Macrophage p38α promotes nutritional steatohepatitis through M1 polarization

Zhang, Xiang; Fan, Li; Wu, Jianfeng; Xu, Hui; Leung, Wing Yan; Fu, Kaili; Wu, Jingtong; Liu, Ken; Man, Kwan; Yang, Xiaoyong; Han, Jiahuai; Ren, Jianlin; Yu, Jun

doi:10.1016/j.jhep.2019.03.014

Cited by 135 publications

(112 citation statements)

References 31 publications

(44 reference statements)

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“…Zhang et al recently reported that the deletion of hepatocyte p38a exacerbated steatosis in HFD‐fed mice. ( 16 ) Surprisingly, in their study, WT and p38a Hep‐/‐ mice gained 7 to 11 g body weight after 12‐week HFD feeding, which is much lower than the typical body weight gain (~20 g) after 12‐week HFD feeding, as observed in our study. Moreover, Zhang et al reported that p38a Hep‐/‐ mice gained much more body weight than WT mice (11 versus 7 g) after 12‐week HFD feeding.…”

Section: Discussioncontrasting

confidence: 88%

“…( 15 ) With regard to lipid metabolism, a recent study demonstrated that liver‐specific p38α knockout mice were more susceptible to HFD‐induced obesity and steatosis accompanied by reduced fatty acid (FA) β‐oxidation. ( 16 ) FA β‐oxidation is mainly controlled by peroxisome proliferator‐activated receptor alpha (PPARα), a ligand‐activated transcription factor that is highly expressed in the liver where FA is actively oxidized. ( 17,18 ) PPARα activity is known to be controlled by many factors and signaling pathways, including p38α, which has been shown to phosphorylate and activate PPARα in cardiac myocytes.…”

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confidence: 99%

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Protective and Detrimental Roles of p38α Mitogen‐Activated Protein Kinase in Different Stages of Nonalcoholic Fatty Liver Disease

et al. 2020

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Background and Aims Neutrophil infiltration is a hallmark of nonalcoholic steatohepatitis (NASH), but how this occurs during the progression from steatosis to NASH remains obscure. Human NASH features hepatic neutrophil infiltration and up‐regulation of major neutrophil‐recruiting chemokines (e.g., chemokine [C‐X‐C motif] ligand 1 [CXCL1] and interleukin [IL]‐8). However, mice fed a high‐fat diet (HFD) only develop fatty liver without significant neutrophil infiltration or elevation of chemokines. The aim of this study was to determine why mice are resistant to NASH development and the involvement of p38 mitogen‐activated protein kinase (p38) activated by neutrophil‐derived oxidative stress in the pathogenesis of NASH. Approach and Results Inflamed human hepatocytes attracted neutrophils more effectively than inflamed mouse hepatocytes because of the greater induction of CXCL1 and IL‐8 in human hepatocytes. Hepatic overexpression of Cxcl1 and/or IL‐8 promoted steatosis‐to‐NASH progression in HFD‐fed mice by inducing liver inflammation, injury, and p38 activation. Pharmacological inhibition of p38α/β or hepatocyte‐specific deletion of p38a (a predominant form in the liver) attenuated liver injury and fibrosis in the HFD+Cxcl1‐induced NASH model that is associated with strong hepatic p38α activation. In contrast, hepatocyte‐specific deletion of p38a in HFD‐induced fatty liver where p38α activation is relatively weak exacerbated steatosis and liver injury. Mechanistically, weak p38α activation in fatty liver up‐regulated the genes involved in fatty acid β‐oxidation through peroxisome proliferator‐activated receptor alpha phosphorylation, thereby reducing steatosis. Conversely, strong p38α activation in NASH promoted caspase‐3 cleavage, CCAAT‐enhancer‐binding proteins homologous protein expression, and B cell lymphoma 2 phosphorylation, thereby exacerbating hepatocyte death. Conclusions Genetic ablation of hepatic p38a increases simple steatosis but ameliorates oxidative stress‐driven NASH, indicating that p38α plays distinct roles depending on the disease stages, which may set the stage for investigating p38α as a therapeutic target for the treatment of NASH.

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Section: Discussioncontrasting

confidence: 88%

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confidence: 99%

Protective and Detrimental Roles of p38α Mitogen‐Activated Protein Kinase in Different Stages of Nonalcoholic Fatty Liver Disease

et al. 2020

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Section: Introductionmentioning

confidence: 99%

“…Nonalcoholic fatty liver disease (NAFLD) has recently emerged as a significantly public health issue because of its high prevalence (1)(2)(3). NAFLD is characterized by a wide spectrum of liver phenotypes ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) (1)(2)(3). The most important clinical challenge in NASH is the progression to liver fibrogenesis, which may gradually develop to cirrhosis and eventually to hepatocellular carcinoma (HCC) (1)(2)(3).…”

