Animal models of chronic liver diseases

Liu, Yan; Meyer, Christoph; Xu, Chengfu; Weng, Honglei; Hellerbrand, Claus; Dijke, Peter ten; Dooley, Steven

doi:10.1152/ajpgi.00199.2012

Cited by 201 publications

(162 citation statements)

References 224 publications

(227 reference statements)

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“…To date, several reviews describing animal models for fibrosis induction have been published. 4,8,[19][20][21] In this review, we recapitulate their findings regarding metalloproteinases of MMP and ADAM families on the background of function of various liver cell types.…”

Section: Liver Models Animal Models Of Liver Fibrosismentioning

confidence: 99%

Metalloproteinases in liver fibrosis: current insights

Zbodakova¹,

Chalupský²,

Turečková³

et al. 2017

MNM

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Liver fibrosis is defined by excessive deposition of extracellular matrix. The fibrotic conditions result from the imbalance between synthesis and deposition of fibrous tissues and decomposition of these matrix proteins. This process can be reversed as a regular part of the healing process after hepatic damage or can become chronic. When the protein matrix synthesis predominates and the decomposition is suppressed, fibrosis will progress into irreversible cirrhosis or steatosis. Among the molecular players involved in fibrotic liver diseases, metalloproteinases of matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase (ADAM) families are critical in the development of liver fibrosis and its resolution. Previously, MMPs were recognized as extracellular matrix degrading enzymes. Currently, they are also known as mediators in a variety of processes related to immunity and tissue repair. In this article, we have reviewed the models of liver fibrosis and findings on MMPs and ADAMs in hepatic fibrosis conditions.

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Section: Liver Models Animal Models Of Liver Fibrosismentioning

confidence: 99%

Metalloproteinases in liver fibrosis: current insights

Zbodakova¹,

Chalupský²,

Turečková³

et al. 2017

MNM

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“…The MCD diet is the most commonly used murine dietary model for acquired NASH, since in contrast to other models, it allows examination of all stages of NASH (i.e., inflammation, oxidative stress, and fibrogenic changes) [20] . Our data implicate p62 as a modulator of endogenous cholesterol synthesis leading to elevated levels of free cholesterol in the liver, ultimately promoting inflammation via the activation of nuclear factor kappa B (NF-κB).…”

Section: Introductionmentioning

confidence: 99%

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

Simon

Kessler

Gemperlein

et al. 2014

WJG

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AIM:To characterize how insulin-like growth factor 2 (IGF2 ) mRNA binding protein p62/IMP2-2 promotes steatohepatitis in the absence of dietary cholesterol. METHODS:Non-alcoholic steatohepatitis (NASH) was induced in wild-type mice and in mice overexpressing p62 specifically in the liver by feeding the mice a methionine and choline deficient (MCD) diet for either two or four weeks. As a control, animals were fed a methionine and choline supplemented diet. Serum triglycerides, cholesterol, glucose, aspartate aminotransferase and alanine transaminase were determined by standard analytical techniques. Hepatic gene expression was determined by real-time reverse transcription-polymerase chain reaction. Generation of reactive oxygen species in liver tissue was quantified as thiobarbituric acid reactive substances using a photometric assay and malondialdehyde as a standard. Tissue fatty acid profiles and cholesterol levels were analyzed by gas chromatographymass spectrometry after hydrolysis. Hepatocellular iron accumulation was determined by Prussian blue staining in paraffin-embedded formalin-fixed tissue. Filipin staining on frozen liver tissue was used to quantify hepatic free cholesterol levels. Additionally, nuclear localization of the nuclear factor kappa B (NF-κB) subunit p65 was examined in frozen tissues. RESULTS:Liver-specific overexpression of the insulin-like growth factor 2 mRNA binding protein 2-2 (IGF2BP2-2/IMP2-2/p62) induces steatosis with regular chow and amplifies NASH-induced fibrosis in the MCD mouse model. Activation of NF-κB and expression of NF-κB target genes suggested an increased inflammatory response in p62 transgenic animals. Analysis of hepatic lipid composition revealed an elevation of monounsaturated fatty acids as well as increased hepatic cholesterol. Moreover, serum cholesterol was significantly elevated in p62 transgenic mice. Dietary cholesterol represents a critical factor for the development of NASH from hepatic steatosis. Filipin staining revealed increased free cholesterol in p62 transgenic livers, which were not diet-derived. The mRNA levels of the rate-limiting enzyme for cholesterol synthesis 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase or HMGCR) were not significantly upregulated, potentially due to increased cholesterol biosynthesis via elevated sterol regulatory element binding transcription factor 2 (SREBF2 ) gene expression and increased iron deposition in transgenic animals. CONCLUSION:This study provides evidence that p62/IGF2BP2-2 drives the progression of NASH through elevation of hepatic iron deposition and increased production of hepatic free cholesterol.

