Kupffer cells: increasingly significant role in nonalcoholic fatty liver disease

Zhang, Wenfeng; Wu, Yuzhang; Mu, Di; Gong, Jianping; Wu, Chuan-Xin; Huang, Chun Chih

doi:10.1016/s1665-2681(19)31247-5

Cited by 88 publications

(76 citation statements)

References 72 publications

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“…KCs, the resident macrophages in liver tissue, are first triggered and initiated an innate immune response [4–5]. Additionally, the innate function of KCs such as phagocytosis and autophagy, are impaired by FFA [15, 27].…”

Section: Discussionmentioning

confidence: 99%

Foxo3a-dependent Bim transcription protects mice from a high fat diet via inhibition of activation of the NLRP3 inflammasome by facilitating autophagy flux in Kupffer cells

Liu

Zhang

et al. 2017

Oncotarget

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BackgroundThe role of Foxo3a in the regulation of autophagy flux and activation of the NLRP3 inflammasome in KCs suffering from HFD conditions is unknown.ResultsUp-regulation of Foxo3a restored autophagy flux and dampened the activation of the NLRP3 inflammasome in KCs stimulated with PA and LPS. In contrast, down-regulation of Foxo3a increased blockage of autophagy flux and promoted NLRP3 inflammasome activation. Additionally, mRNA levels of Bim were significantly changed with the alteration of Foxo3a in KCs under PA and LPS stimulation among foxo3a targeted genes. Overexpression of Bim restored autophagy influx and attenuated NLRP3 inflammasome pathway activation. In addition, autophagy formation was restored, and activation of NLRP3 inflammasome was inhibited in KCs isolated from mice treated with Iturin A and fed with a HFD.Materials and methodsAutophagy flux in KCs and activation levels of NLRP3 inflammasome were evaluated after altering the expression of Foxo3a in KCs before stimulation with PA and LPS. Additionally, various target genes of Foxo3a were measured in KCs pretreated with an agonist (Iturin A) or inhibitor (SC97) of Foxo3a after KCs stimulation with PA and LPS in order to hunt for targets of Foxo3a. Activation levels of NLRP3 inflammasome in isolated KCs, as well as autophagy flux, were measured after mice were treated with Iturin A and fed with a HFD for 16 weeks.ConclusionsFoxo3a restores autophagy flux and attenuates the activation of the NLRP3 inflammasome by promoting the transcription of Bim, suggesting a potential therapeutic target in NAFLD and other obesity-related diseases.

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Section: Discussionmentioning

confidence: 99%

Foxo3a-dependent Bim transcription protects mice from a high fat diet via inhibition of activation of the NLRP3 inflammasome by facilitating autophagy flux in Kupffer cells

Liu

Zhang

et al. 2017

Oncotarget

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“…UPR activation in the liver has been extensively studied in light of the increasing prevalence of (NAFLD), which is the leading cause of non-alcoholic and non-viral liver-associated illness and death in the United States 154 . Hepatic steatosis, which is the mildest form of NAFLD, can progress to non-alcoholic steatohepatitis (NASH) through a process that involves free fatty acid and lipid accumulation in hepatocytes followed by a series of innate immune responses in leukocytes, including in liver-resident macrophages that are known as Kupffer cells 155 . It has been shown that ER stress can induce liver steatosis through effects on lipid synthesis and inflammation, but high-fat feeding-induced steatosis itself can also trigger ER stress, thereby providing a positive feedback loop that amplifies liver inflammation and injury 156 .…”

Section: The Pathological Upr In Inflammatory Diseasementioning

confidence: 99%

The unfolded protein response in immunity and inflammation

et al. 2016

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The unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation. In this Review, we discuss the importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune response. In addition, we review current insights into how the UPR is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour responses.

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“…Macrophage-mediated inflammation in NASH is associated with toll-like receptor (TLR) activation; this is particularly true for TLR4 [65]. During liver injury, macrophages release proinflammatory cytokines such as IL-1 β , TNF α , and IL-6 through the activation of TLR4 [66].…”

Section: Inflammatory Mediators and Immune Alterationsmentioning

confidence: 99%

Pathogenesis of Nonalcoholic Steatohepatitis: Interactions between Liver Parenchymal and Nonparenchymal Cells

Magee

Zou

Zhang

2016

BioMed Research International

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Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in the Western countries, affecting up to 25% of the general population and becoming a major health concern in both adults and children. NAFLD encompasses the entire spectrum of fatty liver disease in individuals without significant alcohol consumption, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is a manifestation of the metabolic syndrome and hepatic disorders with the presence of steatosis, hepatocyte injury (ballooning), inflammation, and, in some patients, progressive fibrosis leading to cirrhosis. The pathogenesis of NASH is a complex process and implicates cell interactions between liver parenchymal and nonparenchymal cells as well as crosstalk between various immune cell populations in liver. Lipotoxicity appears to be the central driver of hepatic cellular injury via oxidative stress and endoplasmic reticulum (ER) stress. This review focuses on the contributions of hepatocytes and nonparenchymal cells to NASH, assessing their potential applications to the development of novel therapeutic agents. Currently, there are limited pharmacological treatments for NASH; therefore, an increased understanding of NASH pathogenesis is pertinent to improve disease interventions in the future.

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Kupffer cells: increasingly significant role in nonalcoholic fatty liver disease

Cited by 88 publications

References 72 publications

Foxo3a-dependent Bim transcription protects mice from a high fat diet via inhibition of activation of the NLRP3 inflammasome by facilitating autophagy flux in Kupffer cells

Foxo3a-dependent Bim transcription protects mice from a high fat diet via inhibition of activation of the NLRP3 inflammasome by facilitating autophagy flux in Kupffer cells

The unfolded protein response in immunity and inflammation

Pathogenesis of Nonalcoholic Steatohepatitis: Interactions between Liver Parenchymal and Nonparenchymal Cells

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