Inhibition of human 3-hydroxy-3-methylglutaryl CoA reductase by peptides leading to cholesterol homeostasis through SREBP2 pathway in HepG2 cells

Kumar, Varun; Sharma, Praveen; Bairagya, Hridoy R.; Sharma, Sujata; Singh, T.P.; Tiku, Purnima Kaul

doi:10.1016/j.bbapap.2019.04.002

Cited by 15 publications

(12 citation statements)

References 52 publications

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“…Moreover, di-and tripeptides are readily absorbed by enterocytes via PepT1 transport and are less susceptible to hydrolysis by plasma enzymes during transport; both of these factors increase their chances of reaching the hepatocytes intact [25]. However, larger peptides, such as IAVPGEVA and IAVPTGVA obtained from soybean glycinin [26], and NALEPDNRIESEGG, NALEPDNRIES and PFVKSEPIPETNNE from pigeon peas [19], also bind to the catalytic site of 3-hydroxy-3-methylglutaryl-CoA reductase. These peptides also modulate cholesterol metabolism by activating the LDLR-SREBP2 pathway, which increases LDL uptake by HepG2 cells [19,26].…”

Section: Peptide-binding Sites Within Hmg-coa Reductase In Silicomentioning

confidence: 99%

“…However, larger peptides, such as IAVPGEVA and IAVPTGVA obtained from soybean glycinin [26], and NALEPDNRIESEGG, NALEPDNRIES and PFVKSEPIPETNNE from pigeon peas [19], also bind to the catalytic site of 3-hydroxy-3-methylglutaryl-CoA reductase. These peptides also modulate cholesterol metabolism by activating the LDLR-SREBP2 pathway, which increases LDL uptake by HepG2 cells [19,26]. Nevertheless, peptides consisting of four or more amino acids are prone to hydrolysis, creating dipeptides and tripeptides [27].…”

Section: Peptide-binding Sites Within Hmg-coa Reductase In Silicomentioning

confidence: 99%

“…Several studies have proposed that bioactive peptides, particularly those of legume seed origin, represent a possible alternative to statin drugs [13][14][15][16][17], as well as other natural compounds (salvianolic acid, curcumin, and docosanol) [18]. The cholesterol-lowering properties of some of these peptides have been demonstrated in vitro and in vivo [19][20][21]. However, the mechanisms by which they exert these effects have not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

“…However, the mechanisms by which they exert these effects have not been fully elucidated. Nevertheless, inhibition of endogenous cholesterol synthesis has been suggested as a putative mechanism of action [19,22]. Peptides appear to interact within the catalytic site of HMG-CoA reductase, resulting in induced fit and its consequent loss of activity via a statin-like mechanism [20,21,23].…”

Section: Introductionmentioning

confidence: 99%

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IAF, QGF, and QDF Peptides Exhibit Cholesterol-Lowering Activity through a Statin-like HMG-CoA Reductase Regulation Mechanism: In Silico and In Vitro Approach

Silva

Philadelpho

Santos

et al. 2021

IJMS

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In this study, in silico approaches are employed to investigate the binding mechanism of peptides derived from cowpea β-vignin and HMG-CoA reductase. With the obtained information, we designed synthetic peptides to evaluate their in vitro enzyme inhibitory activity. In vitro, the total protein extract and <3 kDa fraction, at 5000 µg, support this hypothesis (95% and 90% inhibition of HMG-CoA reductase, respectively). Ile-Ala-Phe, Gln-Gly-Phe, and Gln-Asp-Phe peptides were predicted to bind to the substrate binding site of HMGCR via HMG-CoAR. In silico, it was established that the mechanism of HMG-CoA reductase inhibition largely entailed mimicking the interactions of the decalin ring of simvastatin and via H-bonding; in vitro studies corroborated the predictions, whereby the HMG-CoA reductase activity was decreased by 69%, 77%, and 78%, respectively. Our results suggest that Ile-Ala-Phe, Gln-Gly-Phe, and Gln-Asp-Phe peptides derived from cowpea β-vignin have the potential to lower cholesterol synthesis through a statin-like regulation mechanism.

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Section: Peptide-binding Sites Within Hmg-coa Reductase In Silicomentioning

confidence: 99%

Section: Peptide-binding Sites Within Hmg-coa Reductase In Silicomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

IAF, QGF, and QDF Peptides Exhibit Cholesterol-Lowering Activity through a Statin-like HMG-CoA Reductase Regulation Mechanism: In Silico and In Vitro Approach

Silva

Philadelpho

Santos

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…It has been reported that inflammatory cytokines can aggravate cholesterol accumulation in hepatocytes by disturbing SREBP2 regulation, and that SREBP2 expression inhibition can significantly increase cholesterol accumulation [27]. In addition, SREBP2 can specifically bind to SREs on lipid-related genes, such as LDLR and HMGCR, to directly regulate and maintain intracellular cholesterol homeostasis when intracellular cholesterol is deficient [28, 29]. Thus, SREBP2 expression inhibition could disrupt SREBP2-mediated LDLR and HMGCR feedback regulation, thereby causing excess accumulation of cholesterol.…”

