Liver inflammation and fibrosis

Koyama, Yukinori; Brenner, David A.

doi:10.1172/jci88881

Cited by 947 publications

(849 citation statements)

References 155 publications

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“…Consistent with above observation, we have found that Hsf1 303A/307A mice exhibit high levels of expression of specific Hsps (and likely other genes) in the liver, kidney, spleen and heart tissues and at least as we present in the liver tissue, this is associated with increased levels of CD11b and phosphorylated c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinases (ERK) signaling and an increased expression of transcription factors associated with lipogenesis. This phenotype is a hallmark of low, but sustained levels of inflammation that is observed following alterations in the liver metabolism induced by a variety of conditions that eventually can lead to fatty liver disease and hepatocellular carcinoma (47,48). Contrary to the mutant Hsf1 303A/307A mice that exhibit increased activity that leads to an age-dependent metabolic syndrome, the whole body deletion of hsf1 are resistant to multiple tumor types (3,7,49).…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Abrogation of heat shock factor 1 (Hsf1) phosphorylation deregulates its activity and lowers activation threshold, leading to obesity in mice

et al. 2017

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Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Abrogation of heat shock factor 1 (Hsf1) phosphorylation deregulates its activity and lowers activation threshold, leading to obesity in mice

et al. 2017

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“…Similarly, obesity has been associated with the presence of other immune cells in liver, including T cells and neutrophils. Yukinori Koyama and David Brenner discuss the close connection between obesity, diabetes, hepatic inflammation, and the development of nonalcoholic fatty liver disease (NAFLD), which can progress to nonalcoholic steatohepatitis (NASH) and eventually frank cirrhosis due to sequential activation of inflammation and fibrosis (10).…”

Section: Mechanisms Of Inflammation-induced Insulin Resistancementioning

confidence: 99%

Inflammatory mechanisms linking obesity and metabolic disease

Saltiel¹,

Olefsky²

2017

Journal of Clinical Investigation

1,542

1,077

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We are in the midst of a worldwide obesity epidemic. Over 1.9 billion people are now obese or overweight, including more than 50 million children under age 5, and the worldwide prevalence of obesity has doubled since 1980 (1). The complications of obesity are taking a major public health toll, which will only worsen in future years. Among the most devastating of these complications is type 2 diabetes (T2D). Most patients with T2D are obese or overweight, and there are numerous longitudinal studies linking obesity with insulin resistance, a frequent forerunner of diabetes.Over the past two decades, the search for a mechanism linking the pathogenesis of obesity with insulin resistance and diabetes has revealed a close relationship between nutrient excess and activation of the innate immune system in most organs pertinent to energy homeostasis (2-4). Numerous studies indicate that inflammation occurs as a consequence of obesity, and recent insights suggest that it may play a causative role in generating insulin resistance, defective insulin secretion, and disruption of other aspects of energy homeostasis. The nature of obesityinduced inflammation differs from other inflammatory paradigms in that it involves tonic activation of the innate immune system that impacts metabolic homeostasis, in some cases over a lifetime. Inflammation also leads to maladaptive responses such as fibrosis and necrosis that can cause significant tissue damage. Moreover, obesity-induced inflammation is unique in that it involves multiple organs, including adipose, pancreas, liver, skeletal muscle, heart, and brain. These features of obesity-induced inflammation present a challenge to understanding the underlying mechanisms and the manner by which they impact metabolic systems. In this issue of the JCI, a group of experts have provided reviews that dive deeply into the mechanisms by which obesity-induced inflammation influences metabolic homeostasis, surveying the modes and mechanisms of inflammation in different tissues and how they might contribute to disease. These Reviews also discuss how inflammation can lead to other aspects of metabolic syndrome, including hyperphagia, reduced energy expenditure, β cell dysfunction, and liver disease, and summarize the status of therapeutic interventions that target inflammation in the context of metabolic syndrome. Activation of the innate immune system in obesityMuch of what has been learned about the immune response to obesity has come from studies in adipose tissue, although it is clear that inflammation occurs in other organs as well. Adipose depots normally contain multiple immune cells that together surveil and maintain the integrity and hormonal sensitivity of adipocytes. In lean animals, these immune cells operate in an overall Th2 or type 2 state that coordinately controls tissue integrity and metabolism by controlling the activity of subsets of T lymphocytes. These cells release a cascade of cytokines that coordinately regulate other immune cells, including eosinophils, mast cells, and othe...

