Hepatic gene expression profiling reveals perturbed calcium signaling in a mouse model lacking both LDL receptor and Apobec1 genes

Dutta, Ranjan; Singh, Uma Maheshwar; Li, Tong Bin; Fornage, Myriam; Teng, Ba Bie

doi:10.1016/s0021-9150(03)00133-3

Cited by 33 publications

(49 citation statements)

References 37 publications

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“…Thus, this phenotype resembles the pathophysiology of human familial hypercholesterolemia as previously reported (11,29,34). Another animal model is the ApoE Ϫ/Ϫ mouse, which lacks ApoE, a ligand for receptors in the liver that clear remnants of chylomicrons and VLDL from circulation.…”

Section: Apobec1supporting

confidence: 67%

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Fortilin reduces apoptosis in macrophages and promotes atherosclerosis

Pinkaew

Chen

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Atherosclerosis, a deadly disease insufficiently addressed by cholesterol-lowering drugs, needs new therapeutic strategies. Fortilin, a 172-amino acid multifunctional polypeptide, binds p53 and blocks its transcriptional activation of Bax, thereby exerting potent antiapoptotic activity. Although fortilin-overexpressing mice reportedly exhibit hypertension and accelerated atherosclerosis, it remains unknown if fortilin, not hypertension, facilitates atherosclerosis. Our objective was to test the hypothesis that fortilin in and of itself facilitates atherosclerosis by protecting macrophages against apoptosis. We generated fortilin-deficient ( fortilin+/−) mice and wild-type counterparts ( fortilin+/+) on a LDL receptor ( Ldlr)−/− apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 ( Apobec1)−/− hypercholesterolemic genetic background, incubated them for 10 mo on a normal chow diet, and assessed the degree and extent of atherosclerosis. Despite similar blood pressure and lipid profiles, fortilin+/− mice exhibited significantly less atherosclerosis in their aortae than their fortilin +/+ littermate controls. Quantitative immunostaining and flow cytometry analyses showed that the atherosclerotic lesions of fortilin+/− mice contained fewer macrophages than those of fortilin+/+ mice. In addition, there were more apoptotic cells in the intima of fortilin+/− mice than in the intima of fortilin+/+ mice. Furthermore, peritoneal macrophages from fortilin+/− mice expressed more Bax and underwent increased apoptosis, both at the baseline level and in response to oxidized LDL. Finally, hypercholesterolemic sera from Ldlr−/− Apobec1−/− mice induced fortilin in peritoneal macrophages more robustly than sera from control mice. In conclusion, fortilin, induced in the proatherosclerotic microenvironment in macrophages, protects macrophages against Bax-induced apoptosis, allows them to propagate, and accelerates atherosclerosis. Anti-fortilin therapy thus may represent a promising next generation antiatherosclerotic therapeutic strategy.

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Section: Apobec1supporting

confidence: 67%

“…Ϫ/Ϫ mice were originally generated by crossbreeding Ldlr Ϫ/Ϫ mice (Jackson Lab, Bar Harbor, ME) and Apobec1 Ϫ/Ϫ mice (31c); these double-knockout mice have previously been characterized (11,34). Genotyping of Ldlr…”

Section: Apobec1mentioning

confidence: 99%

Fortilin reduces apoptosis in macrophages and promotes atherosclerosis

Pinkaew

Chen

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…It implies that any inappropriate expression of a member of the DNA deaminase family can have potential oncogenic activity. 59,60) Furthermore, most of human carcinomas were caused by APOBEC1 mediated mRNA editing. [61][62][63] Thus, the down-regulated APOBEC1 may potentially allow deactivating the tumor progression of A375 melanoma cells.…”

Section: Discussionmentioning

confidence: 99%

Toxicogenomics of Kojic Acid on Gene Expression Profiling of A375 Human Malignant Melanoma Cells

