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Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 30131

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Prof. Dr. Rolf Teschke

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Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Goethe University, 999035 Frankfurt, Germany
Interests: Heavy metals; Heavy metal uptake; Heavy metal disposition, Heavy metal homeostasis; Haber Weiss reaction; Fenton reaction; Benefits and risks for human health; Environmental pollution
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Dear Colleagues,

Liver injury by potentially toxic exogenous and endogenous compounds presents major molecular, mechanistic, and medical challenges. Among the hepatotoxic exogenous compounds are conventional drugs, herbal drugs including various traditional herbal products and so-called herbal supplements lacking supplementary features in patients with a normal balanced diet, alcoholic beverages, industrial chemicals such as aliphatic halogenated hydrocarbons (e.g., carbon tetrachloride), environmental chemicals such as heavy metals, nature-based products, and compounds ingested with some fungi. Liver injury caused by endogenous hepatotoxic compounds is the main focus of this special issue. Endogenous hepatotoxic compounds are found in individuals suffering from hereditary diseases such as hemochromatosis caused by iron overload, Wilson disease due to copper overload, Gaucher disease caused by the accumulation of glucocerebroside, hepatic porphyria due to metabolic problems of heme synthesis, and a vast range of other hereditary diseases. Finally, much interest has focused more recently on molecular, mechanistic, and clinical aspects in overweight patients with nonalcoholic fatty liver disease and progression to nonalcoholic steatonecrosis (NASH) and nonalcoholic liver cirrhosis, including rare hepatocellular carcinoma.

We welcome submissions to the International Journal of Molecular Sciences (IF 5.923) which focus on molecular, mechanistic, and medical challenges; purely clinical papers are discouraged.

Prof. Dr. Rolf Teschke
Guest Editor

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Keywords

Liver injury
molecular
nonalcoholic fatty liver disease
nonalcoholic steatonecrosis
nonalcoholic liver cirrhosis
hepatocellular carcinoma

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Research

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17 pages, 1903 KiB

Open AccessArticle

Metabolomic Analysis of Pediatric Patients with Idiosyncratic Drug-Induced Liver Injury According to the Updated RUCAM

by Francisco Andújar-Vera, María Luisa Alés-Palmer, Paloma Muñoz-de-Rueda, Iván Iglesias-Baena and Esther Ocete-Hita

Int. J. Mol. Sci. 2023, 24(17), 13562; https://doi.org/10.3390/ijms241713562 - 1 Sep 2023

Cited by 3 | Viewed by 1284

Abstract

Hepatotoxicity, a common adverse drug effect, has been extensively studied in adult patients. However, it is equally important to investigate this condition in pediatric patients to develop personalized treatment strategies for children. This study aimed to identify plasma biomarkers that characterize hepatotoxicity in pediatric patients through an observational case–control study. Metabolomic analysis was conducted on 55 pediatric patients with xenobiotic liver toxicity and 88 healthy controls. The results revealed clear differences between the two groups. Several metabolites, including hydroxydecanoylcarnitine, octanoylcarnitine, lysophosphatidylcholine, glycocholic acid, and taurocholic acid, were identified as potential biomarkers (area under the curve: 0.817; 95% confidence interval: 0.696–0.913). Pathway analysis indicated involvement of primary bile acid biosynthesis and the metabolism of taurine and hypotaurine (p < 0.05). The findings from untargeted metabolomic analysis demonstrated an increase in bile acids in children with hepatotoxicity. The accumulation of cytotoxic bile acids should be further investigated to elucidate the role of these metabolites in drug-induced liver injury. Full article

(This article belongs to the Special Issue Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges 2.0)

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19 pages, 9202 KiB

Open AccessArticle

Deficiency of S100A9 Alleviates Sepsis-Induced Acute Liver Injury through Regulating AKT-AMPK-Dependent Mitochondrial Energy Metabolism

by Yanting Zhang, Feng Wu, Fei Teng, Shubin Guo and Huihua Li

Int. J. Mol. Sci. 2023, 24(3), 2112; https://doi.org/10.3390/ijms24032112 - 20 Jan 2023

