Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HIV lipodystrophy is a heterogeneous syndrome, which has yet to be objectively defined, comprising peripheral lipoatrophy, central fat accumulation and lipomata, along with hyperlipidaemia, insulin resistance and lactic acidaemia. Both nucleoside analogues and protease inhibitors are involved, but there are also host factors that probably place some patients at greater risk. The pathogenesis is increasingly understood, with evidence of interference of several regulatory proteins such as sterol regulatory enhancer binding protein-1, the proteasome, mitochondrial DNA polymerase gamma and GLUT-4. Along with the issues of cosmesis and stigmatization, a principal clinical concern that arises with lipodystrophy is a possible increased risk of accelerated atherosclerosis. A variety of therapeutic interventions, designed to limit these risks, are under evaluation, but none is conclusively shown to be of value.
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PMID:HIV lipodystrophy: risk factors, pathogenesis, diagnosis and management. 1287 May 40

The Seipin/BSCL2 gene was originally identified as a loss-of-function gene for congenital generalized lipodystrophy type 2 (CGL2), a condition characterized by severe lipoatrophy, insulin resistance, hypertriglyceridaemia and mental retardation. Recently, gain-of-toxic-function mutations (namely, mutations N88S and S90L) in the seipin gene have been identified in autosomal dominant motor neuron diseases such as Silver syndrome/spastic paraplegia 17 (SPG17) (OMIM #270685) and distal hereditary motor neuropathy type V (dHMN-V) (OMIM #182960). Detailed phenotypic analyses have revealed that upper motor neurons, lower motor neurons and peripheral motor axons are variously affected in patients with these mutations. The clinical spectrum for these mutations is broad, encompassing Silver syndrome, some variants of Charcot-Marie-Tooth disease type 2, dHMNV and spastic paraplegia, even within a common pedigree. Therefore, we propose that seipin-related motor neuron diseases can be collectively referred to as 'seipinopathies'. Expression of the seipin protein can be detected in motor neurons in the spinal cord and white matter in the frontal lobe. This is consistent with the distribution of seipinopathies in the upper and lower motor neurons. Recent studies have shown that seipin, an endoplasmic reticulum (ER)-resident membrane protein, is an N-glycosylated protein that is proteolytically cleaved into N- and C-terminal fragments and is polyubiquitinated. Interestingly, the N88S and S90L mutations are in the N-glycosylation motif, and these mutations enhance ubiquitination and degradation of seipin by the ubiquitin-proteasome system (UPS). Furthermore, both mutations appear to result in proteins that are improperly folded, which leads to accumulation of the mutant protein in the ER. We have shown that expression of mutant forms of seipin in cultured cells activates the unfolded protein response (UPR) pathway and induces ER stress-mediated cell death. These findings suggest that seipinopathies are novel conformational diseases and that neurodegeneration in these diseases is tightly associated with ER stress, which has recently been reported to be associated with other neurodegenerative diseases. Further study of the pathological mechanisms of the mutant forms of seipin may lead to important new insights into motor neuron diseases, including other spastic paraplegia diseases and amyotrophic lateral sclerosis.
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PMID:Seipinopathy: a novel endoplasmic reticulum stress-associated disease. 1879 Aug 19

Patients treated with highly active antiretroviral therapy may develop metabolic side effects such as hyperlipidemia, insulin resistance, lipoatrophy and lactic acidosis. The pathophysiology of these metabolic abnormalities is unknown, although some, e.g., lactic acidosis and lipoatrophy, are more associated with nucleoside use while protease inhibitors (PIs) have been shown to contribute to hyperlipidemia and insulin resistance. Identifying new PIs that are not associated with dyslipidemia has been hindered by the lack of mechanistic information and the unavailability of relevant animal models. In order to understand the molecular mechanism behind the hyperlipidemia associated with other protease inhibitors, and to develop a more effective, faster screen for compounds with this liability, we have analyzed expression profiles from PI-treated animals. Previously, we have shown that treatment of rats with ritonavir results in increases in the expression of proteasomal subunit genes in the liver. We show this increase is similar in rats treated with bortezomib, a proteasome inhibitor. In addition, we have treated rats with additional protease inhibitors, including atazanavir, which is associated with lower rates of lipid elevations in the clinic when administered in the absence of ritonavir. Our results indicate a strong correlation between proteasomal induction and lipid elevations, and have allowed us to develop a rapid screen for identifying novel PIs that do not induce the proteasome.
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PMID:Identification of proteasome gene regulation in a rat model for HIV protease inhibitor-induced hyperlipidemia. 2022 37

Reduction in mortality and increased average life span of the human immunodeficiency virus (HIV)-infected patients treated with antiretroviral therapy (ART) are associated with the risk of unwanted effects, such as insulin resistance and dyslipidemia with cardiovascular complications. Antiretroviral therapy may also be associated with lipodystrophy characterized as peripheral lipoatrophy with central fat accumulation. Understanding the molecular mechanisms of lipodystrophy caused by ART is important for therapeutic strategy and the prediction of side-effects. Influence of protease inhibitor saquinavir (SQV) on preadipocyte differentiation was analyzed in in vitro human Chub-S7 cell line model. For measurement of the effects of SQV the drug was added to differentiated or non-differentiated cells. The influence of SQV on changes in the profile of gene expression was verified by microarray and changes in lipid species content were analyzed using GC-MS/MS. Results were confirmed by real-time PCR and analysis of autophagy. Addition of SQV to differentiated Chub-S7 cells lead to removal of lipids deposited in lipid droplets, down-regulation of expression of transcription factors and markers of adipocyte differentiation. Antiviral activity of SQV based on its non-selective inhibition of proteases resulted in proteasome inhibition, induction of endoplasmic reticulum stress and induction of macroautophagy. This activity was accompanied by an increase in PI, PEPL, PC lipid species especially with MUFA and PUFA. Additionally up-regulation of miR-100-3p, miR-222-5p, miR-483-5p were found, which correlated with obesity, insulin resistance, increasing insulin secretion and activation of lipolysis. Our results indicated that SQV, by inhibition of proteasome protein degradation, activated the unfolded protein response resulting in autophagic breakdown of lipids deposited in adipose tissue causing lipodystrophy.
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PMID:The human immunodeficiency virus (HIV1) protease inhibitor sanquinavir activates autophagy and removes lipids deposited in lipid droplets. 2861 78