ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways

Zhang, Zongli; Yuan, Yue; Hu, Lin; Tang, Jian; Zhao, Meng; Gao, Yujiu; Ma, Shinan; Wang, Xiaoli; Yuan, Yahong; Zhang, Qiufang; Cai, Weibin; Ruan, Xiuhang; Guo, Xingrong

doi:10.1016/j.jare.2022.08.006

Cited by 30 publications

(21 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Liver brosis, if not well controlled, can progress to HCC [12]. Although, we further demonstrated that ANGPTL8 expression gradually increases as NAFLD progresses and is highest in patients with HCC [11], Whether ANGPTL8 plays a role in hepatocarcinogenesis is unclear.…”

Section: Introductionmentioning

confidence: 64%

“…Although the expression and prognostic potential of ANGPTL8 in different cancers have been analyzed [8], these studies have primarily considered tumor molecular pro ling data for their conclusions, and little is known regarding the function of ANGPTL8 in different cancers. It is now evident that ANGPTL8 contributes to in ammatory diseases [9,10], our previous research determined that ANGPTL8 is a proin ammatory cytokine secreted by hepatocytes into the liver microenvironment to regulate hepatic stellate cell activation, which in turn accelerates nonalcoholic fatty liver disease (NAFLD)-associated liver brogenesis [11]. Liver brosis, if not well controlled, can progress to HCC [12].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dual role of ANGPTL8 in promoting tumor cell proliferation and immune escape during hepatocarcinogenesis

Guo¹,

Gao²,

Yuan³

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

The interplay between hepatocellular carcinoma (HCC) cells and the tumor microenvironment is essential for hepatocarcinogenesis, but their contributions to HCC development are incompletely understood. We assessed the role of ANGPTL8, a protein secreted by HCC cells, in hepatocarcinogenesis and the mechanisms through which ANGPTL8 mediates crosstalk between HCC cells and tumor-associated macrophages. Immunohistochemical, Western blotting, RNA-Seq and Flow cytometry analysis of ANGPTL8 were performed. A series of in vitro and in vivo experiments were conducted to reveal the role of ANGPTL8 in the progression of HCC. ANGPTL8expression was positively correlated with tumor malignancy in HCC, and high ANGPTL8 expression was associated with poor overall survival (OS) and disease-free survival (DFS). ANGPTL8 promoted HCC cell proliferation in vitro and in vivo, and ANGPTL8KO inhibited the development of HCC in both DEN-induced and DEN-plus-CCL4-induced mouse HCC tumors. Mechanistically, the ANGPTL8–LILRB2/PIRB interaction promoted polarization of macrophages to the immunosuppressive M2 phenotype in macrophages and recruiting immunosuppressive T cells. In hepatocytes, ANGPTL8-mediated stimulation of LILRB2/PIRB regulated the ROS/ERK pathway and upregulated autophagy, leading to proliferation of HCC cells. Our data support that ANGPTL8 has dual role of in promoting tumor cell proliferation and immune escape during hepatocarcinogenesis.

show abstract

Section: Introductionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Dual role of ANGPTL8 in promoting tumor cell proliferation and immune escape during hepatocarcinogenesis

Guo¹,

Gao²,

Yuan³

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, an interference of chronic insulin resistance/dysglycemia and acute inflammation regarding betatrophin/ANGPTL8 regulation can be hypothesized, since we found no significant association with any further laboratory or clinical parameter evaluated in this study that could otherwise explain our observation. In addition, Metformin was recently shown to act as a betatrophin/ANGPTL8 inhibitor under experimental conditions and we observed significantly reduced VAT expression in treated patients [ 32 ]. Otherwise, a minority of the subjects in the insulin-resistant subgroup were exclusively under chronic Metformin medication, which was discontinued according to national treatment standards before elective surgery.…”

Section: Discussionmentioning

confidence: 93%

Associations of Betatrophin/ANGPTL8 with Septic Dyslipidemia in Human Peritonitis: An Explorative Analysis

et al. 2022

View full text Add to dashboard Cite

Sepsis is defined by life-threatening organ dysfunction mediated by the host’s response to infection. This can result in septic dyslipidemia, which is involved in the neutralization of pathogen-related lipids. Knowledge of the regulatory mechanisms of septic dyslipidemia is incomplete. The cytokine betatrophin/Angiopoietin-like protein 8 (ANGPTL8) plays a role in the regulation of triacylglyceride metabolism, though its function in septic dyslipidemia remains unknown. Sixty-six patients were enrolled in a cross-sectional study. Circulating concentrations and adipose tissue (AT) mRNA expression of betatrophin/ANGPTL8 were studied in patients suffering from peritoneal sepsis. Insulin-resistant individuals and subjects without metabolic derangement/systemic inflammation were enrolled as controls. All underwent open abdominal surgery. Circulating betatrophin/ANGPTL8 was analyzed by an enzyme-linked immunosorbent assay and AT mRNA expression levels were assessed by real-time PCR. Standard laboratory analyses including lipid electrophoresis were evaluated. Sepsis patients showed pronounced septic dyslipidemia (p < 0.05 for all major lipid classes). Despite comparable betatrophin/ANGPTL8 mRNA expression in AT (p = 0.24), we found significantly increased circulating betatrophin/ANGPTL8 with septic dyslipidemia (p = 0.009). Expression levels of betatrophin/ANGPTL8 in AT correlated with circulating concentrations in both control groups (r = 0.61; p = 0.008 and r = 0.43; p = 0.034), while this association was undetectable in sepsis. After stratification, betatrophin/ANGPTL8 remained associated with hypertriacylglyceridemia (p < 0.05).

