Human low-density lipoprotein receptor gene and its regulation

Kong, Weijia; Liu, Jingwen; Jiang, Jian‐Dong

doi:10.1007/s00109-005-0717-6

Cited by 48 publications

(39 citation statements)

References 81 publications

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“…However, the cholesterollowering efficacy of BBR seems to be mainly attributable to LDL receptor up-regulation. 3,4) Our previous results showed that BBR increased LDL receptor mRNA stability and expression level in an extracellular signal-regulated kinase (ERK)-dependent manner; as BBR could activate ERK directly in liver cells and U0126, a specific inhibitor of mitogen-activated protein kinase kinase (MAPKK or MEK) could abolish the effects of BBR on LDL receptor.4) These results suggest that BBR up-regulates LDL receptor through the ERK MAPK signal-transduction pathway which may include the sequential activation of three kinases: Raf-1, MEK, and ERK.12) The ERK MAPK cascade could be activated by various extracellular stimuli and could help to transduce signals from cell surface to nucleus. Numerous studies demonstrate that the ERK MAPK cascade has close relationship to cell proliferation, differentiation, migration and death.…”

mentioning

confidence: 99%

Berberine Up-Regulates Hepatic Low-Density Lipoprotein Receptor through Ras-Independent but AMP-Activated Protein Kinase-Dependent Raf-1 Activation

Jiang

Kong

2014

Biological & Pharmaceutical Bulletin

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Our previous studies showed that berberine (BBR) increases liver low-density lipoprotein (LDL) receptor expression in an extracellular signal-regulated kinase (ERK)-dependent manner. This study was designed to explore the upstream cellular signaling molecules recruited by BBR to activate the ERK mitogen-activated protein kinase (MAPK) cascade. Chemical inhibitors such as GW5074, manumycin A, and compound C or specific small interfering RNAs (siRNAs) were used in the blocking experiments; Western blot was used to determine the phosphorylation of kinases; real-time reverse transcriptase polymerase chain reaction (RT-PCR) was used to determine the expression level of LDL receptor mRNA. Our results indicate that BBR increases p-Raf-1 (ser338) level time and dose dependently in HL-7702 cells, but has no influence on Ras activity; the stimulating activities of BBR on Raf-1 signaling and LDL receptor expression can be blocked by GW5074 completely, but not by manumycin A, a Ras inhibitor. BBR activates hepatic Raf-1 signaling and up-regulates LDL receptor expression in a rat model of hyperlipidemia with no impact on liver Ras activity. Importantly, our results show that the stimulating activities of BBR on hepatic Raf-1 signaling and LDL receptor expression are totally blocked by compound C, a selective inhibitor of AMP-activated protein kinase (AMPK), and also by silencing its expression with siRNA. Taken together, our results demonstrate for the first time that BBR up-regulates LDL receptor expression through Ras-independent, but AMPK-dependent Raf-1 activation in liver cells. Our study will help to elucidate the molecular pharmacology of BBR and provide new scientific evidence for its clinical application.Key words berberine; low-density lipoprotein (LDL) receptor; Raf-1; AMP-activated protein kinase (AMPK); RasThe low-density lipoprotein (LDL) receptor is a transmembrane glycoprotein which is mainly responsible for the clearance of atherogenic lipoproteins from blood. 1) Defects of the human LDL receptor could cause familial hypercholesterolemia (FH), which may lead to atherosclerosis and coronary heart disease (CHD), if there are no medical interventions. 2)For decades, pharmacological modulation of the LDL receptor was proved to be useful to treat hypercholesterolemia and related cardiovascular diseases in clinic.3)The expression of the LDL receptor gene is subjected to complex regulations, which include transcriptional as well as post-transcriptional events.3) For example, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or "statins" could induce the transcription of the LDL receptor gene through the sterol regulatory element-binding protein (SREBP) pathway.3) And our previous studies proved that natural product berberine (BBR) was able to up-regulate the LDL receptor gene at the post-transcriptional level. 4) BBR (molecular weight: 371.8) is a kind of isoquinoline alkaloid isolated from plants such as Rhizoma coptidis (huanglian) or Hydrastis canadensis (goldenseal) and has multiple pharmaco...

