Dataset Information

High Concentrations of Rosiglitazone Reduce mRNA and Protein Levels of LRP1 in HepG2 Cells.

ABSTRACT: Low-density lipoprotein receptor-related protein 1 (LRP1) is an endocytic receptor involved in the uptake of a variety of molecules, such as apoE, ?2-macroglobulin, and the amyloid ? peptide (A?), for either transcellular transport, protein trafficking or lysosomal degradation. The LRP1 gene can be transcribed upon activation of peroxisome proliferator receptor activated-? (PPAR?) by the potent PPAR? agonist, rosiglitazone (RGZ). In previous studies, RGZ was shown to upregulate LRP1 levels in concentrations between 0.1 and 5 ?M in HepG2 cells. In this study, we sought to replicate previous studies and to investigate the molecular mechanism by which high concentrations of RGZ reduce LRP1 levels in HepG2 cells. Our data confirmed that transcriptional activation of LRP1 occurred in response to RGZ at 3 and 10 ?M, in agreement with the study reported by Moon et al. (2012a). On the other hand, we found that high concentrations of RGZ decreased both mRNA and protein levels of LRP1. Mechanistically, transcriptional dysregulation of LRP1 was affected by the downregulation of PPAR? in a time- and concentration-dependent manner. However, downregulation of PPAR? was responsible for only 40% of the LRP1 reduction and thereby the remaining loss of LRP1 (60%) was found to be through degradation in the lysosomal system. In conclusion, our findings demonstrate the mechanisms by which high concentrations of RGZ caused LRP1 levels to be reduced in HepG2 cells. Taken together, this data will be helpful to better explain the pharmacological modulation of this pivotal membrane receptor by PPAR? agonists.

SUBMITTER: Rondon-Ortiz AN

PROVIDER: S-EPMC5696635 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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High Concentrations of Rosiglitazone Reduce mRNA and Protein Levels of LRP1 in HepG2 Cells.

Rondón-Ortiz Alejandro N AN Lino Cardenas Christian L CL Martínez-Málaga Jimena J Gonzales-Urday Ana L AL Gugnani Kuljeet S KS Böhlke Mark M Maher Timothy J TJ Pino-Figueroa Alejandro J AJ

Frontiers in pharmacology 20171114

Low-density lipoprotein receptor-related protein 1 (LRP1) is an endocytic receptor involved in the uptake of a variety of molecules, such as apoE, α2-macroglobulin, and the amyloid β peptide (Aβ), for either transcellular transport, protein trafficking or lysosomal degradation. The <i>LRP1</i> gene can be transcribed upon activation of peroxisome proliferator receptor activated-γ (PPARγ) by the potent PPARγ agonist, rosiglitazone (RGZ). In previous studies, RGZ was shown to upregulate LRP1 level ...[more]

PMID: 29201005

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Project description:BackgroundRadix Astragali (Astragalus membranaceus var. mongholicus (Bunge)) and Coptis chinensis (Coptis chinensis var. angustiloba) are two commonly prescribed traditional Chinese herbs for diabetes. Astragalus Polysaccharide (AP) and Berberine (BBR) are active ingredients of these two herbs respectively and they are scientifically proved to have immunomodulatory and anti-inflammatory effects. They are also known for their antidiabetic potential by ameliorating insulin resistance (IR). AP and BBR have shown different advantages in treating diabetes according to previous reports. However, very few studies focus on the combined activities of the two potential antidiabetic ingredients. In this study, we discovered that reactive oxygen species (ROS) accumulated in IR-hepG2 cells and APBBR can decrease ROS level in model group significantly. We conjectured that APBBR can ameliorate IR in hepG2 cells by decreasing ROS level. In order to verify this hypothesis, we obtained phenotype and transcriptome information of IR-HepG2 cells and explore the underlying mechanism of the combination of AP and BBR(APBBR) activity on the relationship between ROS change in IR at whole-transcriptome level, so as to shed new light to efficacy and application of APBBR in treating diabetes.MethodsThe IR cell model was established with high-level insulin intervention. Glucose content, HepG2 cell viability as well as ROS level was detected to study the effect of IR-hepG2 cell phenotype. Unbiased genome-wide RNA sequencing was used to investigate alterations in experimental groups. Then, GO and KEGG functional enrichment was performed to explore the function and pathway of target genes. Venn analysis found out the differentially expressed lncRNAs that had close relationship with IR and ROS. Finally, we screened out candidate lncRNAs and these target genes to construct interaction network of differentiated lncRNA-miRNA-mRNA by according to the principle of competitive endogenous RNA (ceRNA).ResultsThe biochemical experiments showed that APBBR administration could improve the proliferation activity of IR-HepG2 cells and decrease ROS level in model cells. The GO and KEGG functional enrichment analyses demonstrated several mRNAs remarkably enriched in biological processes and signaling pathways related to ROS production and IR progression. Interaction network suggest that APBBR ameliorates IR in HepG2 cells by regulating the expression of multiple genes and activating relevant signaling pathway to decrease ROS level. Thus, we demonstrated that APBBR ameliorated IR in hepG2 cells via the ROS-dependent pathway.

Dataset Information

High Concentrations of Rosiglitazone Reduce mRNA and Protein Levels of LRP1 in HepG2 Cells.

Publications

High Concentrations of Rosiglitazone Reduce mRNA and Protein Levels of LRP1 in HepG2 Cells.

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