Cited by 19 | Viewed by 3523

Abstract

Acute liver injury (ALI) is recognized as a serious complication of sepsis in patients in intensive care units (ICUs). S100A8/A9 is known to promote inflammation and immune responses. However, the role of S100A8/A9 in the regulation of sepsis-induced ALI remains known. Our results indicated that S100A8/A9 expression was significantly upregulated in the livers of septic mice 24 h after cecal ligation and a puncture (CLP) operation. Moreover, S100A9-KO in mice markedly attenuated CLP-induced liver dysfunction and injury, promoting the AMPK/ACC/GLUT4-mediated increases in fatty acid and glucose uptake as well as the improvement in mitochondrial function and ATP production. In contrast, treatment with the AMPK inhibitor Compound C reversed the inhibitory effects of S100A9 KO on CLP-induced liver dysfunction and injury in vivo. Finally, the administration of the S100A9 inhibitor Paquinimod (Paq) to WT mice protected against CLP-induced mortality, liver injury and mitochondrial dysfunction. In summary, our findings demonstrate for the first time that S100A9 plays an important pro-inflammatory role in sepsis-mediated ALI by regulating AKT-AMPK-dependent mitochondrial energy metabolism and highlights that targeting S100A9 may be a promising new approach for the prevention and treatment of sepsis-related liver injury. Full article

(This article belongs to the Special Issue Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges 2.0)

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19 pages, 4866 KiB

Open AccessArticle

Hepatoprotective Effects of a Natural Flavanol 3,3′-Diindolylmethane against CCl₄-Induced Chronic Liver Injury in Mice and TGFβ1-Induced EMT in Mouse Hepatocytes via Activation of Nrf2 Cascade

by Suvesh Munakarmi, Yamuna Gurau, Juna Shrestha, Prabodh Risal, Ho Sung Park, Hyun Beak Shin and Yeon Jun Jeong

Int. J. Mol. Sci. 2022, 23(19), 11407; https://doi.org/10.3390/ijms231911407 - 27 Sep 2022

Cited by 10 | Viewed by 2998

Abstract

Hepatic fibrosis is a form of irregular wound-healing response with acute and chronic injury triggered by the deposition of excessive extracellular matrix. Epithelial–mesenchymal transition (EMT) is a dynamic process that plays a crucial role in the fibrogenic response and pathogenesis of liver fibrosis. In the present study, we postulated a protective role of 3,3′-diindolylmethane (DIM) against TGF-β1 mediated epithelial–mesenchymal transition (EMT) in vitro and carbon tetrachloride (CCl4)-induced liver fibrosis in mice. TGF-β1-induced AML-12 hepatocyte injury was evaluated by monitoring cell morphology, measuring reactive oxygen species (ROS) and mitochondrial membrane potential, and quantifying apoptosis, inflammatory, and EMT-related proteins. Furthermore, CCl4-induced liver fibrosis in mice was evaluated by performing liver function tests, including serum ALT and AST, total bilirubin, and albumin to assess liver injury and by performing H&E and Sirius red staining to determine the degree of liver fibrosis. Immunoblotting was performed to determine the expression levels of inflammation, apoptosis, and Nrf2/HO-1 signaling-related proteins. DIM treatment significantly restored TGF-β1-induced morphological changes, inhibited the expression of mesenchymal markers by activating E-cadherin, decreased mitochondrial membrane potential, reduced ROS intensity, and upregulated levels of Nrf2-responsive antioxidant genes. In the mouse model of CCl4-induced liver fibrosis, DIM remarkably attenuated liver injury and liver fibrosis, as reflected by the reduced ALT and AST parameters with increased serum Alb activity and fewer lesions in H&E staining. It also mitigated the fibrosis area in Sirius red and Masson staining. Taken together, our results suggest a possible molecular mechanism of DIM by suppressing TGF-β1-induced EMT in mouse hepatocytes and CCl4-induced liver fibrosis in mice. Full article

(This article belongs to the Special Issue Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges 2.0)

