Impaired plasmalogen synthesis dysregulates liver X receptor-dependent transcription in cerebellum

2019 ◽  
Vol 166 (4) ◽  
pp. 353-361 ◽  
Author(s):  
Masanori Honsho ◽  
Fabian Dorninger ◽  
Yuichi Abe ◽  
Daiki Setoyama ◽  
Ryohei Ohgi ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Cholesterol Biosynthesis ◽  
Wild Type Mouse ◽  
Fatty Acyl ◽  
Cholesterol Homeostasis ◽  
Squalene Epoxidase ◽  
Peroxisomal Membrane ◽  
X Receptors ◽  
The Stability ◽  
Coa Reductase

Abstract Synthesis of ethanolamine plasmalogen (PlsEtn) is regulated by modulating the stability of fatty acyl-CoA reductase 1 (Far1) on peroxisomal membrane, a rate-limiting enzyme in plasmalogen synthesis. Dysregulation of plasmalogen homeostasis impairs cholesterol biosynthesis in cultured cells by altering the stability of squalene epoxidase (SQLE). However, regulation of PlsEtn synthesis and physiological consequences of plasmalogen homeostasis in tissues remain unknown. In the present study, we found that the protein but not the transcription level of Far1 in the cerebellum of the Pex14 mutant mouse expressing Pex14p lacking its C-terminal region (Pex14ΔC/ΔC) is higher than that from wild-type mouse, suggesting that Far1 is stabilized by the lowered level of PlsEtn. The protein level of SQLE was increased, whereas the transcriptional activity of the liver X receptors (LXRs), ligand-activated transcription factors of the nuclear receptor superfamily, is lowered in the cerebellum of Pex14ΔC/ΔC and the mice deficient in dihydroxyacetonephosphate acyltransferase, the initial enzyme for the synthesis of PlsEtn. These results suggest that the reduction of plasmalogens in the cerebellum more likely compromises the cholesterol homeostasis, thereby reducing the transcriptional activities of LXRs, master regulators of cholesterol homeostasis.

scholarly journals LXRβ controls glioblastoma cell growth, lipid balance, and immune modulation independently of ABCA1

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Deven Patel ◽  
Fahim Ahmad ◽  
Diane M. Kambach ◽  
Qian Sun ◽  
Alan S. Halim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Modulation ◽  
Cell Cycle Progression ◽  
Mevalonate Pathway ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
Immune Response Gene ◽  
Glioblastoma Cells ◽  
X Receptors ◽  
Patient Prognosis

Abstract Cholesterol is a critical component of membranes and a precursor for hormones and other signaling molecules. Previously, we showed that unlike astrocytes, glioblastoma cells do not downregulate cholesterol synthesis when plated at high density. In this report, we show that high cell density induces ABCA1 expression in glioblastoma cells, enabling them to get rid of excess cholesterol generated by an activated cholesterol biosynthesis pathway. Because oxysterols are agonists for Liver X Receptors (LXRs), we investigated whether increased cholesterol activates LXRs to maintain cholesterol homeostasis in highly-dense glioblastoma cells. We observed that dense cells had increased oxysterols, which activated LXRβ to upregulate ABCA1. Cells with CRISPR-mediated knockdown of LXRβ, but not ABCA1, had decreased cell cycle progression and cell survival, and decreased feedback repression of the mevalonate pathway in densely-plated glioma cells. LXRβ gene expression poorly correlates with ABCA1 in glioblastoma patients, and expression of each gene correlates with poor patient prognosis in different prognostic subtypes. Finally, gene expression and lipidomics analyses cells revealed that LXRβ regulates the expression of immune response gene sets and lipids known to be involved in immune modulation. Thus, therapeutic targeting of LXRβ in glioblastoma might be effective through diverse mechanisms.

scholarly journals An alternative membrane topology permits lipid droplet localization of peroxisomal fatty acyl-CoA reductase 1

2018 ◽  
Author(s):  
Tarik Exner ◽  
Inés Romero-Brey ◽  
Eden Yifrach ◽  
Jhon Rivera-Monroy ◽  
Bianca Schrul ◽  
...  
Keyword(s):  
Lipid Droplet ◽  
Lipid Droplets ◽  
Subcellular Fractionation ◽  
Fatty Acyl ◽  
Membrane Topology ◽  
Unexpected Finding ◽  
Peroxisomal Membrane ◽  
Fluorescent Reporter ◽  
Coa Reductase ◽  
Exclusive Group

