Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex

Xie, Liping; Yuan, Yang; Xu, Simiao; Lü, Sijia; Gu, Jinyang; Wang, Yanping; Wang, Yibing; Zhang, Xianjing; Chen, Suzhen; Li, Jian; Lu, Junxi; Sun, Honglin; Hu, Ruixiang; Piao, Hulin; Wang, Wen; Wang, Cunchuan; Wang, Jing; Li, Na; White, Morris F.; Liu, Han; Wang, Jia; Miao, Ji

doi:10.1016/j.celrep.2022.111498

Cited by 28 publications

(22 citation statements)

References 60 publications

(72 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As a principal cop binding protein, Cp also played a vital role in holding hepatic copper homeostasis by regulating the transport of copper. A present study revealed that CP might be a target to ameliorate NAFLD development by modulating copper-SCO1-AMPK signaling pathway (Xie et al, 2022). Therefore, MT1 plays a crucial role in inflammatory and immunity diseases by acting as an intracellular iron transport agent (Dai et al, 2021).…”

Section: Discussionmentioning

confidence: 66%

Bicyclol attenuates high fat diet-induced non-alcoholic fatty liver disease/non-alcoholic steatohepatitis through modulating multiple pathways in mice

Jia

et al. 2023

Front. Pharmacol.

View full text Add to dashboard Cite

Introduction: The pathological progression of non-alcoholic fatty liver disease (NAFLD) is driven by multiple factors, and non-alcoholic steatohepatitis (NASH) represents its progressive form. In our previous studies, we found that bicyclol had beneficial effects on NAFLD/ NASH. Here we aim to investigate the underlying molecular mechanisms of the bicyclol effect on NAFLD/NASH induced by high-fat diet (HFD) feeding.Methods: A mice model of NAFLD/NASH induced by HFD-feeding for 8 weeks was used. As a pretreatment, bicyclol (200 mg/kg) was given to mice by oral gavage twice daily. Hematoxylin and eosin (H&E) stains were processed to evaluate hepatic steatosis, and hepatic fibrous hyperplasia was assessed by Masson staining. Biochemistry analyses were used to measure serum aminotransferase, serum lipids, and lipids in liver tissues. Proteomics and bioinformatics analyses were performed to identify the signaling pathways and target proteins. Data are available via Proteome X change with identifier PXD040233. The real-time RT-PCR and Western blot analyses were performed to verify the proteomics data.Results: Bicyclol had a markedly protective effect against NAFLD/NASH by suppressing the increase of serum aminotransferase, hepatic lipid accumulation and alleviating histopathological changes in liver tissues. Proteomics analyses showed that bicyclol remarkably restored major pathways related to immunological responses and metabolic processes altered by HFD feeding. Consistent with our previous results, bicyclol significantly inhibited inflammation and oxidative stress pathway related indexes (SAA1, GSTM1 and GSTA1). Furthermore, the beneficial effects of bicyclol were closely associated with the signaling pathways of bile acid metabolism (NPC1, SLCOLA4 and UGT1A1), cytochrome P450-mediated metabolism (CYP2C54, CYP3A11 and CYP3A25), biological processes such as metal ion metabolism (Ceruloplasmin and Metallothionein-1), angiogenesis (ALDH1A1) and immunological responses (IFI204 and IFIT3).Discussion: These findings suggested that bicyclol is a potential preventive agent for NAFLD/NASH by targeting multiple mechanisms in future clinical investigations.

show abstract

Section: Discussionmentioning

confidence: 66%

Bicyclol attenuates high fat diet-induced non-alcoholic fatty liver disease/non-alcoholic steatohepatitis through modulating multiple pathways in mice

Jia

et al. 2023

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…Recently, Duan et al claimed that activated PPARa/HMGCS2/NRF2/ARE pathway might induce ferroptosis [ 36 ]. In addition, HMGCS2 (at both the protein and mRNA levels) may be involved in ceruloplasmin-mediated copper metabolism [ 37 ], implying that HMGCS2 may play a regulatory role in the process of ferroptosis and cuproptosis. Cytochrome P450 family 1 subfamily A member 1 (CYP1A1) is one of the main P450 enzymes and is highly expressed in the liver and urinary bladder.…”