Cheng

Liu

Sheu

et al. 2006

Biological & Pharmaceutical Bulletin

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Kojic acid is a natural product and normally used as a food additive and preservative, a skin-whitening agent in cosmetics, a plant growth regulator and a chemical intermediate. Using DNA microarray technology, the overall biological effects of kojic acid on the gene expression profiling of a human skin A375 malignant melanoma cells were examined. After treatment with kojic acid, a total of 361 differentially expressed genes were distinctively changed with 136 up-regulated genes and 225 down-regulated genes. We used the bioinformatics tool to search the gene ontology and category classification of differentially expressed genes that provided the useful information of expressed genes belonging to cellular component, molecular function and biological process in regulation of melanogenesis. Seven down-regulated genes of APOBEC1, ARHGEF16, CD22, FGFR3, GALNT1, UNC5C and ZNF146 that were typically validated by the real-time quantitative PCR (RT-qPCR) analysis technology showed to be the tumor suppressor genes in melanoma cancer cells. Thus, microarray technology coupled with RT-qPCR offered a high throughput method to explore the number of differentially expressed genes responding to kojic acid and their biological functions, and led to more understanding of kojic acid effects on skin cancer therapy and related side effects. Moreover, the differentially expressed genes may become useful markers of skin malignant melanoma for further diagnostic and therapeutic applications.

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“…[16][17][18] Teng et al, [16][17][18] as well as others, 19 developed the LDb mouse model by deleting the genes encoding the LDLR and the apoB mRNA editing enzyme (Apobec1). In contrast to wild-type mice or Ldlr −/− mice, the phenotype of the LDb mice closely mimics humans with hyperlipidemia characterized by the secretion of apoB100-containing lipoproteins only, with increased plasma levels of LDL-cholesterol and decreased levels of high-density lipoprotein (HDL)-cholesterol.…”

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confidence: 99%

Proprotein Convertase Subtilisin/Kexin Type 9 Interacts With Apolipoprotein B and Prevents Its Intracellular Degradation, Irrespective of the Low-Density Lipoprotein Receptor

Sun

Samarghandi²,

Zhang³

et al. 2012

ATVB

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Objective-Proprotein convertase subtilisin/kexin type 9 (PCSK9) negatively regulates the low-density lipoprotein (LDL) receptor (LDLR) in hepatocytes and therefore plays an important role in controlling circulating levels of LDL-cholesterol. To date, the relationship between PCSK9 and metabolism of apolipoprotein B (apoB), the structural protein of LDL, has been controversial and remains to be clarified. Methods and Results-We assessed the impact of PCSK9 overexpression (≈400-fold above baseline) on apoB synthesis and secretion in 3 mouse models: wild-type C57BL/6 mice and LDLR-null mice (Ldlr −/− and Ldlr). Irrespective of LDLR expression, mice transduced with the PCSK9 gene invariably exhibited increased levels of plasma cholesterol, triacylglycerol, and apoB. Consistent with these findings, the levels of very-low-density lipoprotein and LDL were also increased whereas high-density lipoprotein levels were unchanged. Importantly, we demonstrated that endogenous PCSK9 interacted with apoB in hepatocytes. The PCSK9/apoB interaction resulted in increased production of apoB, possibly through the inhibition of intracellular apoB degradation via the autophagosome/lysosome pathway. Conclusion-We propose a new role for PCSK9 that involves shuttling between apoB and LDLR. The present study thus provides new insights into the action of PCSK9 in regulating apoB metabolism.

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Hepatic gene expression profiling reveals perturbed calcium signaling in a mouse model lacking both LDL receptor and Apobec1 genes

Cited by 33 publications

References 37 publications

Fortilin reduces apoptosis in macrophages and promotes atherosclerosis

Fortilin reduces apoptosis in macrophages and promotes atherosclerosis

Toxicogenomics of Kojic Acid on Gene Expression Profiling of A375 Human Malignant Melanoma Cells

Proprotein Convertase Subtilisin/Kexin Type 9 Interacts With Apolipoprotein B and Prevents Its Intracellular Degradation, Irrespective of the Low-Density Lipoprotein Receptor

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