Identification of amino acid residues in the MT-loop of MT1-MMP critical for its ability to cleave low-density lipoprotein receptor

Wang, Maggie Haitian; Alabi, Adekunle; Gu, Hongmei; Gill, Govind; Zhang, Ziyang; Jarad, Suha; Xia, Xiao-Dan; Shen, Yishi; Wang, Guiqing; Zhang, Dawei

doi:10.3389/fcvm.2022.917238

Cited by 7 publications

(4 citation statements)

References 69 publications

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“…siRNA was introduced into cells (primary hepatocytes, LX-2, and HepG2) using Lipofectamine 3000 (Invitrogen). Equal amounts of plasmids containing HA-tagged SAA1 and Myc-DDK-tagged Surf4 were introduced into HepG2 cells using Lipofectamine 3000 as previously described [ 63 ].…”

Section: Methodsmentioning

confidence: 99%

Hepatic Surf4 Deficiency Impairs Serum Amyloid A1 Secretion and Attenuates Liver Fibrosis in Mice

Wang,

Li,

Gill

et al. 2024

Research

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Liver fibrosis is a severe global health problem. However, no effective antifibrotic drugs have been approved. Surf4 is primarily located in the endoplasmic reticulum (ER) and mediates the transport of secreted proteins from the ER to the Golgi apparatus. Knockout of hepatic Surf4 ( Surf4 LKO ) in mice impairs very-low-density lipoprotein secretion without causing overt liver damage. Here, we found that collagen levels are significantly reduced in the liver of Surf4 LKO mice compared with control Surf4 flox mice, as demonstrated by proteomics, Western blot, and quantitative reverse transcription polymerase chain reaction. Therefore, this study aims to investigate whether and how hepatic Surf4 affects liver fibrosis. We observed that CCl 4 -induced liver fibrosis is significantly lower in Surf4 LKO mice than in Surf4 flox mice. Mechanistically, hepatic Surf4 deficiency reduces serum amyloid A1 (SAA1) secretion and hepatic stellate cell (HSC) activation. Surf4 coimmunoprecipitates and colocalizes with SAA1. Lack of hepatic Surf4 significantly reduces SAA1 secretion from hepatocytes, and SAA1 activates cultured human HSCs (LX-2 cells). Conditioned medium (CM) from Surf4-deficient primary hepatocytes activates LX-2 cells to a much lesser extent than CM from Surf4 flox primary hepatocytes, and this reduced effect is restored by the addition of recombinant SAA1 to CM from Surf4-deficient hepatocytes. Knockdown of SAA1 in primary hepatocytes or TLR2 in LX-2 cells significantly reduces LX-2 activation induced by CM from Surf4 flox hepatocytes but not from Surf4 LKO hepatocytes. Furthermore, knockdown of SAA1 significantly ameliorates liver fibrosis in Surf4 flox mice but does not further reduce liver fibrosis in Surf4 LKO mice. We also observe substantial expression of Surf4 and SAA1 in human fibrotic livers. Therefore, hepatic Surf4 facilitates SAA1 secretion, activates HSCs, and aggravates liver fibrosis, suggesting that hepatic Surf4 and SAA1 may serve as treatment targets for liver fibrosis.

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Section: Methodsmentioning

confidence: 99%

Hepatic Surf4 Deficiency Impairs Serum Amyloid A1 Secretion and Attenuates Liver Fibrosis in Mice

Wang,

Li,

Gill

et al. 2024

Research

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“…In addition to the proteolytic cleavage of the LDLR by γ-secretase, two zinc metalloproteases also cleave the receptor, MT1-MMP and BMP1. MT1-MMP cleaves the LDLR adjacent to the plasma membrane ( Figures 1H and 2 ) [ 56 ]. MT1-MMP is a transmembrane protease that has major and well-established functions in the remodelling of extracellular matrix proteins [ 57 ].…”

Section: Ldlr Regulationmentioning

confidence: 99%

Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation

Aldworth,

Hooper

2024

Biochemical Society Transactions

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The amount of the low-density lipoprotein receptor (LDLR) on the surface of hepatocytes is the primary determinant of plasma low-density lipoprotein (LDL)-cholesterol level. Although the synthesis and cellular trafficking of the LDLR have been well-documented, there is growing evidence of additional post-translational mechanisms that regulate or fine tune the surface availability of the LDLR, thus modulating its ability to bind and internalise LDL-cholesterol. Proprotein convertase subtilisin/kexin type 9 and the asialoglycoprotein receptor 1 both independently interact with the LDLR and direct it towards the lysosome for degradation. While ubiquitination by the E3 ligase inducible degrader of the LDLR also targets the receptor for lysosomal degradation, ubiquitination of the LDLR by a different E3 ligase, RNF130, redistributes the receptor away from the plasma membrane. The activity of the LDLR is also regulated by proteolysis. Proteolytic cleavage of the transmembrane region of the LDLR by γ-secretase destabilises the receptor, directing it to the lysosome for degradation. Shedding of the extracellular domain of the receptor by membrane-type 1 matrix metalloprotease and cleavage of the receptor in its LDL-binding domain by bone morphogenetic protein-1 reduces the ability of the LDLR to bind and internalise LDL-cholesterol at the cell surface. A better understanding of how the activity of the LDLR is regulated will not only unravel the complex biological mechanisms controlling LDL-cholesterol metabolism but also could help inform the development of alternative pharmacological intervention strategies for the treatment of hypercholesterolaemia.

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“…Additionally, recent advancements in molecular biology, particularly in the study of lipid metabolism, have offered new strategies for the development of antimalarial drugs [10 -12]. By targeting the critical metabolic pathways of malaria parasites, these studies hold potential for the development of more effective therapeutic agents [13][14][15]. Concurrently, machine learning technologies, especially the application of Extreme Gradient Boosting Decision Trees (XGBoost), have been employed to enhance the accuracy of malaria diagnostic tools [16,17].…”

Section: Development History and Research Status Of Amodiaquinementioning

confidence: 99%

Process Flow for the Research, Development, and Manufac-Turing of Amodiaquine Dihydrochloride Dihydrate, an Anti-Malarial Drug

Yang

2022

IAET

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This study focuses on the synthesis of amodiaquine dihydrochloride dihydrate and evaluates the performance of a new process against existing methods using several key indicators. The target compounds were synthesized successfully through experimental design and data collection, with their quality thoroughly assessed. Results indicate that the new process significantly enhances yield, purity, and crystal structure. Also, by utilizing highly efficient catalysts and finely tuning reaction conditions, the improvements in yield and purity are substantial. The new process not only enhances production efficiency but also significantly reduces waste, aligning well with the principles of green chemistry. Additionally, this paper discusses the potential industrial application of the new process. Despite facing challenges such as equipment costs, scale-up, and market acceptance in its industrialization, the new process's superior performance and promising prospects provide a strong foundation for its future implementation.

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Identification of amino acid residues in the MT-loop of MT1-MMP critical for its ability to cleave low-density lipoprotein receptor

Cited by 7 publications

References 69 publications

Hepatic Surf4 Deficiency Impairs Serum Amyloid A1 Secretion and Attenuates Liver Fibrosis in Mice

Hepatic Surf4 Deficiency Impairs Serum Amyloid A1 Secretion and Attenuates Liver Fibrosis in Mice

Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation

Process Flow for the Research, Development, and Manufac-Turing of Amodiaquine Dihydrochloride Dihydrate, an Anti-Malarial Drug

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