AbstractFatty acyl-CoA reductase 1 (Far1) is an ubiquitously expressed peroxisomal membrane protein generating fatty alcohols required for the biosynthesis of ether lipids.Lipid droplet localization of human Far1 was observed by fluorescence microscopy under conditions of increased triglyceride synthesis in tissue culture cells. This unexpected finding was supported further by correlative light electron microscopy and subcellular fractionation. Selective permeabilization and N-glycosylation tagging suggest that Far1 is able to assume two different membrane topologies, differing in the orientation of the short hydrophilic C-terminus towards the lumen or the cytosol, respectively. Two closely spaced hydrophobic domains are contained within the C-terminal region. When analyzed separately, the second domain was sufficient for the localization of a fluorescent reporter to lipid droplets. Targeting of Far1 to lipid droplets was not impaired in either pex19 or TRC40/ASNA1 CRISPR/Cas9 knockout cells.In conclusion, our data suggest that Far1 is a novel member of the rather exclusive group of dual topology membrane proteins. At the same time, Far1 shows lipid metabolism-dependent differential subcellular localizations to peroxisomes and lipid droplets.

scholarly journals LXRβ controls glioblastoma cell growth, lipid balance, and immune modulation independently of ABCA1

2019 ◽  
Author(s):  
Deven Patel ◽  
Fahim Ahmad ◽  
Diane M. Kambach ◽  
Qian Sun ◽  
Alan S. Halim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Modulation ◽  
Cell Cycle Progression ◽  
Mevalonate Pathway ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
Immune Response Gene ◽  
Glioblastoma Cells ◽  
X Receptors ◽  
Patient Prognosis

Cholesterol is a critical component of membranes and a precursor for hormones and other signaling molecules. Previously, we showed that unlike astrocytes, glioblastoma cells do not downregulate cholesterol synthesis when plated at high density. In this report, we show that high cell density induces ABCA1 expression in glioblastoma cells, enabling them to get rid of excess cholesterol generated by an activated cholesterol biosynthesis pathway. Because oxysterols are agonists for Liver X Receptors (LXRs), we investigated whether increased cholesterol activates LXRs to maintain cholesterol homeostasis in highly-dense glioblastoma cells. We observed that dense cells had increased oxysterols, which activated LXRβ to upregulate ABCA1. Cells with CRISPR-mediated knockdown of LXRβ, but not ABCA1, had decreased cell cycle progression and cell survival, and decreased feedback repression of the mevalonate pathway in densely-plated glioma cells. LXRβ gene expression poorly correlates with ABCA1 in glioblastoma patients, and expression of each gene correlates with poor patient prognosis in different prognostic subtypes. Finally, gene expression and lipidomics analyses of crLXRβ cells revealed that LXRβ regulates the expression of immune response gene sets and lipids known to be involved in immune modulation. Thus, therapeutic targeting of LXRβ in glioblastoma might be effective through diverse mechanisms.

scholarly journals LXR as a novel antithrombotic target

Blood ◽  
2011 ◽  
Vol 117 (21) ◽  
pp. 5751-5761 ◽  
Author(s):  
Michael Spyridon ◽  
Leonardo A. Moraes ◽  
Chris I. Jones ◽  
Tanya Sage ◽  
Parvathy Sasikumar ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Human Platelets ◽  
Cholesterol Homeostasis ◽  
In Vivo Model ◽  
Protective Effects ◽  
Atherosclerotic Lesions ◽  
Antithrombotic Effects ◽  
X Receptors ◽  
The Stability

Abstract Liver X receptors (LXRs) are transcription factors involved in the regulation of cholesterol homeostasis. LXR ligands have athero-protective properties independent of their effects on cholesterol metabolism. Platelets are involved in the initiation of atherosclerosis and despite being anucleate express nuclear receptors. We hypothesized that the athero-protective effects of LXR ligands could be in part mediated through platelets and therefore explored the potential role of LXR in platelets. Our results show that LXR-β is present in human platelets and the LXR ligands, GW3965 and T0901317, modulated nongenomically platelet aggregation stimulated by a range of agonists. GW3965 caused LXR to associate with signaling components proximal to the collagen receptor, GPVI, suggesting a potential mechanism of LXR action in platelets that leads to diminished platelet responses. Activation of platelets at sites of atherosclerotic lesions results in thrombosis preceding myocardial infarction and stroke. Using an in vivo model of thrombosis in mice, we show that GW3965 has antithrombotic effects, reducing the size and the stability of thrombi. The athero-protective effects of GW3965, together with its novel antiplatelet/thrombotic effects, indicate LXR as a potential target for prevention of athero-thrombotic disease.

scholarly journals A key mammalian cholesterol synthesis enzyme, squalene monooxygenase, is allosterically stabilized by its substrate

