Inhibition of human 3-hydroxy-3-methylglutaryl CoA reductase by peptides leading to cholesterol homeostasis through SREBP2 pathway in HepG2 cells.
IR@CFTRI: CSIR-Central Food Technological Research Institute, Mysore
View Archive Info| Field | Value | |
| Relation |
http://ir.cftri.com/13964/
https://doi.org/10.1016/j.bbapap.2019.04.002 |
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| Title |
Inhibition of human 3-hydroxy-3-methylglutaryl CoA reductase by peptides
leading to cholesterol homeostasis through SREBP2 pathway in HepG2 cells.
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| Creator |
Varun, Kumar
Sharma, P. Bairagya, H. R. Sharma, S. Singh, T. P. Purnima Kaul, Tiku |
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| Subject |
25 Peptide Chemistry
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| Description |
In mammalian cells, human 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a rate-limiting endoplasmic
reticulum (ER) bonded enzyme, plays a central role in the cholesterol homeostasis via the negative
feedback mechanism. The present study indicates that the interactions of novel peptides with the catalytic
domain of HMGCR, provides an alternative therapeutic candidate for reducing cholesterol. The potential natural
origin of HMGCR peptide inhibitors were filtered from the peptide library using the molecular docking, which
revealed three strong candidates for inhibition. This information was used for synthesizing peptides, which were
evaluated for inhibition against HMGCR. The stronger docking interactions were confirmed by experimental
dissociation constant (KD) values of 9.1×10−9 M, 1.4×10−8M and 1.2×10−8M for peptides NALEPDNRIESEGG
(Pep-1), NALEPDNRIES (Pep-2) and PFVKSEPIPETNNE (Pep-3) respectively. The immunological based
interactions show a strong evidence of peptide-HMGCR complexes. The LDL uptake showed enhancements after
treatments with peptides in the extracellular environment of HepG2 cells, which was further, corroborated
through increase in the immunofluorescence signal of the localized LDL-R protein expression on the cell
membrane. The results showed that the mRNA and protein expression of transcription factors were significantly
up-regulated showing regulation of cholesterol biosynthesis in peptide treated HepG2 cells. The binding of
transcription factors, sterol regulatory element (SRE) and cAMP-response element (CRE) on HMGCR promotor
further confirms the cholesterol biosynthesis regulation. All the above results suggested a key role of peptide/s in
alleviating cholesterol accumulation in tissue via inhibition of rate-limiting HMGCR enzyme.
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| Date |
2019
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| Type |
Article
PeerReviewed |
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| Format |
pdf
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| Language |
en
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| Identifier |
http://ir.cftri.com/13964/1/BBA%20-%20Proteins%20and%20Proteomics%201867%20%282019%29%20604%E2%80%93615.pdf
Varun, Kumar and Sharma, P. and Bairagya, H. R. and Sharma, S. and Singh, T. P. and Purnima Kaul, Tiku (2019) Inhibition of human 3-hydroxy-3-methylglutaryl CoA reductase by peptides leading to cholesterol homeostasis through SREBP2 pathway in HepG2 cells. BBA - Proteins and Proteomics, 1867. pp. 604-615. |
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