CELSR2 deficiency suppresses lipid accumulation in hepatocyte by impairing the UPR and elevating ROS level

Tan, Junyang; Che, Yaping; Liu, Yanyan; Hu, Jiaqiao; Wang, Wenjun; Hu, Liubing; Zhou, Qinghua; Wang, Hao; Li, Jianshuang

doi:10.1096/fj.202100786rr

Cited by 12 publications

(11 citation statements)

References 44 publications

(95 reference statements)

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“…Moreover, CELSR2 de ciency impaired the physiological unfolded protein response, which damaged the endoplasmic reticulum homeostasis, and elevated the ROS level. Furthermore, CELSR2 depletion impaired cell survival by suppressing cell proliferation and promoting apoptosis [24]. CELSR2 depletion inhibited liver cancer cell proliferation and invasion [25].…”

Section: Discussionmentioning

confidence: 99%

“…CELSR2 expression in the liver was closely associated with lower circulating low-density lipoprotein levels [22,23]. CELSR2 expression decreased in the liver of the patients with non-alcoholic fatty liver disease (NAFLD) [24]. CELSR2 loss signi cantly suppressed the expression of lipid synthesis enzymes and decreased lipid accumulation in hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

“…In the present research, the Mn administration improved the expression of CELSR2 gene by 1.53, 1.43 and 1.17 times on the 1st, 3rd and 5th day, respectively. Therefore, we speculated that Mn exposure might increase the lipid accumulation by enhancing CELSR2 expression in liver [24].…”

Section: Discussionmentioning

confidence: 99%

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Unveiling the Hub Genes Associated with Manganese-Induced Hepatotoxicity

Yang

Wang

et al. 2023

Preprint

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Excessive exposure to manganese (Mn) can cause severe toxicity in human and animal organs, particularly the liver. However, the specific mechanisms of Mn-induced hepatotoxicity remain unclear. Thus, the objective of this study was to identify the key genes associated with hepatotoxicity caused by Mn administration. We obtained the gene expression data set GSE59923 from the Gene Expression Omnibus, which included liver samples treated with manganese chloride (MnCl2) as well as control samples. Through our analysis, we identified 222, 351, and 494 differentially expressed genes (DEGs) in the livers treated with MnCl2 at 700 mg/kg on the 1st, 3rd, and 5th day, respectively. Notably, we found a total of 27 overlapping DEGs in the liver samples. Biological process analysis revealed that these common DEGs were associated with the response to xenobiotic stimulus, cellular calcium ion homeostasis, and ion transmembrane transport. Pathway analysis further indicated the involvement of cAMP, p53, PI3K-Akt, MAPK, and AMPK signaling pathways in Mn-induced hepatotoxicity. Furthermore, we identified several important genes, including CCR2, CDKN1A, CELSR2, LCN2, and PER2, which appeared to play a role in Mn-induced hepatotoxicity. Taken together, this study sheds light on the molecular mechanisms underlying Mn-induced hepatotoxicity, contributing to our overall understanding of this condition.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Unveiling the Hub Genes Associated with Manganese-Induced Hepatotoxicity

Yang

Wang

et al. 2023

Preprint

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“…GO analysis of the Differentially Expressed Genes significant changes was performed using Metascape website ( https://metascape.org/gp/index.html#/main/step1 ) 60 . For gene set enrichment analysis, we applied GSEA v4.1.0 to various functional characteristic gene signatures as described previously 61 , 62 . GSEA was performed using the “Hallmark” or “KEGG” gene sets to identify enriched signatures.…”

Section: Methodsmentioning

confidence: 99%

C11orf54 promotes DNA repair via blocking CMA-mediated degradation of HIF1A

et al. 2023

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C11orf54 is an ester hydrolase highly conserved across different species. C11orf54 has been identified as a biomarker protein of renal cancers, but its exact function remains poorly understood. Here we demonstrate that C11orf54 knockdown decreases cell proliferation and enhances cisplatin-induced DNA damage and apoptosis. On the one hand, loss of C11orf54 reduces Rad51 expression and nuclear accumulation, which results in suppression of homologous recombination repair. On the other hand, C11orf54 and HIF1A competitively interact with HSC70, knockdown of C11orf54 promotes HSC70 binding to HIF1A to target it for degradation via chaperone-mediated autophagy (CMA). C11orf54 knockdown-mediated HIF1A degradation reduces the transcription of ribonucleotide reductase regulatory subunit M2 (RRM2), which is a rate-limiting RNR enzyme for DNA synthesis and DNA repair by producing dNTPs. Supplement of dNTPs can partially rescue C11orf54 knockdown-mediated DNA damage and cell death. Furthermore, we find that Bafilomycin A1, an inhibitor of both macroautophagy and chaperone-mediated autophagy, shows similar rescue effects as dNTP treatment. In summary, we uncover a role of C11orf54 in regulating DNA damage and repair through CMA-mediated decreasing of HIF1A/RRM2 axis.

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“…SORT1 plays a significant role in lipid uptake, and it seems to be involved in the regulation of hepatic secretion of VLDL [ 112 ]. Although the significant association in the CELSR2 - SORT1 region is usually attributed to SORT1 , a study claimed that CELSR2 deficiency suppresses lipid accumulation in hepatocytes [ 113 ]. The region of the neurocan ( NCAN , Chr 19) gene includes the gene for transmembrane 6 superfamily member 2 ( TM6SF2 ).…”

Section: Genetics Of Ldl Cholesterol In the Big-data Eramentioning

confidence: 99%

Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability

Martín‐Campos

2021

Biomedicines

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Changes in plasma low-density lipoprotein cholesterol (LDL-c) levels relate to a high risk of developing some common and complex diseases. LDL-c, as a quantitative trait, is multifactorial and depends on both genetic and environmental factors. In the pregenomic age, targeted genes were used to detect genetic factors in both hyper- and hypolipidemias, but this approach only explained extreme cases in the population distribution. Subsequently, the genetic basis of the less severe and most common dyslipidemias remained unknown. In the genomic age, performing whole-exome sequencing in families with extreme plasma LDL-c values identified some new candidate genes, but it is unlikely that such genes can explain the majority of inexplicable cases. Genome-wide association studies (GWASs) have identified several single-nucleotide variants (SNVs) associated with plasma LDL-c, introducing the idea of a polygenic origin. Polygenic risk scores (PRSs), including LDL-c-raising alleles, were developed to measure the contribution of the accumulation of small-effect variants to plasma LDL-c. This paper discusses other possibilities for unexplained dyslipidemias associated with LDL-c, such as mosaicism, maternal effect, and induced epigenetic changes. Future studies should consider gene–gene and gene–environment interactions and the development of integrated information about disease-driving networks, including phenotypes, genotypes, transcription, proteins, metabolites, and epigenetics.

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CELSR2 deficiency suppresses lipid accumulation in hepatocyte by impairing the UPR and elevating ROS level

Cited by 12 publications

References 44 publications

Unveiling the Hub Genes Associated with Manganese-Induced Hepatotoxicity

Unveiling the Hub Genes Associated with Manganese-Induced Hepatotoxicity

C11orf54 promotes DNA repair via blocking CMA-mediated degradation of HIF1A

Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability

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