2020 ◽  
Vol 117 (13) ◽  
pp. 7150-7158 ◽  
Author(s):  
Hiromasa Yoshioka ◽  
Hudson W. Coates ◽  
Ngee Kiat Chua ◽  
Yuichi Hashimoto ◽  
Andrew J. Brown ◽  
...  
Keyword(s):  
Biosynthetic Pathway ◽  
Cholesterol Synthesis ◽  
Cholesterol Biosynthesis ◽  
Squalene Epoxidase ◽  
Reporter Cell ◽  
Accelerated Degradation ◽  
Squalene Monooxygenase ◽  
Cholesterol Biosynthetic Pathway ◽  
The Stability ◽  
Rate Limiting

Cholesterol biosynthesis is a high-cost process and, therefore, tightly regulated by both transcriptional and posttranslational negative feedback mechanisms in response to the level of cellular cholesterol. Squalene monooxygenase (SM, also known as squalene epoxidase or SQLE) is a rate-limiting enzyme in the cholesterol biosynthetic pathway and catalyzes epoxidation of squalene. The stability of SM is negatively regulated by cholesterol via its N-terminal regulatory domain (SM-N100). In this study, using a SM-luciferase fusion reporter cell line, we performed a chemical genetics screen that identified inhibitors of SM itself as up-regulators of SM. This effect was mediated through the SM-N100 region, competed with cholesterol-accelerated degradation, and required the E3 ubiquitin ligase MARCH6. However, up-regulation was not observed with statins, well-established cholesterol biosynthesis inhibitors, and this pointed to the presence of another mechanism other than reduced cholesterol synthesis. Further analyses revealed that squalene accumulation upon treatment with the SM inhibitor was responsible for the up-regulatory effect. Using photoaffinity labeling, we demonstrated that squalene directly bound to the N100 region, thereby reducing interaction with and ubiquitination by MARCH6. Our findings suggest that SM senses squalene via its N100 domain to increase its metabolic capacity, highlighting squalene as a feedforward factor for the cholesterol biosynthetic pathway.

Regulation of hepatic cholesterol biosynthesis by berberine during hyperhomocysteinemia

2011 ◽  
Vol 300 (3) ◽  
pp. R635-R643 ◽  
Author(s):  
Nan Wu ◽  
Lindsei K. Sarna ◽  
Yaw L. Siow ◽  
Karmin O
Keyword(s):  
Lipid Accumulation ◽  
Reductase Activity ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
Enzyme Treatment ◽  
Hepatic Cholesterol ◽  
Hmg Coa Reductase ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Coa Reductase

Hyperhomocysteinemia, an elevation of blood homocysteine levels, is a metabolic disorder associated with dysfunction of multiple organs. We previously demonstrated that hyperhomocysteinemia stimulated hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase leading to hepatic lipid accumulation and liver injury. The liver plays an important role in cholesterol biosynthesis and overall homeostasis. HMG-CoA reductase catalyzes the rate-limiting step in cholesterol biosynthesis. Hepatic HMG-CoA reductase is a major target for lowering cholesterol levels in patients with hypercholesterolemia. The aim of the present study was to examine the effect of berberine, a plant-derived alkaloid, on hepatic cholesterol biosynthesis in hyperhomocysteinemic rats and to identify the underlying mechanism. Hyperhomocysteinemia was induced in Sprague-Dawley rats by feeding a high-methionine diet for 4 wk. HMG-CoA reductase activity was markedly elevated in the liver of hyperhomocysteinemic rats, which was accompanied by hepatic lipid accumulation. Activation of HMG-CoA reductase was caused by an increase in its gene expression and a reduction in its phophorylation (an inactive form of the enzyme). Treatment of hyperhomocysteinemic rats with berberine for 5 days inhibited HMG-CoA reductase activity and reduced hepatic cholesterol content. Such an inhibitory effect was mediated by increased phosphorylation of HMG-CoA reductase. Berberine treatment also improved liver function. These results suggest that berberine regulates hepatic cholesterol biosynthesis via increased phosphorylation of HMG-CoA reductase. Berberine may be therapeutically useful for the management of cholesterol homeostasis.

scholarly journals Schnyder corneal dystrophy-associated UBIAD1 inhibits ER-associated degradation of HMG CoA reductase in mice

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Youngah Jo ◽  
Jason S Hamilton ◽  
Seonghwan Hwang ◽  
Kristina Garland ◽  
Gennipher A Smith ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Cultured Cells ◽  
Corneal Dystrophy ◽  
Vitamin K2 ◽  
Cholesterol Homeostasis ◽  
Biosynthetic Enzyme ◽  
Hmg Coa Reductase ◽  
Golgi Transport ◽  
Coa Reductase ◽  
Schnyder Corneal Dystrophy