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12 pages, 1691 KiB

Open AccessArticle

Diclofenac-Induced Cytotoxicity in Direct and Indirect Co-Culture of HepG2 Cells with Differentiated THP-1 Cells

by Atsushi Kawase, Ouka Takashima, Satsuki Tanaka, Hiroaki Shimada and Masahiro Iwaki

Int. J. Mol. Sci. 2022, 23(15), 8660; https://doi.org/10.3390/ijms23158660 - 4 Aug 2022

Cited by 4 | Viewed by 2573

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (DIC) frequently induce drug-induced liver injury (DILI). It is unclear whether macrophages such as M1 and M2 participate in NSAID-associated DILI; elucidating this relationship could lead to a better understanding of the detailed mechanism of DILI. We co-cultured human hepatoma HepG2 cells with M1 or M2 derived from human monocytic leukemia THP-1 cells to examine the roles of M1 and M2 in DIC-induced cytotoxicity. DIC was added to the direct or indirect co-cultures of HepG2 cells with M1 or M2 (HepG2/M1 or HepG2/M2, respectively) at cell ratios of (1:0, 1:0.1, 1:0.4, and 1:1). In both direct and indirect HepG2/M2 co-cultures (1:0.4), there was lower lactate dehydrogenase release compared with HepG2/M1 co-cultures. Other NSAIDs as well as DIC showed similar protective effects of DIC-induced cytotoxicity. There were only slight differences in mRNA levels of apoptosis- and endoplasmic reticulum stress-associated factors between M1 and M2 after DIC treatment, suggesting that other factors determined the protective effects of M2 on DIC-induced cytotoxicity. Levels of high mobility group box 1 (HMGB1) in the medium and the mRNA expression levels of HMGB1 receptors were different between M1 and M2 after DIC treatment. Increased HMGB1 concentrations and expression of toll-like receptor 2 mRNA in M1 were observed compared with M2 after DIC treatment. In conclusion, these results suggested that the HMGB1/TLR2 signaling axis can be suppressed in M2 but not M1, leading to the different roles of M1 and M2 in NSAID-induced cytotoxicity. Full article

(This article belongs to the Special Issue Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges 2.0)

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15 pages, 11544 KiB

Open AccessArticle

RIPK1 in Liver Parenchymal Cells Limits Murine Hepatitis during Acute CCl₄-Induced Liver Injury

by Huma Hameed, Muhammad Farooq, Céline Vuillier, Claire Piquet-Pellorce, Annaïg Hamon, Marie-Thérèse Dimanche-Boitrel, Michel Samson and Jacques Le Seyec

Int. J. Mol. Sci. 2022, 23(13), 7367; https://doi.org/10.3390/ijms23137367 - 1 Jul 2022

Cited by 2 | Viewed by 2376

Abstract

Some life-threatening acute hepatitis originates from drug-induced liver injury (DILI). Carbon tetrachloride (CCl₄)-induced acute liver injury in mice is the widely used model of choice to study acute DILI, which pathogenesis involves a complex interplay of oxidative stress, necrosis, and apoptosis. Since the receptor interacting protein kinase-1 (RIPK1) is able to direct cell fate towards survival or death, it may potentially affect the pathological process of xenobiotic-induced liver damage. Two different mouse lines, either deficient for Ripk1 specifically in liver parenchymal cells (Ripk1^LPC-KO) or for the kinase activity of RIPK1 (Ripk1^K45A, kinase dead), plus their respective wild-type littermates (Ripk1^fl/fl, Ripk1^wt/wt), were exposed to single toxic doses of CCl₄. This exposure led in similar injury in Ripk1^K45A mice and their littermate controls. However, Ripk1^LPC-KO mice developed more severe symptoms with massive hepatocyte apoptosis as compared to their littermate controls. A pretreatment with a TNF-α receptor decoy exacerbated liver apoptosis in both Ripk1^fl/fl and Ripk1^LPC-KO mice. Besides, a FasL antagonist promoted hepatocyte apoptosis in Ripk1^fl/fl mice but reduced it in Ripk1^LPC-KO mice. Thus, the scaffolding properties of RIPK1 protect hepatocytes from apoptosis during CCl₄ intoxication. TNF-α and FasL emerged as factors promoting hepatocyte survival. These protective effects appeared to be independent of RIPK1, at least in part, for TNF-α, but dependent on RIPK1 for FasL. These new data complete the deciphering of the molecular mechanisms involved in DILI in the context of research on their prevention or cure. Full article

