Recombinant humanized IgG1 maintain liver triglyceride homeostasis through Arylacetamide deacetylase in ApoE−/− mice

Xiao, Sujun; Lin, Run; Duan, Rui; Li, Zhonghao; Tang, Dongmei; Liu, Xianyan; Liu, Yan; Zhao, Ming

doi:10.1016/j.intimp.2022.108741

Cited by 5 publications

(5 citation statements)

References 35 publications

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“…Our previously experimental data have confirmed that the recombinant humanized IgG1 antibody maintains liver triglyceride homeostasis through arylacetamide deacetylase [ 7 ]. Recently, we found that the antibody promotes macrophages to engulf lipids and efflux to HDL through ABCA1 (data not shown), one of the key proteins in RCT.…”

Section: Introductionmentioning

confidence: 66%

“…The neonatal FC receptor (FcRn) is a specific IgG receptor involved in the transcellular transport of IgG, and we previously demonstrated that FcRn is responsible for the regulation of arylacetamide deacetylase expression in the presence of recombinant humanized IgG1 [ 7 ]. To determine whether FcRn is responsible for the upregulation expression of ApoA-I, ApoA-II, and SR-BI induced by the antibody, we first knockdown endogenous FcRn in HepG2 cells by FcRn-specific siRNA ( Figure 6 A−C).…”

Section: Resultsmentioning

confidence: 99%

“…FcRn siRNA was designed and synthesized by GenePharma (Suzhou, China). The recombinant humanized IgG1 antibody (clone NO.6, 14, 27, and 64, namely 6 Ab, 14 Ab, 27 Ab, and 64 Ab) was produced by our laboratory; the effectiveness of 14 Ab had been confirmed in our previous work [ 7 , 14 ]. In this paper, we mainly focus on 6 Ab and 14 Ab, and 64 Ab was an isotype-matched control IgG1 antibody [ 14 ].…”

Section: Methodsmentioning

confidence: 95%

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Recombinant Humanized IgG1 Antibody Promotes Reverse Cholesterol Transport through FcRn-ERK1/2-PPARα Pathway in Hepatocytes

Zhang

Liu

et al. 2022

IJMS

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Hyperlipidemia-associated lipid disorders are considered the cause of atherosclerotic cardiovascular disease. Reverse cholesterol transport (RCT) is a mechanism by which excess peripheral cholesterol is transported to the liver and further converted into bile acid for excretion from the body in feces, which contributes to reducing hyperlipidemia as well as cardiovascular disease. We previously found that the recombinant humanized IgG1 antibody promotes macrophages to engulf lipids and increases cholesterol efflux to high-density lipoprotein (HDL) through ATP-binding cassette sub-family A1 (ABCA1), one of the key proteins related to RCT. In the present study, we explored other RCT related proteins expression on hepatocytes, including scavenger receptor class B type I (SR-BI), apolipoprotein A-I (ApoA-I), and apolipoprotein A-II (ApoA-II), and its modulation mechanism involved. We confirmed that the recombinant humanized IgG1 antibody selectively activated ERK1/2 to upregulate SR-BI, ApoA-I, and ApoA-II expression in mice liver and human hepatocellular carcinoma cell lines HepG2 cells. The rate-limiting enzymes of bile acid synthesis, including cholesterol 7α-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1), exhibited a significant increase when treated with the recombinant humanized IgG1 antibody, as well as increased excretion of bile acids in feces. Besides, abolishment or mutation of peroxisome proliferator-activated receptor α (PPARα)/RXR binding site on SR-BI promoter eliminated SR-BI reporter gene luciferase activity even in the presence of the recombinant humanized IgG1 antibody. Knock down the neonatal Fc receptor (FcRn) on hepatocytes impaired the effect of recombinant humanized IgG1 antibody on activation of ERK1/2, as well as upregulation of SR-BI, ApoA-I, and ApoA-II expression. In conclusion, one of the mechanisms on the recombinant humanized IgG1 antibody attenuates hyperlipidemia in ApoE−/− mice model fed with high-fat-diet might be through reinforcement of liver RCT function in an FcRn-ERK1/2-PPARα dependent manner.