Autosomal-dominant Schnyder corneal dystrophy (SCD) is characterized by corneal opacification owing to overaccumulation of cholesterol. SCD is caused by mutations in UBIAD1, which utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize vitamin K2. Using cultured cells, we previously showed that sterols trigger binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase (HMGCR), thereby inhibiting its endoplasmic reticulum (ER)-associated degradation (ERAD) (Schumacher et al. 2015). GGpp triggers release of UBIAD1 from HMGCR, allowing maximal ERAD and ER-to-Golgi transport of UBIAD1. SCD-associated UBIAD1 resists GGpp-induced release and is sequestered in ER to inhibit ERAD. We now report knockin mice expressing SCD-associated UBIAD1 accumulate HMGCR in several tissues resulting from ER sequestration of mutant UBIAD1 and inhibition of HMGCR ERAD. Corneas from aged knockin mice exhibit signs of opacification and sterol overaccumulation. These results establish the physiological significance of UBIAD1 in cholesterol homeostasis and indicate inhibition of HMGCR ERAD contributes to SCD pathogenesis.

scholarly journals Liver X receptor in cholesterol metabolism

2009 ◽  
Vol 204 (3) ◽  
pp. 233-240 ◽  
Author(s):  
Chunyan Zhao ◽  
Karin Dahlman-Wright
Keyword(s):  
Dna Sequences ◽  
Target Genes ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Absorption ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Cholesterol Homeostasis ◽  
X Receptors ◽  
Derivatives Of

The liver X receptors (LXRs) are nuclear receptors that are activated by endogenous oxysterols, oxidized derivatives of cholesterol. There are two isoforms of LXR, LXRα (NR1H3) and LXRβ (NR1H2). Both LXRα and LXRβ regulate gene expression by binding to DNA sequences associated with target genes as heterodimers with isoforms of the retinoid X receptor (RXR), RXRα (NR2B1), RXRβ (NR2B2), and RXRγ (NR2B3). LXRs act as cholesterol sensors: when cellular oxysterols accumulate as a result of increasing concentrations of cholesterol, LXR induces the transcription of genes that protect cells from cholesterol overload. In this review, we summarize the roles of LXRs in controlling cholesterol homeostasis, including their roles in bile acid synthesis and metabolism/excretion, reverse cholesterol transport, cholesterol biosynthesis and uptake, and cholesterol absorption/excretion in the intestine. The overlapping and distinct roles of the LXRα and LXRβ isoforms, and the potential use of LXRs as attractive targets for treatment of cardiovascular disease are also discussed.

scholarly journals Characterizing the Role of HMG-CoA Reductase in Aryl Hydrocarbon Receptor-Mediated Liver Injury in C57BL/6 Mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Peter Dornbos ◽  
Amanda Jurgelewicz ◽  
Kelly A. Fader ◽  
Kurt Williams ◽  
Timothy R. Zacharewski ◽  
...  
Keyword(s):  
Liver Injury ◽  
Aryl Hydrocarbon Receptor ◽  
Cholesterol Biosynthesis ◽  
Competitive Inhibitor ◽  
Cholesterol Homeostasis ◽  
Hepatic Glycogen ◽  
Alcoholic Fatty Liver ◽  
Female Mice ◽  
Aryl Hydrocarbon ◽  
The Impact

Abstract The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. The prototypical ligand of the AHR is an environmental contaminant called 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD exposure is associated with many adverse health outcomes in humans including non-alcoholic fatty liver disease (NAFLD). Previous studies suggest that AHR ligands alter cholesterol homeostasis in mice through repression of genes involved in cholesterol biosynthesis, such as Hmgcr, which encodes the rate-limiting enzyme of cholesterol biosynthesis called 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR). In this study, we sought to characterize the impact of HMGCR repression in TCDD-induced liver injury. C57BL/6 mice were exposed to TCDD in the presence or absence of simvastatin, a competitive inhibitor of HMGCR. Simvastatin exposure decreased TCDD-induced hepatic lipid accumulation in both sexes, but was most prominent in females. Simvastatin and TCDD (S + T) co-treatment increased hepatic AHR-battery gene expression and liver injury in male, but not female, mice. In addition, the S + T co-treatment led to an increase in hepatic glycogen content that coincides with heavier liver in female mice. Results from this study suggest that statins, which are amongst the most prescribed pharmaceuticals, may protect from AHR-mediated steatosis, but alter glycogen metabolism and increase the risk of TCDD-elicited liver damage in a sex-specific manner.

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