scholarly journals ALS-Causing Protein TDP-43 Impairs SREBP2 Cholesterol Regulation

2021 ◽  
Author(s):  
Naohiro Egawa ◽  
Yuishin Izumi ◽  
Itaru Tsuge ◽  
Koji Fujita ◽  
Hitoshi Shimano ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Binding Protein ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Transcriptome Profiling ◽  
Cholesterol Homeostasis ◽  
Neuronal Cultures ◽  
Element Binding Protein ◽  
Induced Pluripotent ◽  
Als Patients

Abstract Dyslipidemia is correlated with the prognosis of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder characterized pathologically by TAR DNA binding protein (TDP-43) inclusions. We investigated molecular mechanisms of lipid metabolism regulated by TDP-43 in ALS. Expression microarray and RNA deep sequencing (RNA-Seq) were performed using cell lines expressing doxycycline-inductive TDP-43. Gene expression and transcriptome profiling identified 434 significantly altered genes under high levels of TDP-43 (Tukey’s test, P < 0.05) including sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol homeostasis and its downstream genes. TDP-43 overexpression impaired SREBP2 transcriptional activity, leading to inhibition of cholesterol biosynthesis via the nutrient- and growth factor-responsive kinase mTOR Complex I (mTORC1). The amount of cholesterol was significantly decreased in motor neuronal cultures derived from ALS-patient induced pluripotent stem cells (iPSCs) as well as in the spinal fluids of ALS patients and in the spinal cord of ALS model mice. Impairment of cholesterol synthesis is caused by an increase in toxic function of TDP-43 in ALS.

scholarly journals Quercetin 3-Glucoside Protects Neuroblastoma (SH-SY5Y) Cellsin Vitroagainst Oxidative Damage by Inducing Sterol Regulatory Element-binding Protein-2-mediated Cholesterol Biosynthesis

2007 ◽  
Vol 283 (4) ◽  
pp. 2231-2245 ◽  
Author(s):  
Ramani Soundararajan ◽  
Alexander D. Wishart ◽  
H. P. Vasantha Rupasinghe ◽  
Mayi Arcellana-Panlilio ◽  
Carolanne M. Nelson ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Binding Protein ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

scholarly journals Maprotiline Suppresses Cholesterol Biosynthesis and Hepatocellular Carcinoma Progression Through Direct Targeting of CRABP1

2021 ◽  
Vol 12 ◽  
Author(s):  
Cancan Zheng ◽  
Yidong Zhu ◽  
Qinwen Liu ◽  
Tingting Luo ◽  
Wenwen Xu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Binding Protein ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Antitumor Effects ◽  
Element Binding Protein ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related death and has a poor prognosis worldwide, thus, more effective drugs are urgently needed. In this article, a small molecule drug library composed of 1,056 approved medicines from the FDA was used to screen for anticancer drugs. The tetracyclic compound maprotiline, a highly selective noradrenergic reuptake blocker, has strong antidepressant efficacy. However, the anticancer effect of maprotiline remains unclear. Here, we investigated the anticancer potential of maprotiline in the HCC cell lines Huh7 and HepG2. We found that maprotiline not only significantly restrained cell proliferation, colony formation and metastasis in vitro but also exerted antitumor effects in vivo. In addition to the antitumor effect alone, maprotiline could also enhance the sensitivity of HCC cells to sorafenib. The depth studies revealed that maprotiline substantially decreased the phosphorylation of sterol regulatory element-binding protein 2 (SREBP2) through the ERK signaling pathway, which resulted in decreased cholesterol biosynthesis and eventually impeded HCC cell growth. Furthermore, we identified cellular retinoic acid binding protein 1 (CRABP1) as a direct target of maprotiline. In conclusion, our study provided the first evidence showing that maprotiline could attenuate cholesterol biosynthesis to inhibit the proliferation and metastasis of HCC cells through the ERK-SREBP2 signaling pathway by directly binding to CRABP1, which supports the strategy of repurposing maprotiline in the treatment of HCC.

scholarly journals Ring finger protein 5 activates sterol regulatory element–binding protein 2 (SREBP2) to promote cholesterol biosynthesis via inducing polyubiquitination of SREBP chaperone SCAP

2020 ◽  
Vol 295 (12) ◽  
pp. 3918-3928 ◽  
Author(s):  
Yen-Chou Kuan ◽  
Yu Takahashi ◽  
Takashi Maruyama ◽  
Makoto Shimizu ◽  
Yoshio Yamauchi ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Cholesterol Metabolism ◽  
Binding Protein ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Ring Finger ◽  
Ring Finger Protein ◽  
Finger Protein ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Sterol regulatory element–binding protein 2 (SREBP2) is the master transcription factor that regulates cholesterol metabolism. SREBP2 activation is regulated by SREBP chaperone SCAP. Here we show that ring finger protein 5 (RNF5), an endoplasmic reticulum-anchored E3 ubiquitin ligase, mediates the Lys-29–linked polyubiquitination of SCAP and thereby activates SREBP2. RNF5 knockdown inhibited SREBP2 activation and reduced cholesterol biosynthesis in human hepatoma cells, and RNF5 overexpression activated SREBP2. Mechanistic studies revealed that RNF5 binds to the transmembrane domain of SCAP and ubiquitinates the Lys-305 located in cytosolic loop 2 of SCAP. Moreover, the RNF5-mediated ubiquitination enhanced an interaction between SCAP luminal loop 1 and loop 7, a crucial event for SREBP2 activation. Notably, an overexpressed K305R SCAP variant failed to restore the SREBP2 pathway in SCAP-deficient cell lines. These findings define a new mechanism by which an ubiquitination-induced SCAP conformational change regulates cholesterol biosynthesis.