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“…Liver damage causes inflammation, which accelerates fibrosis by releasing HSCstimulating cytokines [30][31][32]. Based on the severe hepatic injury with inflammation in the livers of the PbA-injected mice in this study, we evaluated whether PbA infection promotes liver fibrosis.…”

Section: Hepatic Fibrosis Is Enhanced In the Livers Of Pba-infected Micementioning

confidence: 99%

Blood-Stage Plasmodium Berghei ANKA Infection Promotes Hepatic Fibrosis by Enhancing Hedgehog Signaling in Mice

Kim

Wang

Lee

et al. 2018

Cell Physiol Biochem

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Background/Aims: Malaria is the most deadly parasitic infection in the world, resulting in damage to various organs, including the liver, of the infected organism; however, the mechanism causing this damage in the liver remains unclear. Liver fibrosis, a major characteristic of liver diseases, occurs in response to liver injury and is regulated by a complex network of signaling pathways. Hedgehog (Hh) signaling orchestrates a number of hepatic responses including hepatic fibrogenesis. Therefore, we investigated whether Hh signaling influenced the liver’s response to malarial infection. Methods: Eight-week-old male C57BL/6 mice inoculated with blood containing Plasmodium berghei ANKA (PbA)-infected erythrocytes were sacrificed when the level of parasitemia in the blood reached 10% or 30%, and the livers were collected for biochemical analysis. Liver responses to PbA infection were examined by hematoxylin and eosin staining, real-time polymerase chain reaction, immunohistochemistry and western blot. Results: Severe hepatic injury, such as ballooned hepatocytes, sinusoidal dilatation, and infiltrated leukocytes, was evident in the livers of the malaria-infected mice. Hypoxia was also induced in 30% parasitemia group. With the accumulation of Kupffer cells, inflammation markers, TNF-α, interleukin-1β, and chemokine (C-X-C motif) ligand 1, were significantly upregulated in the infected group compared with the control group. Expression of fibrotic markers, including transforming growth factor-β, α-smooth muscle actin (α-SMA), collagen 1a1, thymosin β4, and vimentin, were significantly higher in the infected groups than in the control group. With increased collagen deposition, hepatic stellate cells expressing α-SMA accumulated in the liver of the PbA-infected mice, whereas those cells were rarely detected in the livers of the control mice. The levels of Hh signaling and Yes-associated protein (YAP), two key regulators for hepatic fibrogenesis, were significantly elevated in the infected groups compared with the control group. Treatment of mice with Hh inhibitor, GDC-0449, reduced hepatic inflammation and fibrogenesis with Hh suppression in PbA-infected mice. Conclusion: Our results demonstrate that HSCs are activated in and Hh and YAP signaling are associated with this process, contributing to increased hepatic fibrosis in malaria-infected livers.

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Liver inflammation and fibrosis

Cited by 947 publications

References 155 publications

WITHDRAWN: Abrogation of heat shock factor 1 (Hsf1) phosphorylation deregulates its activity and lowers activation threshold, leading to obesity in mice

WITHDRAWN: Abrogation of heat shock factor 1 (Hsf1) phosphorylation deregulates its activity and lowers activation threshold, leading to obesity in mice

Inflammatory mechanisms linking obesity and metabolic disease

Blood-Stage Plasmodium Berghei ANKA Infection Promotes Hepatic Fibrosis by Enhancing Hedgehog Signaling in Mice

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