Role of Mcpip1 in obesity‐induced hepatic steatosis as determined by myeloid and liver‐specific conditional knockouts

Pydyn, Natalia; Żurawek, Dariusz; Kozieł, Joanna; Kuś, Edyta; Wojnar-Lasoń, Kamila; Jasztal, Agnieszka; Fu, Mingui; Jura, Jolanta; Kotlinowski, Jerzy

doi:10.1111/febs.16040

Cited by 4 publications

(3 citation statements)

References 60 publications

(89 reference statements)

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“…To test this hypothesis in vivo , we induced Mcpip1 deletion in myeloid cells creating the Mcpip1 fl/fl LysM Cre mouse model. The Mcpip1 protein has established role in controlling the inflammatory state at both systemic and organ-specific levels 29,31,55 . Mcpip1 is an endonuclease that regulates inflammation by direct destabilization of mRNA transcripts encoding e.g.…”

Section: Discussionmentioning

confidence: 99%

“…IL-1β or IL-6 cytokines 29,56 , and by indirect reduction of TNFα levels 30,56 . Importantly, the Mcpip1 fl/fl LysM Cre mouse model has previously been used to investigate the role of sterile inflammation in different organs 55–57 . Here, we show that Mcpip1 fl/fl LysM Cre mouse model effectively mimics sterile liver inflammation and LSEC dysfunction offering a tool for searching new anti- inflammatory therapeutic strategies for the liver.…”

Section: Discussionmentioning

confidence: 99%

“…IL-1β or IL-6 cytokines 29,56 , and by indirect reduction of TNFα levels 30,56 . Importantly, the Mcpip1 fl/fl LysM Cre mouse model has previously been used to investigate the role of sterile inflammation in different organs [55][56][57] . Here, In this work, we asked the question whether there is a biological target other than the regulation of systemic inflammation whose modulation might contribute to the reduction of symptoms of liver inflammation.…”

Section: These Findings Highlightmentioning

confidence: 99%

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Diosmetin alleviates liver inflammation by improving liver sinusoidal endothelial cell dysfunction

Żurawek,

Pydyn,

Major

et al. 2023

Preprint

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Background & Aims: Tumor necrosis factor-alpha (TNFalpha) induces pro-inflammatory activation in liver sinusoidal endothelial cells (LSEC) and liver inflammation. However, knowledge about whether modulating LSEC activation can alleviate liver inflammation is scarce. This study aimed to establish and validate an animal model mimicking LSEC dysfunction observed in patients with elevated plasma levels of TNFalpha, and explore whether vasoactive flavonoid diosmetin could serve as a therapeutic agent for liver inflammation. Approach & Results: Genetic deletion of Mcpip1 in myeloid leukocytes (Mcpip1fl/flLysMCre) resulted in the development of systemic and liver inflammation in mice. Symptoms were compared with those in liver samples from obese humans with elevated TNFalpha. Mice were treated with diosmetin, and its effectiveness in alleviating liver inflammation was evaluated. Elevated TNFalpha correlated with reduced Mcpip1 expression in peripheral blood mononuclear cells and LSEC dysfunction in obese patients. Mcpip1 knockout in myeloid cells in mice replicated molecular signs observed in human samples. Diosmetin efficiently reduced LSEC activation and liver inflammation in Mcpip1fl/flLysMCre mice. Diosmetin's effects may stem from inhibiting NF-kappaB-p50 subunit production in TNFalpha-activated endothelial cells. Conclusions: Diosmetin treatment efficiently restricted liver inflammation, despite ongoing systemic inflammation, by diminishing LSEC dysfunction. Mcpip1fl/flLysMCre mice mimic symptoms of liver inflammation observed in humans and can be useful in studies on new anti-inflammatory therapies for the liver. We show that diosmetin, a vasoactive flavonoid that is successfully used in the clinic to treat chronic venous insufficiency, has also strong anti-inflammatory properties in the liver. This suggests that diosmetin treatment may be tested in humans as a supportive therapy for liver inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…IL-1β or IL-6 cytokines 29,56 , and by indirect reduction of TNFα levels 30,56 . Importantly, the Mcpip1 fl/fl LysM Cre mouse model has previously been used to investigate the role of sterile inflammation in different organs [55][56][57] . Here, In this work, we asked the question whether there is a biological target other than the regulation of systemic inflammation whose modulation might contribute to the reduction of symptoms of liver inflammation.…”