show abstract

“…Given that ANGPTL8 is a secreted protein and is not expressed in mouse primary microglia or BV2 cells, we investigated potential ANGPTL8 receptors on the cell membranes of microglia. Our previous studies have shown that LILRB2 (the human immune inhibitory receptor leukocyte immunoglobulin-like receptor B2) and PirB (its mouse ortholog paired immunoglobulin-like receptor) are receptors for ANGPTL8 [23]. PIRB is expressed in mouse primary microglia and BV2 cells.…”

Section: Discussionmentioning

confidence: 99%

“…However, additional studies have reported that serum ANGPTL8 levels were increased in patients with diverse diseases associated with aging induced by chronic in ammation, such as nonalcoholic fatty liver disease (NAFLD), diabetes, and metabolic syndrome [18,22]. Our previous research showed that liver-derived ANGPTL8, as a proin ammatory factor, activates hepatic stellate cells to promote liver brosis [23]. Notably, our preliminary screening found that ANGPTL8 knockout delayed aging-induced hair graying and cognitive decline in mice.…”

Section: Introductionmentioning

confidence: 99%

ANGPTL8 as an Inflammatory Trigger Aggravated Microglial Pyroptosis in the Pathogenesis of Alzheimer’s Disease

Wei

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Increasing evidence indicates that Alzheimer’s disease (AD) is not only a disease of the brain but also an autoimmune disorder of innate immunity. Pyroptosis-mediated inflammation activates microglia, which are innate immune regulators that play an important role in AD formation. New studies have found that some peripheral proinflammatory cytokines can penetrate the blood–brain barrier (BBB), thereby activating microglial pyroptosis and promoting inflammation in the brain. However, the impact of the liver-brain axis on the development of AD remains elusive. Here, we show that liver-secreted ANGPTL8 acts as an inflammatory trigger and penetrates the BBB, contributing to the progression of AD. Methods: ANGPTL8-/- mice were crossed with 5×FAD mice to obtain WT, 5×FAD, ANGPTL8-/-, and ANGPTL8-/- 5×FAD mice. We checked whether ANGPTL8 knockout affected learning and memory impairment using the Morris water maze (MWM) task. Tiofavin-S (Tio-S) and Nissl staining were used to analyze amyloid β (Aβ) deposition and the number of neurons in the four groups of mice. The effects of ANGPTL8 on the activation of microglia and neuroinflammation were analyzed in vitro and in vivo by immunofluorescence and flow cytometry. Extracting single-cell sequencing library data and in situ hybridization, etc., were used to analyze the source of ANGPTL8 that promotes AD progression. RNA interference assay, transmission electron microscopy, western blotting, etc., were used to study the mechanisms of ANGPTL8 in regulating AD progression. Finally, drug screening was used to identify an effective inhibitor of ANGPTL8. Results: ANGPTL8 knockout improved cognitive functions and decreased Ab deposition in 5xFAD mice. ANGPTL8 levels were significantly increased in the livers of 5xFAD mice and upregulated by Aβ stimulation. Secreted Aβ in turn promotes the expression of ANGPTL8, and secreted ANGPTL8 acts as an inflammatory trigger and directly interacts with the microglia membrane receptor PIRB to activate downstream PIRB/NLRP3 signaling, thereby inhibiting the phagocytic capacity of microglia to reduce the clearance of Aβ by promoting pyroptosis. The antidiabetic drug metformin can inhibit the expression of ANGPTL8 and improve the learning and memory of 5xFAD mice. Conclusions: Our study identified ANGPTL8 as a novel peripheral inflammatory trigger that regulates the liver-brain axis and aggravates microglial pyroptosis via the PIRB/NLRP3 pathway to accelerate the pathogenesis of AD. Our results also indicate that the serum ANGPTL8 level represents a potential diagnostic marker for diseases featuring AD and that targeting ANGPTL8 holds great promise for developing innovative therapies to treat AD.

show abstract

ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways

Cited by 30 publications

References 61 publications

Dual role of ANGPTL8 in promoting tumor cell proliferation and immune escape during hepatocarcinogenesis

Dual role of ANGPTL8 in promoting tumor cell proliferation and immune escape during hepatocarcinogenesis

Associations of Betatrophin/ANGPTL8 with Septic Dyslipidemia in Human Peritonitis: An Explorative Analysis

ANGPTL8 as an Inflammatory Trigger Aggravated Microglial Pyroptosis in the Pathogenesis of Alzheimer’s Disease

Contact Info

Product

Resources

About