A researcher’s guide to preclinical mouse NASH models

Gallage, Suchira; Avila, Jose Efren Barragan; Ramadori, Pierluigi; Focaccia, Enrico; Rahbari, Mohammad; Ali, Adnan; Malek, Nisar P.; Anstee, Quentin M.; Heikenwälder, M

doi:10.1038/s42255-022-00700-y

Cited by 91 publications

(62 citation statements)

References 140 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In 2-month-old C57BL/6J mice, steatohepatitis was induced by 4-week administration of a diet poor in methionine (reduced by 66% compared to standard diet), deficient in choline, and fat-rich (46% kcal from fat), called MCDHFD [ 12 , 13 ]. Although mouse models of NASH, whether they are dietary, genetic, or toxin based, resemble many features of human NASH, none mimics the human state completely; for instance, while hepatic ballooning is a common occurrence in human NAFLD/NASH, it rarely occurs in mice [ 14 ]. MCDHFD induces NAFLD and NASH in male C57BL6/J mice in an accelerated manner compared with the Western diet and the choline-deficient models and does not cause significant weight loss like a classical methionine–choline-deficient diet [ 15 ].…”

Section: Methodsmentioning

confidence: 99%

Low-Dose Acetylsalicylic Acid and Mitochondria-Targeted Antioxidant Mitoquinone Attenuate Non-Alcoholic Steatohepatitis in Mice

et al. 2023

View full text Add to dashboard Cite

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. NAFLD can evolve from simple fatty liver to non-alcoholic steatohepatitis (NASH), and ultimately, to cirrhosis. Inflammation and oxidative stress, promoted by mitochondrial dysfunction, play a crucial role in the onset and development of NASH. To date, no therapy has been approved for NAFLD and NASH. The aim of this study is to evaluate if the anti-inflammatory activity of acetylsalicylic acid (ASA) and the mitochondria-targeted antioxidant effect of mitoquinone could hinder the progression of non-alcoholic steatohepatitis. In mice, fatty liver was induced through the administration of a deficient in methionine and choline and rich in fat diet. Two experimental groups were treated orally with ASA or mitoquinone. Histopathologic evaluation of steatosis and inflammation was performed; the hepatic expression of genes associated with inflammation, oxidative stress, and fibrosis was evaluated; the protein expression of IL-10, cyclooxygenase 2, superoxide dismutase 1, and glutathione peroxidase 1 in the liver was analyzed; a quantitative analysis of 15-epi-lipoxin A4 in liver homogenates was performed. Mitoquinone and ASA significantly reduced liver steatosis and inflammation by decreasing the expression of TNFα, IL-6, Serpinb3, and cyclooxygenase 1 and 2 and restoring the anti-inflammatory IL-10. Treatment with mitoquinone and ASA increased the gene and protein expression of antioxidants, i.e., catalase, superoxide dismutase 1, and glutathione peroxidase 1, and decreased the expression of profibrogenic genes. ASA normalized the levels of 15-epi-Lipoxin A4. In mice fed with a deficient in methionine and choline and rich in fat diet, mitoquinone and ASA reduce steatosis and necroinflammation and may represent two effective novel strategies for the treatment of non-alcoholic steatohepatitis.

show abstract

Section: Methodsmentioning

confidence: 99%

Low-Dose Acetylsalicylic Acid and Mitochondria-Targeted Antioxidant Mitoquinone Attenuate Non-Alcoholic Steatohepatitis in Mice

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Irrespective of the degree of brosis, Ex-BM CD34 + cell transplantation signi cantly diminished activated hepatic stellate cell level and inhibited collagen production, resulting in reduced liver brosis. CDAHFD60-fed mice are capable of rapidly developing brosis, leading to NASH with severe brosis even at 12 weeks (20,21). Here, we also evaluated a 20-week model of a more advanced brosis and found that Ex-BM CD34 + cell transplantation exerted an anti-brotic effect.…”

Section: Discussionmentioning

confidence: 73%

CD34+ cell transplantation alleviates fibrotic liver injury via innate immune modulation in non-alcoholic steatohepatitis mice

