Apolipoprotein A4 regulates the immune response in carbon tetrachloride-induced chronic liver injury in mice

Wang, Yinan; Yang, Ziyu; Yang, Wenyan; Li, Xiaoming; Li, Shengbin

doi:10.1016/j.intimp.2020.107222

Cited by 14 publications

(10 citation statements)

References 26 publications

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“…Among the genes with the highest differences, many have been identified to be closely related to the occurrence and development of LF, such as ApoA4 (apolipoprotein A4). Wang Y. et al (2021) found that ApoA4 may reduce LF and liver injury by inhibiting LF mediators and inflammatory cytokines and suppressing proinflammatory hepatic M1 cell invasion. Although some genes have not been proven to be related to LF, they are involved in fibrosis in other tissues.…”

Section: Discussionmentioning

confidence: 97%

Comprehensive Analysis of the Transcriptome-Wide m6A Methylation Modification Difference in Liver Fibrosis Mice by High-Throughput m6A Sequencing

Chang

Chen

et al. 2021

Front. Cell Dev. Biol.

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N6-Methyladenosine (m6A), a unique and common mRNA modification method in eukaryotes, is involved in the occurrence and development of many diseases. Liver fibrosis (LF) is a common response to chronic liver injury and may lead to cirrhosis and even liver cancer. However, the involvement of m6A methylation in the development of LF is still unknown. In this study, we performed a systematic evaluation of hepatic genome-wide m6A modification and mRNA expression by m6A-seq and RNA-seq using LF mice. There were 3,315 genes with significant differential m6A levels, of which 2,498 were hypermethylated and 817 hypomethylated. GO and KEGG analyses illustrated that differentially expressed m6A genes were closely correlated with processes such as the endoplasmic reticulum stress response, PPAR signaling pathway and TGF-β signaling pathway. Moreover, a total of 90 genes had both a significant change in the m6A level and mRNA expression shown by joint analysis of m6A-seq and RNA-seq. Hence, the critical elements of m6A modification, including methyltransferase WTAP, demethylases ALKBH5 and binding proteins YTHDF1 were confirmed by RT-qPCR and Western blot. In an additional cell experiment, we also observed that the decreased expression of WTAP induced the development of LF as a result of promoting hepatic stellate cell (HSC) activation. Therefore, this study revealed unique differential m6A methylation patterns in LF mice and suggested that m6A methylation was associated with the occurrence and course of LF to some extent.

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Section: Discussionmentioning

confidence: 97%

Comprehensive Analysis of the Transcriptome-Wide m6A Methylation Modification Difference in Liver Fibrosis Mice by High-Throughput m6A Sequencing

Chang

Chen

et al. 2021

Front. Cell Dev. Biol.

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“…APOA4, a lipid-binding protein, is involved in the synthesis of cholesterol, steroids, and other lipids, and improves glucose homeostasis ( 72 ). The anti-inflammatory and antioxidant activities of APOA4 are crucial for maintaining hepatic homeostasis ( 73 , 74 ). In our study, APOA4 was downregulated, indicating that Cd injury affected fat metabolism, inflammation, and oxidative stress in the liver.…”

Section: Discussionmentioning

confidence: 99%

Whole Transcriptome Profiling of the Effects of Cadmium on the Liver of the Xiangxi Yellow Heifer

Wei

Yi²,

Shen

et al. 2022

Front. Vet. Sci.

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Cadmium (Cd) is a major heavy metal toxicant found in industrial zones. Humans and animals are exposed to it through their diet, which results in various physiological problems. In the current study, the toxic effects of Cd on the liver were investigated by whole-transcriptome sequencing (RNA-seq) of the livers of Xiangxi heifers fed a diet with excess Cd. We randomly divided six healthy heifers into two groups. The first group received a control diet, whereas the second group received Cd-exceeding diets for 100 days. After 100 days, the livers were collected. A total of 551 differentially expressed mRNAs, 24 differentially expressed miRNAs, and 169 differentially expressed lncRNAs were identified (p < 0.05, |log2FC| >1). Differentially expressed genes (DEGs) were analyzed by gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. We found that under Cd exposure, DEGs were enriched in the adenosine 5'-monophosphate–activated protein kinase pathway, which is involved in autophagy regulation, and the peroxisome proliferator–activated receptor pathway, which is involved in lipid metabolism. In addition, the apolipoprotein A4 gene, which has anti-inflammatory and antioxidant effects, the anti-apoptotic gene ATPase H+/K+ transporting the nongastric alpha2 subunit, and the cholesterol metabolism–associated gene endothelial lipase gene were significantly downregulated. C–X–C motif chemokine ligand 3, cholesterol 7α-hydroxylase, and stearoyl-CoA desaturase, which are involved in the development of fatty liver, were significantly upregulated. These genes revealed the main effects of Cd on the liver of Xiangxi yellow heifers. The current study provides insightful information regarding the DEGs involved in autophagy regulation, apoptosis, lipid metabolism, anti-inflammation, and antioxidant enzyme activity. These may serve as useful biomarkers for predicting and treating Cd-related diseases in the future.