(This article belongs to the Special Issue Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges 2.0)

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12 pages, 1584 KiB

Open AccessArticle

Stereoselective Covalent Adduct Formation of Acyl Glucuronide Metabolite of Nonsteroidal Anti-Inflammatory Drugs with UDP-Glucuronosyltransferase

by Atsushi Kawase, Rio Yamashita, Tsubasa Yoshizato, Mashiro Yoshikawa, Hiroaki Shimada and Masahiro Iwaki

Int. J. Mol. Sci. 2022, 23(9), 4724; https://doi.org/10.3390/ijms23094724 - 25 Apr 2022

Cited by 2 | Viewed by 2455

Abstract

A reactive metabolite of nonsteroidal anti-inflammatory drugs (NSAIDs), acyl-β-D-glucuronide (AG), covalently binds to endogenous proteins. The covalent adduct formation of NSAIDs-AG may lead to the dysfunction of target proteins. Therefore, it is important to clarify the detailed characterization of the formation of covalent protein adducts of NSAID-AG. UDP-glucuronosyltransferase (UGT) catalyzes the conversion of NSAIDs to NSAIDs-AG. The aim of this study was to perform a quantitative analysis of the covalent adduct formation of NSAIDs-AG with UGT. Diclofenac-AG and ketoprofen-AG formed covalent adducts with organelle proteins. Next, the number of covalent adducts formed between NSAIDs-AG and UGT isoforms (UGT1A1, UGT1A9, UGT2B4, and UGT2B9) was determined. The capacity of diclofenac-AG to form covalent adducts with UGT1A9 or UGT2B7 was approximately 10 times higher than that of mefenamic acid-AG. The amounts of covalent adducts of AG of propionic acid derivative NSAIDs with UGT2B were higher than those with UGT1A. Stereoselectivity was observed upon covalent binding to UGT. A significant negative correlation between the half-lives of NSAIDs-AG in phosphate buffers and the amount of covalent adduct with UGT2B7 was observed, suggesting the more labile NSAID-AG forms higher irreversible bindings to UGT. This report provides comprehensive information on the covalent adduct formation of NSAIDs-AGs with UGT. Full article

(This article belongs to the Special Issue Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges 2.0)

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Review

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25 pages, 3360 KiB

Open AccessReview

Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis

by Giovanni Vitale, Alessandro Mattiaccio, Amalia Conti, Sonia Berardi, Vittoria Vero, Laura Turco, Marco Seri and Maria Cristina Morelli

Int. J. Mol. Sci. 2023, 24(6), 5823; https://doi.org/10.3390/ijms24065823 - 18 Mar 2023

Cited by 9 | Viewed by 3422

Abstract

Idiosyncratic Drug-Induced Liver Injury (iDILI) represents an actual health challenge, accounting for more than 40% of hepatitis cases in adults over 50 years and more than 50% of acute fulminant hepatic failure cases. In addition, approximately 30% of iDILI are cholestatic (drug-induced cholestasis (DIC)). The liver’s metabolism and clearance of lipophilic drugs depend on their emission into the bile. Therefore, many medications cause cholestasis through their interaction with hepatic transporters. The main canalicular efflux transport proteins include: 1. the bile salt export pump (BSEP) protein (ABCB11); 2. the multidrug resistance protein-2 (MRP2, ABCC2) regulating the bile salts’ independent flow by excretion of glutathione; 3. the multidrug resistance-1 protein (MDR1, ABCB1) that transports organic cations; 4. the multidrug resistance-3 protein (MDR3, ABCB4). Two of the most known proteins involved in bile acids’ (BAs) metabolism and transport are BSEP and MDR3. BSEP inhibition by drugs leads to reduced BAs’ secretion and their retention within hepatocytes, exiting in cholestasis, while mutations in the ABCB4 gene expose the biliary epithelium to the injurious detergent actions of BAs, thus increasing susceptibility to DIC. Herein, we review the leading molecular pathways behind the DIC, the links with the other clinical forms of familial intrahepatic cholestasis, and, finally, the main cholestasis-inducing drugs. Full article