Section: These Findings Highlightmentioning

confidence: 99%

See 1 more Smart Citation

Diosmetin alleviates liver inflammation by improving liver sinusoidal endothelial cell dysfunction

Żurawek,

Pydyn,

Major

et al. 2023

Preprint

Self Cite

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Depletion of Mcpip1 in murine myeloid cells results in intestinal dysbiosis followed by allergic inflammation

Szukała

Pilarczyk-Zurek

Folkert

et al. 2023

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Hepatic MCPIP1 protein levels are reduced in NAFLD patients and are predominantly expressed in cholangiocytes and liver endothelium

Pydyn

Kadłuczka

Major

et al. 2023

Hepatology Communications

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Background and Aims: NAFLD is characterized by the excessive accumulation of fat in hepatocytes. NAFLD can range from simple steatosis to the aggressive form called NASH, which is characterized by both fatty liver and liver inflammation. Without proper treatment, NAFLD may further progress to life-threatening complications, such as fibrosis, cirrhosis, or liver failure. Monocyte chemoattractant protein-induced protein 1 (MCPIP1, alias Regnase 1) is a negative regulator of inflammation, acting through the cleavage of transcripts coding for proinflammatory cytokines and the inhibition of NF-κB activity. Methods: In this study, we investigated MCPIP1 expression in the liver and peripheral blood mononuclear cells (PBMCs) collected from a cohort of 36 control and NAFLD patients hospitalized due to bariatric surgery or primary inguinal hernia laparoscopic repair. Based on liver histology data (hematoxylin and eosin and Oil Red-O staining), 12 patients were classified into the NAFL group, 19 into the NASH group, and 5 into the control (non-NAFLD) group. Biochemical characterization of patient plasma was followed by expression analysis of genes regulating inflammation and lipid metabolism. The MCPIP1 protein level was reduced in the livers of NAFL and NASH patients in comparison to non-NAFLD control individuals. In addition, in all groups of patients, immunohistochemical staining showed that the expression of MCPIP1 was higher in the portal fields and bile ducts in comparison to the liver parenchyma and central vein. The liver MCPIP1 protein level negatively correlated with hepatic steatosis but not with patient body mass index or any other analyte. The MCPIP1 level in PBMCs did not differ between NAFLD patients and control patients. Similarly, in patients’ PBMCs there were no differences in the expression of genes regulating β-oxidation (ACOX1, CPT1A, and ACC1) and inflammation (TNF, IL1B, IL6, IL8, IL10, and CCL2), or transcription factors controlling metabolism (FAS, LCN2, CEBPB, SREBP1, PPARA, and PPARG). Conclusion: We have demonstrated that MCPIP1 protein levels are reduced in NAFLD patients, but further research is needed to investigate the specific role of MCPIP1 in NAFL initiation and the transition to NASH.

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Role of Mcpip1 in obesity‐induced hepatic steatosis as determined by myeloid and liver‐specific conditional knockouts

Abstract: systemic inflammation, has a more pronounced effect on controlling liver metabolism and homeostasis than the depletion of Mcpip1 in hepatocytes.

Cited by 4 publications

References 60 publications

Diosmetin alleviates liver inflammation by improving liver sinusoidal endothelial cell dysfunction

Diosmetin alleviates liver inflammation by improving liver sinusoidal endothelial cell dysfunction

Depletion of Mcpip1 in murine myeloid cells results in intestinal dysbiosis followed by allergic inflammation

Hepatic MCPIP1 protein levels are reduced in NAFLD patients and are predominantly expressed in cholangiocytes and liver endothelium

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