Section: Introductionmentioning

confidence: 99%

“…NAFLD is characterized by a wide spectrum of liver phenotypes ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) (1)(2)(3). The most important clinical challenge in NASH is the progression to liver fibrogenesis, which may gradually develop to cirrhosis and eventually to hepatocellular carcinoma (HCC) (1)(2)(3). However, the molecular mechanisms underlying NAFLD onset and progression remain poorly understood, and there is currently no approved pharmacological therapy for NASH and fibrosis (1,2).…”

Section: Introductionmentioning

confidence: 99%

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Myricetin Modulates Macrophage Polarization and Mitigates Liver Inflammation and Fibrosis in a Murine Model of Nonalcoholic Steatohepatitis

Yao

et al. 2020

Front. Med.

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This study aimed to investigate the beneficial effects of myricetin in a diet-induced nonalcoholic steatohepatitis (NASH) model and the underlying mechanism. C57BL/6J mice were fed a standard chow or the choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 8 weeks with the treatment of myricetin (100 mg/kg) or vehicle by daily gavage. Hepatic inflammation, steatosis, fibrosis, and hepatic stellate cells (HSC) activation were assessed. We also analyzed M1 and M2 macrophages and its related markers in livers from NASH mice and in RAW264.7 macrophages stimulated by lipopolysaccharide (LPS) or interleukin 4 (IL-4) in vitro. Furthermore, we determined the effect of myricetin on the triggering receptor expressed on myeloid cells-1 (TREM-1), toll like receptor (TLR) 2 and 4, and myeloid differentiation factor 88 (MyD88) signaling both in livers from mice and in RAW264.7 cells stimulated by LPS. Our results revealed that myricetin remarkably ameliorated hepatic steatosis, inflammation, and inhibited hepatic macrophage infiltration in CDAHFD-fed mice. Myricetin-treated to CDAHFD-fed mice also inhibited liver fibrosis and HSC activation when compared with vehicle-treated to those mice. Moreover, myricetin inhibited M1 macrophage polarization and its relative markers in livers of NASH mice while induced M2 polarization. Similarly, in vitro study, myricetin inhibited the LPS-induced mRNA expression of M1 macrophages marker genes and induced IL-4-induced M2 macrophage marker genes in RAW264.7 macrophages. Mechanically, myricetin inhibited the expression of TREM-1 and TLR2/4-MyD88 signaling molecules in livers from NASH mice and in RAW264.7 macrophages stimulated by LPS in vitro. Additionally, myricetin inhibited the activation of nuclear factor (NF)-κB signaling and the phosphorylation of the signal transducer and activation of transcription 3 (STAT3) in LPS-stimulated RAW264.7 macrophages. Taken together, our data indicated that myricetin modulated the polarization of macrophages via inhibiting the TREM-1-TLR2/4-MyD88 signaling molecules in macrophages and therefore mitigated NASH and hepatic fibrosis in the CDAHFD-diet-induced NASH model in mice.

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The signaling pathways in obesity‐related complications

Chandrasekaran,

Weiskirchen

2024

Journal of Cell Communication and Signaling

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Obesity, a rapidly expanding epidemic worldwide, is known to exacerbate many medical conditions, making it a significant factor in multiple diseases and their associated complications. This threatening epidemic is linked to various harmful conditions such as type 2 diabetes mellitus, hypertension, metabolic dysfunction‐associated steatotic liver disease, polycystic ovary syndrome, cardiovascular diseases (CVDs), dyslipidemia, and cancer. The rise in urbanization and sedentary lifestyles creates an environment that fosters obesity, leading to both psychosocial and medical complications. To identify individuals at risk and ensure timely treatment, it is crucial to have a better understanding of the pathophysiology of obesity and its comorbidities. This comprehensive review highlights the relationship between obesity and obesity‐associated complications, including type 2 diabetes, hypertension, (CVDs), dyslipidemia, polycystic ovary syndrome, metabolic dysfunction‐associated steatotic liver disease, gastrointestinal complications, and obstructive sleep apnea. It also explores the potential mechanisms underlying these associations. A thorough analysis of the interplay between obesity and its associated complications is vital in developing effective therapeutic strategies to combat the exponential increase in global obesity rates and mitigate the deadly consequences of this polygenic condition.

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Macrophage p38α promotes nutritional steatohepatitis through M1 polarization

Cited by 135 publications

References 31 publications

Protective and Detrimental Roles of p38α Mitogen‐Activated Protein Kinase in Different Stages of Nonalcoholic Fatty Liver Disease

Protective and Detrimental Roles of p38α Mitogen‐Activated Protein Kinase in Different Stages of Nonalcoholic Fatty Liver Disease

Myricetin Modulates Macrophage Polarization and Mitigates Liver Inflammation and Fibrosis in a Murine Model of Nonalcoholic Steatohepatitis

The signaling pathways in obesity‐related complications

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