Section: Discussionmentioning

confidence: 99%

Estrogen stimulates SREBP2 expression in hepatic cell lines via an estrogen response element in the SREBP2 promoter

Meng

Zong

2019

Cell Mol Biol Lett

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ObjectiveHypoestrogenism in women is strongly associated with menopause and it can lead to lipid disorder, which predisposes people to premature cardiovascular disease. However, the mechanism of lipid disorder remains unclear. Sterol regulatory element-binding protein 2 (SREBP2) is the key transcription factor regulating cholesterol metabolism. We hypothesize that estrogen regulates SREBP2 transcription through an estrogen response element (ERE) in the SREBP2 promoter region.MethodsHuman hepatoblastoma cells (HepG2) were treated with dose-dependent concentrations of estradiol (E2) for 24 h. Then, SREBP2 expression was determined via real-time PCR and immunofluorescence. The expressions of the SREBP2 downstream target genes HMGCR and LDLR were determined via real-time PCR. Lipid secretion in the culture media of HepG2 cells was measured using ELISA. Through bioinformatics analysis, we identified high-scoring ERE-like sequences in the SREBP2 gene promoter. Chromatin immunoprecipitation analysis was used to confirm the ERE. DNA fragments of the putative or mutated ERE-like sequence were synthesized and ligated into pGL3-basic plasmid to construct the SREBP2 promoter luciferase reporter systems. SREBP2-Luciferase (SREBP2-Luc), SREBP2-Mutation (SREBP2-Mut) and the blank control were transfected into hepatic cell lines. Luciferase activities were measured using the dual-luciferase reporter assay system. Chromatin immunoprecipitation analysis and the luciferase reporter assay were repeated in human hepatoma cells (HuH-7).ResultsWe found that E2 dose-dependently increased the expression of SREBP2 in HepG2 cells and that the increased levels were blocked when treated with an estrogen receptor-alpha antagonist. Additionally, E2 increased both HMGCR and LDLR expression and lipid secretion in HepG2 cells. Notably, we identified a functional ERE in the SREBP2 gene promoter, to which E2 could specifically bind and induce transcription.ConclusionsAn ERE was identified in the SREBP2 gene promoter. It mediates the regulation of SREBP2 expression by estrogen in hepatocytes. This study provides a mechanism to link cardiovascular disease with estrogen.

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Flaxseed‐derived peptides ameliorate hepatic cholesterol metabolism in Sprague–Dawley rats fed a high‐cholesterol and high‐fat diet

et al. 2022

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BACKGROUND: Plant peptides have been reported to have cholesterol-lowering activities. Previous research has found that ≤1 kDa flaxseed peptide (FP 5 ) reduces cholesterol absorption and synthesis in vitro. In this research, we investigated the cholesterol-lowering activity of FP 5 in Sprague-Dawley (SD) rats fed a high-cholesterol and high-fat diet. In addition, amino acid sequences of FP 5 were determined by high-performance liquid chromatography-electrospray ionization-Orbitrap mass spectrometry. RESULTS: FP 5 supplement significantly decreased the serum and hepatic cholesterol levels and modulated the hepatic gene and protein expression of cholesterol metabolism-related enzymes or regulators (3-hydroxy-3-methylglutaryl coenzyme A reductase, Low-Density Lipoprotein Receptor (LDLR), Cholesterol 7 ⊍-hydroxylase, Niemann-Pick C1-like 1, ATP-binding cassette transporters G5 and G8). Eleven peptides were identified from FP 5 . These peptides were characterized as hydrophobic amino acids such as leucine (L), proline (P), glycine (G), isoleucine (I) and continuous sequences, including LP, LL, LG and II, with low molecular weights. CONCLUSION: FP 5 has a certain cholesterol-lowering activity in SD rats fed a high-cholesterol and high-fat diet. The possible mechanism for ameliorating hepatic cholesterol metabolism of FP 5 includes inhibiting hepatic cholesterol de novo synthesis, promoting the synthesis and excretion of bile acids, and inhibiting the reabsorption of bile acids during enterohepatic circulation.

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Inhibition of human 3-hydroxy-3-methylglutaryl CoA reductase by peptides leading to cholesterol homeostasis through SREBP2 pathway in HepG2 cells

Cited by 15 publications

References 52 publications

IAF, QGF, and QDF Peptides Exhibit Cholesterol-Lowering Activity through a Statin-like HMG-CoA Reductase Regulation Mechanism: In Silico and In Vitro Approach

IAF, QGF, and QDF Peptides Exhibit Cholesterol-Lowering Activity through a Statin-like HMG-CoA Reductase Regulation Mechanism: In Silico and In Vitro Approach

Estrogen stimulates SREBP2 expression in hepatic cell lines via an estrogen response element in the SREBP2 promoter

Flaxseed‐derived peptides ameliorate hepatic cholesterol metabolism in Sprague–Dawley rats fed a high‐cholesterol and high‐fat diet

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