Masuda

Nakamura

Iwamoto

et al. 2023

Preprint

View full text Add to dashboard Cite

Background/purpose of the study: In drug-induced liver injury, vascular endothelial progenitor cells, specifically the CD34+ cell fractions, have been found to decrease liver fibrosis and promote regeneration. However, it is unclear whether CD34+ cell transplantation has anti-fibrogenic effects on NASH, which has been treated effectively with anti-angiogenic therapy. We investigated the efficacy of ex vivo-expanded CD34+ cells in treating NASH livers. Methods CD34+ cells were isolated from mice bone marrow and effectively expanded over 7 days. The mice were assigned to either a normal chow diet or a choline-deficient, L-amino acid-defined, high-fat diet, which was followed for 12 and 20 weeks to create a mild and severe fibrosis model, respectively. Results Expanded CD34+ cell transplantation ameliorated liver fibrosis, regardless of fibrosis degree, as indicated by the decrease in α-smooth muscle actin-positive cells, hydroxyproline concentration, and fibrogenic gene expression of Col1a1 and Timp1. Furthermore, engrafted CD34+ cells reduced alanine transaminase levels, the number of TUNEL+ hepatocytes, and 8-OHdG concentration. RNA-sequencing data showed that "defense response to virus" was the most down-regulated category in the Gene Ontology analysis and subsequent analysis revealed the suppression of RIG-I-like receptors/IRF7/STAT1/CXCL10 axis in expanded CD34+ cell-transplanted livers. Finally, the downregulation of CXCL10 expression inhibits the mobilization of inflammatory immune cells, macrophages, T cells, and natural killer cells to the NASH liver. Conclusions These findings suggest that transplanted expanded CD34+ cells alleviate fibrotic liver injury in NASH mouse models through possible modulation of the innate immune response, which is abnormally activated by hepatocyte lipotoxicity.

show abstract

“…9b,c). Because mice are inherently resistant to developing NASH on standard high-fat diets 37 , we used a diet high in fructose (17 kcal %), fat (mostly palm oil 40 kcal %), and cholesterol (2%) (HFHF-C) or a matched sucrose, high sugar (dextrose), low-fat (10 kcal % fat) control diet (HSLF) (Fig. 7).…”

Section: Resultsmentioning

confidence: 99%

Adipocyte lipin 1 is positively associated with metabolic health in humans and regulates systemic metabolism in mice

LaPoint

Singer

Ferguson

et al. 2023

Preprint

View full text Add to dashboard Cite

Dysfunctional adipose tissue is believed to promote the development of hepatic steatosis and systemic insulin resistance, but many of the mechanisms involved are still unclear. Lipin 1 catalyzes the conversion of phosphatidic acid to diacylglycerol (DAG), the penultimate step of triglyceride synthesis, which is essential for lipid storage. Herein we found that adipose tissue LPIN1 expression is decreased in people with obesity compared to lean subjects and low LPIN1 expression correlated with multi-tissue insulin resistance and increased rates of hepatic de novo lipogenesis. Comprehensive metabolic and multi-omic phenotyping demonstrated that adipocyte-specific Lpin1-/- mice had a metabolically-unhealthy phenotype, including liver and skeletal muscle insulin resistance, hepatic steatosis, increased hepatic de novo lipogenesis, and transcriptomic signatures of nonalcoholic steatohepatitis that was exacerbated by high-fat diets. We conclude that adipocyte lipin 1-mediated lipid storage is vital for preserving adipose tissue and systemic metabolic health and its loss predisposes mice to nonalcoholic steatohepatitis.

show abstract

A researcher’s guide to preclinical mouse NASH models

Cited by 91 publications

References 140 publications

Low-Dose Acetylsalicylic Acid and Mitochondria-Targeted Antioxidant Mitoquinone Attenuate Non-Alcoholic Steatohepatitis in Mice

Low-Dose Acetylsalicylic Acid and Mitochondria-Targeted Antioxidant Mitoquinone Attenuate Non-Alcoholic Steatohepatitis in Mice

CD34+ cell transplantation alleviates fibrotic liver injury via innate immune modulation in non-alcoholic steatohepatitis mice

Adipocyte lipin 1 is positively associated with metabolic health in humans and regulates systemic metabolism in mice

Contact Info

Product

Resources

About