of PEM in mice efficiently and safely reduced serum TG and increased FGF21 targeting hepatic PPARα. These findings may help explain the multiple beneficial effects of PEM observed in the clinical setting. Full article
(This article belongs to the Special Issue Liver Fibrosis: Molecular Mechanisms, Potential Therapeutic Targets and Clinical Biomarkers)
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12 pages, 1667 KiB  
Article
A Unique Immune-Related Gene Signature Represents Advanced Liver Fibrosis and Reveals Potential Therapeutic Targets
by Pil-Soo Sung, Chang-Min Kim, Jung-Hoon Cha, Jin-Young Park, Yun-Suk Yu, Hee-Jung Wang, Jin-Kyeoung Kim and Si-Hyun Bae
Biomedicines 2022, 10(1), 180; https://doi.org/10.3390/biomedicines10010180 - 16 Jan 2022
Cited by 6 | Viewed by 3392
Abstract
Innate and adaptive immune responses are critically associated with the progression of fibrosis in chronic liver diseases. In this study, we aim to identify a unique immune-related gene signature representing advanced liver fibrosis and to reveal potential therapeutic targets. Seventy-seven snap-frozen liver tissues [...] Read more.
Innate and adaptive immune responses are critically associated with the progression of fibrosis in chronic liver diseases. In this study, we aim to identify a unique immune-related gene signature representing advanced liver fibrosis and to reveal potential therapeutic targets. Seventy-seven snap-frozen liver tissues with various chronic liver diseases at different fibrosis stages (1: n = 12, 2: n = 12, 3: n = 25, 4: n = 28) were subjected to expression analyses. Gene expression analysis was performed using the nCounter PanCancer Immune Profiling Panel (NanoString Technologies, Seattle, WA, USA). Biological meta-analysis was performed using the CBS Probe PINGSTM (CbsBioscience, Daejeon, Korea). Using non-tumor tissues from surgically resected specimens, we identified the immune-related, five-gene signature (CHIT1_FCER1G_OSM_VEGFA_ZAP70) that reliably differentiated patients with low- (F1 and F2) and high-grade fibrosis (F3 and F4; accuracy = 94.8%, specificity = 91.7%, sensitivity = 96.23%). The signature was independent of all pathological and clinical features and was independently associated with high-grade fibrosis using multivariate analysis. Among these genes, the expression of inflammation-associated FCER1G, OSM, VEGFA, and ZAP70 was lower in high-grade fibrosis than in low-grade fibrosis, whereas CHIT1 expression, which is associated with fibrogenic activity of macrophages, was higher in high-grade fibrosis. Meta-analysis revealed that STAT3, a potential druggable target, highly interacts with the five-gene signature. Overall, we identified an immune gene signature that reliably predicts advanced fibrosis in chronic liver disease. This signature revealed potential immune therapeutic targets to ameliorate liver fibrosis. Full article
(This article belongs to the Special Issue Liver Fibrosis: Molecular Mechanisms, Potential Therapeutic Targets and Clinical Biomarkers)
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Review

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13 pages, 1463 KiB  
Review
Significance of Diabetic Kidney Disease Biomarkers in Predicting Metabolic-Associated Fatty Liver Disease
by Jaehyun Bae and Byung-Wan Lee
Biomedicines 2023, 11(7), 1928; https://doi.org/10.3390/biomedicines11071928 - 7 Jul 2023
Cited by 3 | Viewed by 1788
Abstract
Metabolic-associated fatty liver disease (MAFLD) and diabetic kidney disease (DKD) share various pathophysiological factors, and epidemiological evidence suggests that these two diseases are associated. Albuminuria and the estimated glomerular filtration rate, which are conventional biomarkers of DKD, are reportedly associated with the risk [...] Read more.
Metabolic-associated fatty liver disease (MAFLD) and diabetic kidney disease (DKD) share various pathophysiological factors, and epidemiological evidence suggests that these two diseases are associated. Albuminuria and the estimated glomerular filtration rate, which are conventional biomarkers of DKD, are reportedly associated with the risk or severity of MAFLD. Recently, novel DKD biomarkers reflecting renal tubular injury have been introduced to complement conventional DKD markers. In this article, we looked at previous studies that showed an association between MAFLD and DKD, and also reviewed the significance of DKD biomarkers as predictive risk factors for MAFLD. Full article
(This article belongs to the Special Issue Liver Fibrosis: Molecular Mechanisms, Potential Therapeutic Targets and Clinical Biomarkers)
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18 pages, 832 KiB  
Review
The Important Roles of Natural Killer Cells in Liver Fibrosis
by Ming Yang, Ethan Vanderwert, Eric T. Kimchi, Kevin F. Staveley-O’Carroll and Guangfu Li
Biomedicines 2023, 11(5), 1391; https://doi.org/10.3390/biomedicines11051391 - 8 May 2023
Cited by 7 | Viewed by 3355
Abstract
Liver fibrosis accompanies the development of various chronic liver diseases and promotes their progression. It is characterized by the abnormal accumulation of extracellular matrix proteins (ECM) and impaired ECM degradation. Activated hepatic stellate cells (HSCs) are the major cellular source of ECM-producing myofibroblasts. [...] Read more.
Liver fibrosis accompanies the development of various chronic liver diseases and promotes their progression. It is characterized by the abnormal accumulation of extracellular matrix proteins (ECM) and impaired ECM degradation. Activated hepatic stellate cells (HSCs) are the major cellular source of ECM-producing myofibroblasts. If liver fibrosis is uncontrolled, it may lead to cirrhosis and even liver cancer, primarily hepatocellular carcinoma (HCC). Natural killer (NK) cells are a key component of innate immunity and have miscellaneous roles in liver health and disease. Accumulating evidence shows that NK cells play dual roles in the development and progression of liver fibrosis, including profibrotic and anti-fibrotic functions. Regulating NK cells can suppress the activation of HSCs and improve their cytotoxicity against activated HSCs or myofibroblasts to reverse liver fibrosis. Cells such as regulatory T cells (Tregs) and molecules such as prostaglandin E receptor 3 (EP3) can regulate the cytotoxic function of NK cells. In addition, treatments such as alcohol dehydrogenase 3 (ADH3) inhibitors, microRNAs, natural killer group 2, member D (NKG2D) activators, and natural products can enhance NK cell function to inhibit liver fibrosis. In this review, we summarized the cellular and molecular factors that affect the interaction of NK cells with HSCs, as well as the treatments that regulate NK cell function against liver fibrosis. Despite a lot of information about NK cells and their interaction with HSCs, our current knowledge is still insufficient to explain the complex crosstalk between these cells and hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, B cells, and T cells, as well as thrombocytes, regarding the development and progression of liver fibrosis. Full article
(This article belongs to the Special Issue Liver Fibrosis: Molecular Mechanisms, Potential Therapeutic Targets and Clinical Biomarkers)
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