(This article belongs to the Special Issue Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges 2.0)

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13 pages, 1368 KiB

Open AccessReview

Microbiota–Liver Diseases Interactions

by Rosanna Capparelli, Paola Cuomo, Antonio Gentile and Domenico Iannelli

Int. J. Mol. Sci. 2023, 24(4), 3883; https://doi.org/10.3390/ijms24043883 - 15 Feb 2023

Cited by 9 | Viewed by 2498

Abstract

Gut microbiota regulates essential processes of host metabolism and physiology: synthesis of vitamins, digestion of foods non-digestible by the host (such as fibers), and—most important—protects the digestive tract from pathogens. In this study, we focus on the CRISPR/Cas9 technology, which is extensively used to correct multiple diseases, including liver diseases. Then, we discuss the non-alcoholic fatty liver disease (NAFLD), affecting more than 25% of the global population; colorectal cancer (CRC) is second in mortality. We give space to rarely discussed topics, such as pathobionts and multiple mutations. Pathobionts help to understand the origin and complexity of the microbiota. Since several types of cancers have as target the gut, it is vital extending the research of multiple mutations to the type of cancers affecting the gut–liver axis. Full article

(This article belongs to the Special Issue Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges 2.0)

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38 pages, 3599 KiB

Open AccessReview

Targeted Therapies for Hepatocellular Carcinoma Treatment: A New Era Ahead—A Systematic Review

by Christos Damaskos, Nikolaos Garmpis, Dimitrios Dimitroulis, Anna Garmpi, Iason Psilopatis, Panagiotis Sarantis, Evangelos Koustas, Prodromos Kanavidis, Dionysios Prevezanos, Gregory Kouraklis, Michail V. Karamouzis, Georgios Marinos, Konstantinos Kontzoglou and Efstathios A. Antoniou

Int. J. Mol. Sci. 2022, 23(22), 14117; https://doi.org/10.3390/ijms232214117 - 15 Nov 2022

Cited by 10 | Viewed by 3936

Abstract

Hepatocellular carcinoma (HCC) remains one of the most common malignancies and the third cause of cancer-related death worldwide, with surgery being the best prognostic tool. Among the well-known causative factors of HCC are chronic liver virus infections, chronic virus hepatitis B (HBV) and chronic hepatitis virus C (HCV), aflatoxins, tobacco consumption, and non-alcoholic liver disease (NAFLD). There is a need for the development of efficient molecular markers and alternative therapeutic targets of great significance. In this review, we describe the general characteristics of HCC and present a variety of targeted therapies that resulted in progress in HCC therapy. Full article

(This article belongs to the Special Issue Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges 2.0)

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21 pages, 969 KiB

Open AccessReview

The Role of Sex in Acute and Chronic Liver Damage

by Katia Sayaf, Daniela Gabbia, Francesco Paolo Russo and Sara De Martin

Int. J. Mol. Sci. 2022, 23(18), 10654; https://doi.org/10.3390/ijms231810654 - 13 Sep 2022

Cited by 23 | Viewed by 3898

Abstract

Acute and chronic hepatic damages are caused by xenobiotics or different diseases affecting the liver, characterized by different etiologies and pathological features. It has been demonstrated extensively that liver damage progresses differently in men and women, and some chronic liver diseases show a more favorable prognosis in women than in men. This review aims to update the most recent advances in the comprehension of the molecular basis of the sex difference observed in both acute and chronic liver damage. With this purpose, we report experimental studies on animal models and clinical observations investigating both acute liver failure, e.g., drug-induced liver injury (DILI), and chronic liver diseases, e.g., viral hepatitis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), autoimmune liver diseases, and hepatocellular carcinoma (HCC). Full article

(This article belongs to the Special Issue Toxic Liver Injury: Molecular, Mechanistic, and Medical Challenges 2.0)

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