scholarly journals Suppression of the Basic Transcription Element-Binding Protein in Brain Neuronal Cultures Inhibits Thyroid Hormone-Induced Neurite Branching

Endocrinology ◽  
2002 ◽  
Vol 143 (6) ◽  
pp. 2242-2249 ◽  
Author(s):  
Christelle Cayrou ◽  
Robert J. Denver ◽  
Jack Puymirat
Keyword(s):  
Thyroid Hormone ◽  
Molecular Mechanisms ◽  
Binding Protein ◽  
Neuronal Population ◽  
Neuronal Cultures ◽  
Dependent Manner ◽  
Element Binding Protein ◽  
Antisense Odns ◽  
Developing Rat ◽  
Dose Dependent

Abstract The molecular mechanisms underlying the effect of thyroid hormone (T3) on neurite outgrowth are unknown. We recently identified the small GC-box binding protein BTEB (basic transcription element-binding protein) as a T3-regulated gene in the developing rat brain. BTEB mRNAs are rapidly (by 1 h) up-regulated by T3 in primary rat embryonic neuronal cultures. Antisense oligodeoxynucleotides (ODNs), added to the cultures, reduced by 60% the level of BTEB mRNA. Addition of BTEB antisense ODNs to the cultures, before the onset of neurite polarity, had no effect on neurite elaboration but significantly decreased, in a dose-dependent manner, the effect of T3 on neurite branching. We then examined the effects of antisense ODNs on a thyroid hormone target neuronal population, i.e. the acetylcholinesterase-positive neurons after the onset of neurite polarity. Exposure to BTEB antisense ODNs completely abolished the effects of T3 on neurite branching and on the elaboration of neuritic filopodia-like structures in acetylcholinesterase cells. By contrast, antisense ODNs did not alter the effect of T3 on neurite length. Our results show that titration of BTEB levels by T3 regulates the degree of neurite branching and that the T3-induced neurite elongation and the T3-induced neurite branching are regulated by distinct mechanisms.

scholarly journals Transcriptome Profiling Reveals Novel Candidate Genes Related to Hippocampal Dysfunction in SREBP-1c Knockout Mice

2020 ◽  
Vol 21 (11) ◽  
pp. 4131
Author(s):  
Mary Jasmin Ang ◽  
Juhwan Kim ◽  
Sueun Lee ◽  
Sung-Ho Kim ◽  
Jong-Choon Kim ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Biological Effects ◽  
Regulatory Element ◽  
Transcriptome Profiling ◽  
Hippocampal Neurogenesis ◽  
Lipid Homeostasis ◽  
Molecular Evidence ◽  
Protein Levels ◽  
Parkinson’S Diseases ◽  
Element Binding Protein

Lipid homeostasis is an important component of brain function, and its disturbance causes several neurological disorders, such as Huntington’s, Alzheimer’s, and Parkinson’s diseases as well as mood disorders. Sterol regulatory element-binding protein-1c (SREBP-1c) is a key modulatory molecule involved in lipid homeostasis in the central nervous system. However, little is known about the biological effects of SREBP-1c in the brain. Our previous study uncovered that mice deficient in SREBP-1c exhibit schizophrenia-like behaviors. To investigate whether there are novel molecular mechanisms involved in the neurological aberrations caused by SREBP-1c deficiency, we analyzed the transcriptomes of the hippocampus of SREBP-1c knockout (KO) mice and wild-type mice. We found seven differentially expressed genes (three up-regulated and four down-regulated genes) in the hippocampus of SREBP-1c KO mice. For further verification, we selected the three most significantly changed genes: glucagon-like peptide 2 receptors (GLP2R) involved in hippocampal neurogenesis and neuroplasticity as well as in cognitive impairments; necdin (NDN) which is related to neuronal death and neurodevelopmental disorders; and Erb-B2 receptor tyrosine kinase 4 (ERBB4) which is a receptor for schizophrenia-linked protein, neuregulin-1. The protein levels of GLP2R and NDN were considerably decreased, but the level of ERBB4 was significantly increased in the hippocampus of SREBP-1c KO mice. However, further confirmation is warranted to establish the translatability of these findings from this rodent model into human patients. We suggest that these data provide novel molecular evidence for the modulatory role of SREBP-1c in the mouse hippocampus.

scholarly journals Dysregulation of Sterol Regulatory Element-Binding Protein 2 Gene in HIV Treatment-Experienced Individuals

2019 ◽  
Author(s):  
Anuoluwapo Sopeyin ◽  
Lei Zhou ◽  
Min Li ◽  
Lydia Barakat ◽  
Elijah Paintsil
Keyword(s):  
Binding Protein ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hiv Treatment ◽  
Density Lipoprotein Receptor ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Lipid Abnormalities

AbstractWe investigated the effects of antiretroviral therapy (ART) on cholesterol biosynthesis in a case-control study. mRNA and protein expressions of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and ATP binding cassette transporter A1 (ABCA1) were significantly upregulated in cases (HIV+) compared to controls (HIV-). We observed dysregulation between sterol regulatory element-binding protein 2 (SREBP-2, sensory control) and HMGCR and low-density lipoprotein receptor (LDLR) pathways. Dysregulation of cholesterol biosynthesis genes may predate clinical manifestation of ART-induced lipid abnormalities.

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