Differential Deficiency of Mevalonate Kinase and Phosphomevalonate Kinase in Patients with Distinct Defects in Peroxisome Biogenesis: Evidence for a Major Role of Peroxisomes in Cholesterol Biosynthesis

1998 ◽  
Vol 247 (3) ◽  
pp. 663-667 ◽  
Author(s):  
Ronald J.A. Wanders ◽  
Gerrit-Jan Romeijn
Keyword(s):  
Cholesterol Biosynthesis ◽  
Mevalonate Kinase ◽  
Peroxisome Biogenesis ◽  
Phosphomevalonate Kinase

scholarly journals Temperature and Drug Treatments in Mevalonate Kinase Deficiency: AnEx VivoStudy

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Paola Maura Tricarico ◽  
Giulio Kleiner ◽  
Elisa Piscianz ◽  
Valentina Zanin ◽  
Lorenzo Monasta ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Mevalonate Pathway ◽  
Cholesterol Biosynthesis ◽  
Effect Of Temperature ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Febrile Condition ◽  
Inflammatory Phenotype ◽  
Drug Treatments

Mevalonate Kinase Deficiency (MKD) is a rare autosomal recessive inborn disorder of cholesterol biosynthesis caused by mutations in the mevalonate kinase (MK) gene, leading to MK enzyme decreased activity. The consequent shortage of mevalonate-derived isoprenoid compounds results in an inflammatory phenotype, caused by the activation of the NALP3 inflammasome that determines an increased caspase-1 activation and IL-1βrelease. In MKD, febrile temperature can further decrease the residual MK activity, leading to mevalonate pathway modulation and to possible disease worsening. We previously demonstrated that the administration of exogenous isoprenoids such as geraniol or the modulation of the enzymatic pathway with drugs, such as Tipifarnib, partially rescues the inflammatory phenotype associated with the defective mevalonic pathway. However, it has not been investigated yet how temperature can affect the success of these treatments. Thus, we investigated the effect of temperature on primary human monocytes from MKD patients. Furthermore the ability of geraniol and Tipifarnib to reduce the abnormal inflammatory response, already described at physiological temperature in MKD, was studied in a febrile condition. We evidenced the role of temperature in the modulation of the inflammatory events and suggested strongly considering this variable in future researches aimed at finding a treatment for MKD.

scholarly journals Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Vijay R. Varma ◽  
H. Büşra Lüleci ◽  
Anup M. Oommen ◽  
Sudhir Varma ◽  
Chad T. Blackshear ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Tissue ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
Transcriptomic Data ◽  
Brain Cholesterol ◽  
Cholesterol Levels

AbstractThe role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

scholarly journals Blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rachna Manek ◽  
Yao V. Zhang ◽  
Patricia Berthelette ◽  
Mahmud Hossain ◽  
Cathleen S. Cornell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
Animal Behavior ◽  
Phenylalanine Hydroxylase ◽  
Cholesterol Biosynthesis ◽  
Blood Phenylalanine ◽  
Liver Functions ◽  
Unknown Lipid ◽  
Pah Gene

AbstractPhenylketonuria (PKU) is a genetic deficiency of phenylalanine hydroxylase (PAH) in liver resulting in blood phenylalanine (Phe) elevation and neurotoxicity. A pegylated phenylalanine ammonia lyase (PEG-PAL) metabolizing Phe into cinnamic acid was recently approved as treatment for PKU patients. A potentially one-time rAAV-based delivery of PAH gene into liver to convert Phe into tyrosine (Tyr), a normal way of Phe metabolism, has now also entered the clinic. To understand differences between these two Phe lowering strategies, we evaluated PAH and PAL expression in livers of PAHenu2 mice on brain and liver functions. Both lowered brain Phe and increased neurotransmitter levels and corrected animal behavior. However, PAL delivery required dose optimization, did not elevate brain Tyr levels and resulted in an immune response. The effect of hyperphenylalanemia on liver functions in PKU mice was assessed by transcriptome and proteomic analyses. We observed an elevation in Cyp4a10/14 proteins involved in lipid metabolism and upregulation of genes involved in cholesterol biosynthesis. Majority of the gene expression changes were corrected by PAH and PAL delivery though the role of these changes in PKU pathology is currently unclear. Taken together, here we show that blood Phe lowering strategy using PAH or PAL corrects both brain pathology as well as previously unknown lipid metabolism associated pathway changes in liver.

