Of Mice and Men and Nonalcoholic Steatohepatitis

Brenner, David A.

doi:10.1002/hep.30186

Cited by 12 publications

(13 citation statements)

References 9 publications

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“…Despite significant progress in our understanding of the molecular pathways driving liver fibrosis in rodent models, a lack of corollary studies in diseased human liver tissue has hindered translation into effective therapies, with currently no FDA or EMAapproved anti-fibrotic treatments available. Our multi-lineage ligand-receptor analysis demonstrates the complexity of interactions within the fibrotic niche, highlighting why current approaches to treat human liver fibrosis have proven so intractable, and provides a conceptual framework for more rational studies of anti-fibrotic therapies in both preclinical animal models and translational systems such as human liver organoid cultures 5,70,71 . Further, this unbiased multi-lineage approach should inform the design of combination therapies which will very likely be necessary to achieve effective antifibrotic potency 5,6 .…”

Section: Discussionmentioning

confidence: 99%

Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics

Ramachandran

Dobie

Wilson-Kanamori

et al. 2019

Preprint

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Currently there are no effective antifibrotic therapies for liver cirrhosis, a major killer worldwide. To obtain a cellular resolution of directly-relevant pathogenesis and to inform therapeutic design, we profile the transcriptomes of over 100,000 primary human single cells, yielding molecular definitions for the major non-parenchymal cell types present in healthy and cirrhotic human liver. We uncover a novel scar-associated TREM2 + CD9 + macrophage subpopulation with a fibrogenic phenotype, that has a distinct differentiation trajectory from circulating monocytes. In the endothelial compartment, we show that newly-defined ACKR1 + and PLVAP + endothelial cells expand in cirrhosis and are topographically located in the fibrotic septae. Multi-lineage ligand-receptor modelling of specific interactions between the novel scar-associated macrophages, endothelial cells and collagen-producing myofibroblasts in the fibrotic niche, reveals intra-scar activity of several major pathways which promote hepatic fibrosis. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides the conceptual framework required to discover rational therapeutic targets in liver cirrhosis. MainLiver cirrhosis is a major global healthcare burden. Recent estimates suggest that 844 million people worldwide have chronic liver disease, with a mortality rate of two million deaths per year and a rising incidence 1 . In health, the liver serves a myriad of functions including detoxification, metabolism, bile production and immune surveillance. Chronic liver disease, the result of iterative liver injury secondary to any cause, results in progressive fibrosis, disrupted hepatic architecture, vascular changes and aberrant regeneration, defining characteristics of liver cirrhosis 2 . Importantly, the degree of liver fibrosis predicts adverse patient outcomes, including the development of cirrhosis-related complications, hepatocellular carcinoma and death 3 . Hence, there is a clear therapeutic imperative to develop effective anti-fibrotic approaches for patients with chronic liver disease 4-7 .Liver fibrosis involves a complex, orchestrated interplay between multiple nonparenchymal cell (NPC) lineages including immune, endothelial and mesenchymal cells spatially located within areas of scarring, termed the fibrotic niche. Despite rapid progress in our understanding of the cellular interactions underlying liver fibrogenesis accrued using rodent models, there remains a significant 'translational gap' between putative targets and effective patient therapies 4,5 . This is in part due to the very limited definition of the functional heterogeneity and interactome of cell lineages that contribute to the fibrotic niche of human liver cirrhosis, which is imperfectly recapitulated by rodent models 4,6 .Single-cell RNA sequencing (scRNA-seq) has the potential to deliver a step change in both our understanding of healthy tissue homeostasis as well as disease pathogenesis, allowing the interr...

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Section: Discussionmentioning

confidence: 99%

Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics

Ramachandran

Dobie

Wilson-Kanamori

et al. 2019

Preprint

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“…(3,4) Despite considerable progress in our understanding of the pathogenesis of NASH, the critical factors that drive the progression of simple steatosis to NASH remain largely unknown, and existing animal models fail to reflect the full spectrum of NAFLD progression. (5)(6)(7) For example, although chronic feeding of a high-fat diet (HFD) leads to obesity and insulin resistance in mice, two crucial risk factors for NASH, (8) it only mimics the gene expression profile and histopathology of simple steatosis but not those of NASH. (5,6) A key feature of human NASH is a robust infiltration of neutrophils in the liver, which is not significantly observed in fatty livers in individuals with obesity or in HFD-fed mice.…”