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mentioning

confidence: 99%

Berberine Up-Regulates Hepatic Low-Density Lipoprotein Receptor through Ras-Independent but AMP-Activated Protein Kinase-Dependent Raf-1 Activation

Jiang

Kong

2014

Biological & Pharmaceutical Bulletin

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“…The LDL-receptor uptake and clear LDL-C from circulation. This receptor is regulated at the transcriptional or posttranscriptional level (Kong et al, 2006). Simvastatin induced the upregulation of the LDL receptor gene expression.…”

Section: Discussionmentioning

confidence: 99%

The effect of vanadium on rat hypercholesterolemia in the presence and absence of statins

Nasr¹,

Saber²,

Hussam³

et al. 2017

Afr. J. Pharm. Pharmacol.

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Vanadium may or may not be a cholesterol-lowering agent. It could potentially be used as an additional therapy or alone in therapies for treatment of dyslipidemia. This study aimed to investigate the effect of vanadium on hypercholesterolemia in the presence and absence of statins. Sixty rats were divided into five groups. The first group was kept on a normal diet and the second group was kept on a high fat diet. The three remaining groups of rats were prepared for the treatment; one group received simvastatin, one was given vanadium, and the third group was tested with both. Blood samples from all groups were investigated. Body functions were considered a tool in expressing efficacy and toxicity for the three types of treatment and were compared with the control groups. Vanadium alone causes marked increases in cholesterol levels. When added to statins, all lipid values were negatively affected as compared to the statins-only treated group. Rats with high fat diets showed significant (P≤ 0.05) elevation in the levels of serum triglycerides (TG), total cholesterol (TC), low density lipoprotein concentration (LDL-C) and very low density lipoprotein concentration (VLDL-C) as compared to the control group. All generated data proved that vanadium is impracticable for treating dyslipidemia. Vanadium is not safe or efficient in therapies for lowering cholesterol and other lipid levels.

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“…This interpretation is supported by the moderate upregulation of the low density lipoprotein receptor (LDLR) at 3 and 5 h pt (3.4-and 3.3-fold, respectively) via the ERK pathway (74). LDLR is synthesized in the rough ER (73).…”

Section: Is a Function Of Pnpla8 [Intracellular Membrane-associated Cmentioning

confidence: 95%

Time-resolved gene expression profiling of human squamous cell carcinoma cells during the apoptosis process induced by photodynamic treatment with hypericin

Verwanger¹

2009

Int J Oncol

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Abstract. Hypericin is used as a powerful naturally occurring photosensitizer in photodynamic therapy (PDT). Activated by visible light, it kills tumour cells and tissues via generation of reactive oxygen species (ROS). Depending on the protocol, apoptotic cell death can be achieved very effectively by hypericin-PDT. To analyze the fundamental molecular mechanisms leading to apoptosis induced by photodamage especially with regard to human skin cancer cells, we studied the alteration of the gene expression pattern in the human squamous cell carcinoma cell line A-431 at 1.5, 3, 5 and 8 h after hypericin-PDT by cDNA-macroarray technique. Radioactively labelled samples were hybridized onto macroarray filters containing PCR products of 9738 ESTs of the Incyte Human UniGEM Microarray clone set. In total, 168 genes were found to be differentially upregulated and 45 downregulated. Verification of expression changes of 45 genes of interest was performed by quantitative real-time PCR. Due to the observed significant expression changes the following can be concluded: lipoprotein receptor-mediated endocytosis could play a role in the uptake of lipophilic hypericin. Extracellular signal transduction to the cell is reduced, cell detachment facilitated, changes of the morphology, cytoskeleton and formation of apoptotic bodies occur. The promotion of p38 MAPK , ERK, JNK and Ras signalling pathways supports survival and/or apoptosis. Switches between life and death could be the strongly upregulated transcription factors c-jun and FOSB as well as the MAPKphosphatase 1 DUSP-1, possibly activated via H3 histone modifications. ROS activate ER-stress pathways or adaptive response, and provoke damage protection against ROS, partly in a cell-type specific way.

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Human low-density lipoprotein receptor gene and its regulation

Cited by 48 publications

References 81 publications

Berberine Up-Regulates Hepatic Low-Density Lipoprotein Receptor through Ras-Independent but AMP-Activated Protein Kinase-Dependent Raf-1 Activation

Berberine Up-Regulates Hepatic Low-Density Lipoprotein Receptor through Ras-Independent but AMP-Activated Protein Kinase-Dependent Raf-1 Activation

The effect of vanadium on rat hypercholesterolemia in the presence and absence of statins

Time-resolved gene expression profiling of human squamous cell carcinoma cells during the apoptosis process induced by photodynamic treatment with hypericin

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