Section: Discussionmentioning

confidence: 99%

The Role of Ferroptosis and Cuproptosis in Curcumin against Hepatocellular Carcinoma

Liu

Lai

2023

Molecules

View full text Add to dashboard Cite

Background: Among cancer-related deaths, hepatocellular carcinoma (HCC) ranks fourth, and traditional Chinese medicine (TCM) treatment is an important complementary alternative therapy for HCC. Curcumin is a natural ingredient extracted from Curcuma longa with anti-HCC activity, while the therapeutic mechanisms of curcumin remain unclear, especially on ferroptosis and cuproptosis. Methods: Differentially expressed genes (DEGs) of curcumin treatment in PLC, KMCH, and Huh7 cells were identified, respectively. The common genes among them were then obtained to perform functional enrichment analysis and prognostic analysis. Moreover, weighted gene co-expression network analysis (WGCNA) was carried out for the construction of the co-expression network. The ferroptosis potential index (FPI) and the cuproptosis potential index (CPI) were subsequently used to quantitatively analyze the levels of ferroptosis and cuproptosis. Finally, single-cell transcriptome analysis of liver cancer was conducted. Results: We first identified 702, 515, and 721 DEGs from curcumin-treated PLC, KMCH, and Huh7 cells, respectively. Among them, HMOX1, CYP1A1, HMGCS2, LCN2, and MTTP may play an essential role in metal ion homeostasis. By WGCNA, grey60 co-expression module was associated with curcumin treatment and involved in the regulation of ion homeostasis. Furthermore, FPI and CPI assessment showed that curcumin had cell-specific effects on ferroptosis and cuproptosis in different HCC cells. In addition, there are also significant differences in ferroptosis and cuproptosis levels among 16 HCC cell subtypes according to single-cell transcriptome data analysis. Conclusions: We developed CPI and combined it with FPI to quantitatively analyze curcumin-treated HCC cells. It was found that ferroptosis and cuproptosis, two known metal ion-mediated forms of programmed cell death, may have a vital effect in treating HCC with curcumin, and there are significant differences in various liver cancer cell types and curcumin treatment which should be considered in the clinical application of curcumin.

show abstract

“…7 ). Additional conditions resulting in the upregulation of CP expression and downregulation of hepatic copper concentrations are non-alcoholic fatty liver disease (NAFLD) and overnutrition 52 . In contrast to the described steady-state conditions, the secretome analyses herein identified a negative correlation of extracellular CP and SELENOP because of increased CP and decreased SELENOP release (Fig.…”

Section: Discussionmentioning

confidence: 99%

Excessive copper impairs intrahepatocyte trafficking and secretion of selenoprotein P

Hackler

2023

Nat Commun

View full text Add to dashboard Cite

Selenium homeostasis depends on hepatic biosynthesis of selenoprotein P (SELENOP) and SELENOP-mediated transport from the liver to e.g. the brain. In addition, the liver maintains copper homeostasis. Selenium and copper metabolism are inversely regulated, as increasing copper and decreasing selenium levels are observed in blood during aging and inflammation. Here we show that copper treatment increased intracellular selenium and SELENOP in hepatocytes and decreased extracellular SELENOP levels. Hepatic accumulation of copper is a characteristic of Wilson’s disease. Accordingly, SELENOP levels were low in serum of Wilson’s disease patients and Wilson’s rats. Mechanistically, drugs targeting protein transport in the Golgi complex mimicked some of the effects observed, indicating a disrupting effect of excessive copper on intracellular SELENOP transport resulting in its accumulation in the late Golgi. Our data suggest that hepatic copper levels determine SELENOP release from the liver and may affect selenium transport to peripheral organs such as the brain.

show abstract

Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex

Cited by 28 publications

References 60 publications

Bicyclol attenuates high fat diet-induced non-alcoholic fatty liver disease/non-alcoholic steatohepatitis through modulating multiple pathways in mice

Bicyclol attenuates high fat diet-induced non-alcoholic fatty liver disease/non-alcoholic steatohepatitis through modulating multiple pathways in mice

The Role of Ferroptosis and Cuproptosis in Curcumin against Hepatocellular Carcinoma

Excessive copper impairs intrahepatocyte trafficking and secretion of selenoprotein P

Contact Info

Product

Resources

About