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Section: Introductionmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 95%

See 1 more Smart Citation

Recombinant Humanized IgG1 Antibody Promotes Reverse Cholesterol Transport through FcRn-ERK1/2-PPARα Pathway in Hepatocytes

Zhang

Liu

et al. 2022

IJMS

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“…ApoE −/− mice fed a HFD exhibited abnormally elevated plasma triglyceride and cholesterol levels, making them a wellestablished model for investigating hyperlipidemia and its related complications. 27 In this study, ApoE −/− mice on a HFD were orally administered TPS3A to evaluate its effects on the progression of renal tubular ELD (Figure 1A). Serum UA, Cre, and BUN are critical markers for assessing kidney function.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Tea Polysaccharide Ameliorates High-Fat Diet-Induced Renal Tubular Ectopic Lipid Deposition via Regulating the Dynamic Balance of Lipogenesis and Lipolysis

Kuang,

Li,

Qian

et al. 2024

J. Agric. Food Chem.

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Renal tubular ectopic lipid deposition (ELD) plays a significant role in the development of chronic kidney disease, posing a great threat to human health. The present work aimed to explore the intervention effect and potential molecular mechanism of a purified tea polysaccharide (TPS3A) on renal tubular ELD. The results demonstrated that TPS3A effectively improved kidney function and slowed the progression of tubulointerstitial fibrosis in high-fat-diet (HFD)-exposed ApoE −/− mice. Additionally, TPS3A notably suppressed lipogenesis and enhanced lipolysis, as shown by the downregulation of lipogenesis markers (SREBP-1 and FAS) and the upregulation of lipolysis markers (HSL and ATGL), thereby reducing renal tubular ELD in HFD-fed ApoE −/− mice and palmitic-acid-stimulated HK-2 cells. The AMPK-SIRT1-FoxO1 axis is a core signal pathway in regulating lipid deposition. Consistently, TPS3A significantly increased the levels of phosphorylated-AMPK, SIRT1, and deacetylation of Ac-FoxO1. However, these effects of TPS3A on lipogenesis and lipolysis were abolished by AMPK siRNA, SIRT1 siRNA, and FoxO1 inhibitor, resulting in exacerbated lipid deposition. Taken together, TPS3A shows promise in ameliorating renal tubular ELD by inhibiting lipogenesis and promoting lipolysis through the AMPK-SIRT1-FoxO1 signaling pathway.

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“…Their diet was changed to normal chow one week before the first immunization. At 25 weeks of age, mice in the CVI-mAb (IgG1, IgG4, V11, and GAALIE) and HFD groups received intraperitoneal injections of CVI-mAb (1 mg/0.5 mL) and PBS (0.5 mL), respectively [ 59 ]. After two additional injections at 26 and 27 weeks of age, mice were sacrificed at 29 weeks for the following analyses.…”

Section: Methodsmentioning

confidence: 99%

IgG1 Is the Optimal Subtype for Treating Atherosclerosis by Inducing M2 Macrophage Differentiation, and Is Independent of the FcγRIIA Gene Polymorphism

Duan

Liu

Tang

et al. 2023

IJMS

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In recent years, it has been established that atherosclerosis is an autoimmune disease. However, little is currently known about the role of FcγRIIA in atherosclerosis. Herein, we sought to investigate the relationship between FcγRIIA genotypes and the effectiveness of different IgG subclasses in treating atherosclerosis. We constructed and produced different subtypes of IgG and Fc-engineered antibodies. In vitro, we observed the effect of different subtypes of IgG and Fc-engineered antibodies on the differentiation of CD14+ monocytes from patients or healthy individuals. In vivo, Apoe−/− mice were fed a high-fat diet (HFD) for 20 weeks and administered injections of different CVI-IgG subclasses or Fc-engineered antibodies. Flow cytometry was used to assess the polarization of monocytes and macrophages. Although CVI-IgG4 reduced the release of MCP-1 compared to the other subtypes, IgG4 did not yield an anti-inflammatory effect by induction of human monocyte and macrophage differentiation in vitro. Furthermore, genetic polymorphisms of FcγRIIA were not associated with different CVI-IgG subclasses during the treatment of atherosclerosis. In vivo, CVI-IgG1 decreased Ly6Chigh monocyte differentiation and promoted M2 macrophage polarization. We also found that the secretion of IL-10 was upregulated in the CVI-IgG1-treated group, whereas V11 and GAALIE exerted no significant effect. These findings highlight that IgG1 is the optimal subtype for treating atherosclerosis, and CVI-IgG1 can induce monocyte/macrophage polarization. Overall, these results have important implications for the development of therapeutic antibodies.

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Recombinant humanized IgG1 maintain liver triglyceride homeostasis through Arylacetamide deacetylase in ApoE−/− mice

Cited by 5 publications

References 35 publications

Recombinant Humanized IgG1 Antibody Promotes Reverse Cholesterol Transport through FcRn-ERK1/2-PPARα Pathway in Hepatocytes

Recombinant Humanized IgG1 Antibody Promotes Reverse Cholesterol Transport through FcRn-ERK1/2-PPARα Pathway in Hepatocytes

Tea Polysaccharide Ameliorates High-Fat Diet-Induced Renal Tubular Ectopic Lipid Deposition via Regulating the Dynamic Balance of Lipogenesis and Lipolysis

IgG1 Is the Optimal Subtype for Treating Atherosclerosis by Inducing M2 Macrophage Differentiation, and Is Independent of the FcγRIIA Gene Polymorphism

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