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“…Here, we primarily identified APOA4, one of the downstream molecules of HGF-c-Met signaling, to be a soluble PD marker of rh-HGF. Interestingly, it has been demonstrated that APOA4 is not just a constituent of high-density lipoprotein but it exerts anti-oxidant and anti-inflammatory effects to protect liver damage in mice [ 10 , 11 ]. Notably, serum APOA4 seemed to increase in murine ALF over normal mice without exogenous rh-HGF ( Figure 4 A; rh-HGF, 0 mg/kg).…”

Section: Discussionmentioning

confidence: 99%

“…Among those, APOA4, which has been previously known as one of the apolipoproteins, was found to be a soluble PD marker and can be secreted into the blood as a result of HGF-c-Met signaling. Recently, it was reported that APOA4 is not just a constituent of high-density lipoprotein, but it also exerts anti-oxidant and anti-inflammatory effects to protect from liver damage in mice [ 10 , 11 ]. Therefore, validation of the utility of APOA4 as a PD marker of rh-HGF in clinical trials would help pharmacodynamic evaluation of rh-HGF, and furthermore, may give clues to elucidate its mechanism of action in humans, not just by direct effect on hepatocytes but also via APOA4 protein.…”

Section: Introductionmentioning

confidence: 99%

Serum APOA4 Pharmacodynamically Represents Administered Recombinant Human Hepatocyte Growth Factor (E3112)

Motoi

Uesugi

Obara

et al. 2021

IJMS

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Background: Hepatocyte growth factor (HGF) is an endogenously induced bioactive molecule that has strong anti-apoptotic and tissue repair activities. In this research, we identified APOA4 as a novel pharmacodynamic (PD) marker of the recombinant human HGF (rh-HGF), E3112. Methods: rh-HGF was administered to mice, and their livers were investigated for the PD marker. Candidates were identified from soluble proteins and validated by using human hepatocytes in vitro and an animal disease model in vivo, in which its c-Met dependency was also ensured. Results: Among the genes induced or highly enhanced after rh-HGF exposure in vivo, a soluble apolipoprotein, Apoa4, was found to be induced by rh-HGF in the murine liver. By using primary cultured human hepatocytes, the significant induction of human APOA4 was observed at the mRNA and protein levels, and it was inhibited in the presence of a c-Met inhibitor. Although mice constitutively expressed Apoa4 mRNA in the small intestine and the liver, the liver was the primary organ affected by administered rh-HGF to strongly induce APOA4 in a dose- and c-Met-dependent manner. Serum APOA4 levels were increased after rh-HGF administration, not only in normal mice but also in anti-Fas-induced murine acute liver failure (ALF), which confirmed the pharmacodynamic nature of APOA4. Conclusions: APOA4 was identified as a soluble PD marker of rh-HGF with c-Met dependency. It should be worthwhile to clinically validate its utility through clinical trials with healthy subjects and ALF patients.

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Apolipoprotein A4 regulates the immune response in carbon tetrachloride-induced chronic liver injury in mice

Cited by 14 publications

References 26 publications

Comprehensive Analysis of the Transcriptome-Wide m6A Methylation Modification Difference in Liver Fibrosis Mice by High-Throughput m6A Sequencing

Comprehensive Analysis of the Transcriptome-Wide m6A Methylation Modification Difference in Liver Fibrosis Mice by High-Throughput m6A Sequencing

Whole Transcriptome Profiling of the Effects of Cadmium on the Liver of the Xiangxi Yellow Heifer

Serum APOA4 Pharmacodynamically Represents Administered Recombinant Human Hepatocyte Growth Factor (E3112)

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