Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ATPase associated with various cellular activities (AAA-ATPase) p97 (p97) has been implicated in the retrotranslocation of target proteins for delivery to the cytosolic proteasome during endoplasmic reticulum-associated degradation (ERAD). Apolipoprotein B-100 (apoB-100) is an ERAD substrate in liver cells, including the human hepatoma, HepG2. We studied the potential role of p97 in the ERAD of apoB-100 in HepG2 cells using cell permeabilization, coimmunoprecipitation, and gene silencing. Degradation was abolished when HepG2 cytosol was removed by digitonin permeabilization, and treatment of intact cells with the proteasome inhibitor MG132 caused accumulation of ubiquitinated apoB protein in the cytosol. Cross-linking of intact cells with the thiol-cleavable agent dithiobis(succinimidylpropionate) (DSP), as well as nondenaturing immunoprecipitation, demonstrated an interaction between p97 and intracellular apoB. Small interfering ribonucleic acid (siRNA)-mediated reduction of p97 protein increased the intracellular levels of newly synthesized apoB-100, predominantly because of a decrease in the turnover of newly synthesized apoB-100 protein. However, although the posttranslational degradation of newly synthesized apoB-100 was delayed by p97 knockdown, secretion of apoB-100 was not affected. Knockdown of p97 also impaired the release of apoB-100 and polyubiquitinated apoB into the cytosol. In summary, our results suggest that retrotranslocation and proteasomal degradation of apoB-100 can be dissociated in HepG2 cells, and that the AAA-ATPase p97 is involved in the removal of full-length apoB from the biosynthetic pathway to the cytosolic proteasome.
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PMID:The AAA-ATPase p97 facilitates degradation of apolipoprotein B by the ubiquitin-proteasome pathway. 1855 Aug 91

Lipoprotein(a) (Lp(a)) is a low density lipoprotein-like particle in which apolipoprotein B100 is covalently linked to the unique apolipoprotein(a). There is a mounting body of evidence suggesting a role of Lp(a) in the development and progression of several vascular diseases, such as coronary heart disease, ischemic stroke, abdominal aortic aneurysm and venous thromboembolism, so that prominent scientific societies have recently endorsed guidelines and recommendations that increasingly encourage the screening and the therapeutic management of Lp(a) excess. In this article, we review the epidemiologic evidence, guidelines and recommendations concerning the relationship between increased plasma Lp(a) levels and risk of cardiovascular disease or venous thromboembolism by systematically retrieving the most relevant articles from electronic databases. Although uncertainty still remains regarding the opportunity to screen for hyperlipoproteinemia(a), it seems inopportune as yet to measure plasma Lp(a) levels in asymptomatic persons, while its measurement might be of clinical significance in selected categories of patients at intermediate or high cardiovascular risk. The measurement of Lp(a) should be performed by using immunometric, harmonized and size-insensitive techniques and results reported in total lipoprotein mass rather than in traditional units. It is uncertain if Lp(a) genotyping or phenotyping add any additional information for the cardiovascular disease risk stratification. Although the optimal therapeutic management of Lp(a) excess is still controversial, a general agreement exists that very high Lp(a) levels should be lowered in patients with multiple cardiovascular risk factors, preferably with nicotinic acid therapy (e.g., 1.0-3.0 g/day).
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PMID:Screening and therapeutic management of lipoprotein(a) excess: review of the epidemiological evidence, guidelines and recommendations. 2125 36

Apolipoprotein B-100 (apoB-100) is degraded by endoplasmic reticulum-associated degradation (ERAD) when lipid availability limits assembly of VLDLs. The ubiquitin ligase gp78 and the AAA-ATPase p97 have been implicated in the proteasomal degradation of apoB-100. To study the relationship between ERAD and VLDL assembly, we used small interfering RNA (siRNA) to reduce gp78 expression in HepG2 cells. Reduction of gp78 decreased apoB-100 ubiquitination and cytosolic apoB-ubiquitin conjugates. Radiolabeling studies revealed that gp78 knockdown increased secretion of newly synthesized apoB-100 and, unexpectedly, enhanced VLDL assembly, as the shift in apoB-100 density in gp78-reduced cells was accompanied by increased triacylglycerol (TG) secretion. To explore the mechanisms by which gp78 reduction might enhance VLDL assembly, we compared the effects of gp78 knockdown with those of U0126, a mitogen-activated protein kinase/ERK kinase1/2 inhibitor that enhances apoB-100 secretion in HepG2 cells. U0126 treatment increased secretion of both apoB100 and TG and decreased the ubiquitination and cellular accumu-lation of apoB-100. Furthermore, p97 knockdown caused apoB-100 to accumulate in the cell, but if gp78 was concomitantly reduced or assembly was enhanced by U0126 treatment, cellular apoB-100 returned toward baseline. This indicates that ubiquitination commits apoB-100 to p97-mediated retrotranslocation during ERAD. Thus, decreasing ubiquitination of apoB-100 enhances VLDL assembly, whereas improving apoB-100 lipidation decreases its ubiquitination, suggesting that ubiquitination has a regulatory role in VLDL assembly.
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PMID:Ubiquitination regulates the assembly of VLDL in HepG2 cells and is the committing step of the apoB-100 ERAD pathway. 2142 92