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“…Animal models of chronic liver injury with fibrosis partially recapitulate the human condition, but may fail to provide robust human translation due to species differences in metabolism, injury response, and capacity/mechanisms of repair and regeneration (Liu et al, 2013). Cell culture has been used as a surrogate to dissect the mechanistic details underlying HC dysfunction and fibrogenic outcome; however, conventional two-dimensional (2D), cell-based hepatic model systems do not reliably recapitulate liver structure, function, and its inherent multicellular architecture (LeCluyse et al, 2012).…”

mentioning

confidence: 99%

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

et al. 2016

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Compound-induced liver injury leading to fibrosis remains a challenge for the development of an Adverse Outcome Pathway useful for human risk assessment. Latency to detection and lack of early, systematically detectable biomarkers make it difficult to characterize the dynamic and complex intercellular interactions that occur during progressive liver injury. Here, we demonstrate the utility of bioprinted tissue constructs comprising primary hepatocytes, hepatic stellate cells, and endothelial cells to model methotrexate-and thioacetamide-induced liver injury leading to fibrosis. Repeated, low-concentration exposure to these compounds enabled the detection and differentiation of multiple modes of liver injury, including hepatocellular damage, and progressive fibrogenesis characterized by the deposition and accumulation of fibrillar collagens in patterns analogous to those described in clinical samples obtained from patients with fibrotic liver injury. Transient cytokine production and upregulation of fibrosis-associated genes ACTA2 and COL1A1 mimics hallmark features of a classic wound-healing response. A surge in proinflammatory cytokines (eg, IL-8, IL-1b) during the early culture time period is followed by concentration-and treatment-dependent alterations in immunomodulatory and chemotactic cytokines such as IL-13, IL-6, and MCP-1. These combined data provide strong proof-of-concept that 3D bioprinted liver tissues can recapitulate drug-, chemical-, and TGF-b1-induced fibrogenesis at the cellular, molecular, and histological levels and underscore the value of the model for further exploration of compound-specific fibrogenic responses. This novel system will enable a more comprehensive characterization of key attributes unique to fibrogenic agents during the onset and progression of liver injury as well as mechanistic insights, thus improving compound risk assessment.Key words: liver fibrosis in vitro; 3D bioprinted liver; compound-induced liver injury.Chronic liver injury progressing to fibrosis and liver failure can result from a wide range of insults including drug or chemical exposure, metabolic disease, alcoholism, or viral infection, and is a major health burden worldwide with 2% of all deaths attributable to liver cirrhosis Murray et al., 2012). Whereas the major precipitating factors underlying drug-and chemicalinduced fibrosis have been gleaned from animal models, the key initiating and series of adaptive events that perpetuate this response, especially in humans, are still not well understood. Regardless of etiology, progressive fibrotic liver injury is

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Animal models of chronic liver diseases

Cited by 201 publications

References 224 publications

Metalloproteinases in liver fibrosis: current insights

Metalloproteinases in liver fibrosis: current insights

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

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