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confidence: 99%

Interleukin‐22 Ameliorates Neutrophil‐Driven Nonalcoholic Steatohepatitis Through Multiple Targets

et al. 2020

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Background and Aims Nonalcoholic fatty liver disease encompasses a spectrum of diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. At present, how simple steatosis progresses to NASH remains obscure and effective pharmacological therapies are lacking. Hepatic expression of C‐X‐C motif chemokine ligand 1 (CXCL1), a key chemokine for neutrophil infiltration (a hallmark of NASH), is highly elevated in NASH patients but not in fatty livers in obese individuals or in high‐fat diet (HFD)‐fed mice. The aim of this study was to test whether overexpression of CXCL1 itself in the liver can induce NASH in HFD‐fed mice and to test the therapeutic potential of IL‐22 in this new NASH model. Approach and Results Overexpression of Cxcl1 in the liver alone promotes steatosis‐to‐NASH progression in HFD‐fed mice by inducing neutrophil infiltration, oxidative stress, and stress kinase (such as apoptosis signal‐regulating kinase 1 and p38 mitogen‐activated protein kinase) activation. Myeloid cell‐specific deletion of the neutrophil cytosolic factor 1 (Ncf1)/p47phox gene, which encodes a component of the NADPH oxidase 2 complex that mediates neutrophil oxidative burst, markedly reduced CXCL1‐induced NASH and stress kinase activation in HFD‐fed mice. Treatment with interleukin (IL)‐22, a cytokine with multiple targets, ameliorated CXCL1/HFD‐induced NASH or methionine‐choline deficient diet‐induced NASH in mice. Mechanistically, IL‐22 blocked hepatic oxidative stress and its associated stress kinases via the induction of metallothionein, one of the most potent antioxidant proteins. Moreover, although it does not target immune cells, IL‐22 treatment attenuated the inflammatory functions of hepatocyte‐derived, mitochondrial DNA‐enriched extracellular vesicles, thereby suppressing liver inflammation in NASH. Conclusions Hepatic overexpression of CXCL1 is sufficient to drive steatosis‐to‐NASH progression in HFD‐fed mice through neutrophil‐derived reactive oxygen species and activation of stress kinases, which can be reversed by IL‐22 treatment via the induction of metallothionein.

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“…To systemically evaluate the role of SHP-1 in NASH, we used the MCD diet-induced NASH model in vivo in our study. Unlike HFD, MCD diet led to severe liver injury in mice that was histologically similar to human NASH, whereas without weight gain or overt IR [16,28]. This allows for the evaluation the role of SHP-1 on NASH independently from its effects on IR.…”

Section: Discussionmentioning

confidence: 99%

“…Most surprisingly, despite more extensive hepatic steatosis, the inflammatory profiles of the HFD-fed Ptpn6 HKO livers were similar or even improved as compared to their littermates. It should be noted that they used the HFD-induced NAFLD model, which frequently lead to nonalcoholic fatty liver (NAFL) in mice, but without much inflammation or fibrosis [16]. Thus, to extensively elucidate the role of SHP-1 in the progression of NASH, we fed the mice with methionine-and cholinedeficient (MCD) diet, which had been proven to be a useful experimental model for NASH [17].…”

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confidence: 99%

SHP‐1 ameliorates nonalcoholic steatohepatitis by inhibiting proinflammatory cytokine production

et al. 2020

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Inflammation is the main contributor for the pathogenesis of nonalcoholic steatohepatitis (NASH). Src homology region 2 domain‐containing phosphatase 1 (SHP‐1, also known as PTPN6) is regarded as a negative regulator of inflammation, but its role in NASH remains unknown. Here, hepatocyte‐specific Ptpn6 knockout mice (Ptpn6HKO) and adenovirus vector‐mediated ectopic expression of SHP‐1 (AdSHP1) were used to evaluate the role of SHP‐1 in a methionine‐ and choline‐deficient diet‐induced NASH model. Compared with the control littermates, Ptpn6HKO mice show exacerbated hepatic steatosis, inflammation, and fibrosis. Additionally, administration of AdSHP1 significantly ameliorates steatohepatitis and inhibits the expression of proinflammatory cytokines, including transforming growth factor‐β, interleukin‐6, and tumor necrosis factor‐α. Our data indicate that SHP‐1 could be a potential therapeutic target for NASH.

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Of Mice and Men and Nonalcoholic Steatohepatitis

Cited by 12 publications

References 9 publications

Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics

Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics

Interleukin‐22 Ameliorates Neutrophil‐Driven Nonalcoholic Steatohepatitis Through Multiple Targets

SHP‐1 ameliorates nonalcoholic steatohepatitis by inhibiting proinflammatory cytokine production

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