Mevalonate Kinase Deficiency: Disclosing the Role of Mevalonate Pathway Modulation in Inflammation

2012 ◽  
Vol 18 (35) ◽  
pp. 5746-5752 ◽  
Author(s):  
Annalisa Marcuzzi ◽  
Sergio Crovella ◽  
Lorenzo Monasta ◽  
Liza Vecchi Brumatti ◽  
Marco Gattorno ◽  
...  
Keyword(s):  
Mevalonate Pathway ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase

Peroxisomal membrane proteins are properly targeted to peroxisomes in the absence of COPI- and COPII-mediated vesicular transport

2001 ◽  
Vol 114 (11) ◽  
pp. 2199-2204 ◽  
Author(s):  
Tineke Voorn-Brouwer ◽  
Astrid Kragt ◽  
Henk F. Tabak ◽  
Ben Distel
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Secretory Pathway ◽  
Human Fibroblasts ◽  
Vesicle Transport ◽  
Peroxisome Biogenesis ◽  
Peroxisomal Membrane ◽  
Classic Model ◽  
Early Secretory Pathway

The classic model for peroxisome biogenesis states that new peroxisomes arise by the fission of pre-existing ones and that peroxisomal matrix and membrane proteins are recruited directly from the cytosol. Recent studies challenge this model and suggest that some peroxisomal membrane proteins might traffic via the endoplasmic reticulum to peroxisomes. We have studied the trafficking in human fibroblasts of three peroxisomal membrane proteins, Pex2p, Pex3p and Pex16p, all of which have been suggested to transit the endoplasmic reticulum before arriving in peroxisomes. Here, we show that targeting of these peroxisomal membrane proteins is not affected by inhibitors of COPI and COPII that block vesicle transport in the early secretory pathway. Moreover, we have obtained no evidence for the presence of these peroxisomal membrane proteins in compartments other than peroxisomes and demonstrate that COPI and COPII inhibitors do not affect peroxisome morphology or integrity. Together, these data fail to provide any evidence for a role of the endoplasmic reticulum in peroxisome biogenesis.

scholarly journals HSF1 Regulates Mevalonate and Cholesterol Biosynthesis Pathways

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1363 ◽  
Author(s):  
Hyeji Kang ◽  
Taerim Oh ◽  
Young Yil Bahk ◽  
Geon-Hee Kim ◽  
Sang-Yeon Kan ◽  
...  
Keyword(s):  
Cholesterol Biosynthesis ◽  
Metabolic Stress ◽  
Mapk Signaling ◽  
Heat Shock Factor 1 ◽  
Antiproliferative Effects ◽  
Proteotoxic Stress ◽  
Cholesterol Biosynthesis Pathway ◽  
Increased Activity ◽  
Essential Transcription Factor

Heat shock factor 1 (HSF1) is an essential transcription factor in cellular adaptation to various stresses such as heat, proteotoxic stress, metabolic stress, reactive oxygen species, and heavy metals. HSF1 promotes cancer development and progression, and increased HSF1 levels are frequently observed in multiple types of cancers. Increased activity in the mevalonate and cholesterol biosynthesis pathways, which are very important for cancer growth and progression, is observed in various cancers. However, the functional role of HSF1 in the mevalonate and cholesterol biosynthesis pathways has not yet been investigated. Here, we demonstrated that the activation of RAS-MAPK signaling through the overexpression of H-RasV12 increased HSF1 expression and the cholesterol biosynthesis pathway. In addition, the activation of HSF1 was also found to increase cholesterol biosynthesis. Inversely, the suppression of HSF1 by the pharmacological inhibitor KRIBB11 and short-hairpin RNA (shRNA) reversed H-RasV12-induced cholesterol biosynthesis. From the standpoint of therapeutic applications for hepatocellular carcinoma (HCC) treatment, HSF1 inhibition was shown to sensitize the antiproliferative effects of simvastatin in HCC cells. Overall, our findings demonstrate that HSF1 is a potential target for statin-based HCC treatment.

scholarly journals Role of Multidrug Resistance P-glycoproteins in Cholesterol Biosynthesis

1996 ◽  
Vol 271 (5) ◽  
pp. 2634-2640 ◽  
Author(s):  
James E. Metherall ◽  
Huijuan Li ◽  
Kathleen Waugh
Keyword(s):  
Multidrug Resistance ◽  
Cholesterol Biosynthesis
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