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Regulation of G-protein alpha i2 subunit expression by oxidized low-density lipoprotein.

ABSTRACT: Oxidized low-density lipoprotein (LDL) inhibits signalling pathways mediated by pertussis toxin-sensitive guanine nucleotide-binding proteins (Gi proteins). To determine whether this inhibition is due to altered G protein alpha i subunit expression, mRNA and protein levels of alpha i isoforms were assessed in bovine aortic endothelial cells treated with oxidized LDL (0-100 micrograms/ml, 0-72 h). Oxidized LDL did not affect the expression of alpha i3, but did cause time- and concentration-dependent decrease in alpha i2 mRNA and protein resulting in a 3.2- and 3.5-fold reduction, respectively, after 72 h. This decrease in alpha i2 coincided with a 86% decrease in alpha i2 GTPase activity. Nuclear run-off studies did not show any significant effect of oxidized LDL on alpha i2 or alpha i3 transcription. In the presence of actinomycin D, oxidized LDL shortened the t1/2 of alpha i2 mRNA from 16 h to 8 h which was attenuated by cycloheximide. In addition, pulse-chase labelling with [35S]methionine revealed that oxidized LDL reduced the t1/2 of alpha i2 protein from 27 to 14 h. Our results indicate that oxidized LDL can modulate receptor-Gi coupling by downregulating the expression of alpha i2, but not alpha i3. The mechanism involves both mRNA destabilization and protein degradation.

SUBMITTER: Liao JK

PROVIDER: S-EPMC295627 | biostudies-other | 1995 Apr

REPOSITORIES: biostudies-other

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Regulation of G-protein alpha i2 subunit expression by oxidized low-density lipoprotein.

Liao J K JK Clark S L SL

The Journal of clinical investigation 19950401 4

Oxidized low-density lipoprotein (LDL) inhibits signalling pathways mediated by pertussis toxin-sensitive guanine nucleotide-binding proteins (Gi proteins). To determine whether this inhibition is due to altered G protein alpha i subunit expression, mRNA and protein levels of alpha i isoforms were assessed in bovine aortic endothelial cells treated with oxidized LDL (0-100 micrograms/ml, 0-72 h). Oxidized LDL did not affect the expression of alpha i3, but did cause time- and concentration-depend ...[more]

PMID: 7706449

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Project description:Background and aimsAs the incidence of nonalcoholic steatohepatitis (NASH) continues to rise, understanding how normal liver functions are affected during disease is required before developing novel therapeutics which could reduce morbidity and mortality. However, very little is understood about how the transport of proteins and cells from the liver by the lymphatic vasculature is affected by inflammatory mediators or during disease.MethodsTo answer these questions, we utilized a well-validated mouse model of NASH and exposure to highly oxidized low density lipoprotein (oxLDL). In addition to single cell sequencing, multiplexed immunofluorescence and metabolomic analysis of liver lymphatic endothelial cells (LEC)s we evaluated lymphatic permeability and transport both in vitro and in vivo.ResultsConfirming similarities between human and mouse liver lymphatic vasculature in NASH, we found that the lymphatic vasculature expands as disease progresses and results in the downregulation of genes important to lymphatic identity and function. We also demonstrate, in mice with NASH, that fluorescein isothiocyanate (FITC) dextran does not accumulate in the liver draining lymph node upon intrahepatic injection, a defect that was rescued with therapeutic administration of the lymphatic growth factor, recombinant vascular endothelial growth factor C (rVEGFC). Similarly, exposure to oxLDL reduced the amount of FITC-dextran in the portal draining lymph node and through an LEC monolayer. We provide evidence that the mechanism by which oxLDL impacts lymphatic permeability is via a reduction in Prox1 expression which decreases lymphatic specific gene expression, impedes LEC metabolism and reorganizes the highly permeable lymphatic cell-cell junctions which are a defining feature of lymphatic capillaries.ConclusionsWe identify oxLDL as a major contributor to decreased lymphatic permeability in the liver, a change which is consistent with decreased protein homeostasis and increased inflammation during chronic liver disease.

Dataset Information

Regulation of G-protein alpha i2 subunit expression by oxidized low-density lipoprotein.

Publications

Regulation of G-protein alpha i2 subunit expression by oxidized low-density lipoprotein.

Similar Datasets

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