High levels of homocysteine downregulate apolipoprotein E expression<i>via</i>nuclear factor kappa B

Trusca, Violeta Georgeta; Mihai, Adina D; Fuior, Elena Valeria; Fenyo, Ioana Mădălina; Gafencu, Anca Violeta

doi:10.4331/wjbc.v7.i1.178

Cited by 7 publications

(5 citation statements)

References 52 publications

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“…An enrichment of H3K9me3, but not H3K27me3, to the promoter region of Alkbh5 gene locus was observed in IEC4.1 cells following C. parvum infection ( Figure 3E ) or TNF-α stimulation ( Figure S5 ). Consistent with results from previous studies ( 41 , 42 ), the enrichment of p65, H3K9me3, and H3K27me3 to the promoter region of ApoE gene locus, an NF-кB-associated downregulating gene, was detected in infected IEC4.1 cells as a control ( Figure 3E ). These data suggest that NF-кB signaling may count for the suppression of Alkbh5 in cells following C. parvum infection or TNF-α stimulation.…”

Section: Resultssupporting

confidence: 92%

m6A mRNA Methylation Regulates Epithelial Innate Antimicrobial Defense Against Cryptosporidial Infection

Xia

et al. 2021

Front. Immunol.

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Increasing evidence supports that N6-methyladenosine (m6A) mRNA modification may play an important role in regulating immune responses. Intestinal epithelial cells orchestrate gastrointestinal mucosal innate defense to microbial infection, but underlying mechanisms are still not fully understood. In this study, we present data demonstrating significant alterations in the topology of host m6A mRNA methylome in intestinal epithelial cells following infection by Cryptosporidium parvum, a coccidian parasite that infects the gastrointestinal epithelium and causes a self-limited disease in immunocompetent individuals but a life-threatening diarrheal disease in AIDS patients. Altered m6A methylation in mRNAs in intestinal epithelial cells following C. parvum infection is associated with downregulation of alpha-ketoglutarate-dependent dioxygenase alkB homolog 5 and the fat mass and obesity-associated protein with the involvement of NF-кB signaling. Functionally, m6A methylation statuses influence intestinal epithelial innate defense against C. parvum infection. Specifically, expression levels of immune-related genes, such as the immunity-related GTPase family M member 2 and interferon gamma induced GTPase, are increased in infected cells with a decreased m6A mRNA methylation. Our data support that intestinal epithelial cells display significant alterations in the topology of their m6A mRNA methylome in response to C. parvum infection with the involvement of activation of the NF-кB signaling pathway, a process that modulates expression of specific immune-related genes and contributes to fine regulation of epithelial antimicrobial defense.

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Section: Resultssupporting

confidence: 92%

m6A mRNA Methylation Regulates Epithelial Innate Antimicrobial Defense Against Cryptosporidial Infection

Xia

et al. 2021

Front. Immunol.

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“…Elevated homocysteine (Hcy) is a risk factor for AD [ 156 ], positively associated with ApoE4 status [ 157 ], and it is generally accepted that lower Hcy levels are desirable. Interestingly, Hcy can decrease ApoE gene expression in an NFκB-dependent manner [ 158 ]. Since ApoE is required for cholesterol transport within the brain, and ApoE4 astrocytes already exhibit impaired transport ability [ 49 , 50 ], elevated Hcy could exacerbate a metabolic deficiency.…”

Section: Precision Nutrition Considerationsmentioning

confidence: 99%

Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers

et al. 2021

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The ApoE4 allele is the most well-studied genetic risk factor for Alzheimer’s disease, a condition that is increasing in prevalence and remains without a cure. Precision nutrition targeting metabolic pathways altered by ApoE4 provides a tool for the potential prevention of disease. However, no long-term human studies have been conducted to determine effective nutritional protocols for the prevention of Alzheimer’s disease in ApoE4 carriers. This may be because relatively little is yet known about the precise mechanisms by which the genetic variant confers an increased risk of dementia. Fortunately, recent research is beginning to shine a spotlight on these mechanisms. These new data open up the opportunity for speculation as to how carriers might ameliorate risk through lifestyle and nutrition. Herein, we review recent discoveries about how ApoE4 differentially impacts microglia and inflammatory pathways, astrocytes and lipid metabolism, pericytes and blood–brain barrier integrity, and insulin resistance and glucose metabolism. We use these data as a basis to speculate a precision nutrition approach for ApoE4 carriers, including a low-glycemic index diet with a ketogenic option, specific Mediterranean-style food choices, and a panel of seven nutritional supplements. Where possible, we integrate basic scientific mechanisms with human observational studies to create a more complete and convincing rationale for this precision nutrition approach. Until recent research discoveries can be translated into long-term human studies, a mechanism-informed practical clinical approach may be useful for clinicians and patients with ApoE4 to adopt a lifestyle and nutrition plan geared towards Alzheimer’s risk reduction.

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“…The tunicamycin effects in female mice may be related to reported tunicamycin-elicited changes in transcription factor activity (i.e., ATF4, ATF6, XBP, NFkB, CHOP, AP1, NFAT, TCF/LEF, and PXR) ( Jiang et al, 2016 ). In fact, it has been reported that upregulation of NFkB decreased expression of ApoE via interaction with the ApoE promoter ( Trusca et al, 2016 ). Thus, it is possible that tunicamycin may perturb SLCO1B expression in the OATP1B mice by modulating transcription factors associated with ApoE promoter, such as NFkB.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Effects of Different Models of Nonalcoholic Fatty Liver Disease in Transgenic Humanized OATP1B Mice

Bechtold,

Lynch,

Oyanna

et al. 2024

Drug Metab Dispos

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Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 (collectively, OATP1B) transporters encoded by the solute carrier organic anion transporter ( SLCO) genes mediate uptake of multiple pharmaceutical compounds. Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease (NAFLD), decreases OATP1B abundance. This research characterized the pathologic and pharmacokinetics effects of three diet- and one chemical-induced NAFLD model in male and female humanized OATP1B mice, which comprises knock-out of rodent Oatp orthologs and insertion of human SLCO1B1 and SLCO1B3. Histopathology scoring demonstrated elevated steatosis and inflammation scores for all NAFLD-treatment groups. Female mice had minor changes in SLCO1B1 expression in two of the four NAFLD treatment groups, and pitavastatin (PIT) area under the concentration-time curve (AUC) increased in female mice in only one of the diet-induced models. OATP1B3 expression decreased in male and female mice in the chemical-induced NAFLD model, with a coinciding increase in PIT AUC, indicating the chemical-induced model may better replicate changes in OATP1B3 expression and OATP substrate disposition observed in NASH patients. This research also tested a reported multifactorial pharmacokinetic interaction between NAFLD and silymarin, an extract from milk thistle seeds with notable OATP-inhibitory effects. Males showed no change in PIT AUC, whereas female PIT AUC increased 1.55-fold from the diet alone and the 1.88-fold from the combination of diet with silymarin, suggesting that female mice are more sensitive to pharmacokinetic changes than male mice. Overall, the humanized OATP1B model should be used with caution for modeling NAFLD and multifactorial pharmacokinetic interactions. SIGNIFICANCE STATEMENT Advanced stages of NAFLD cause decreased hepatic OATP1B abundance and increase systemic exposure to OATP substrates in human patients. The humanized OATP1B mouse strain may provide a clinically relevant model to recapitulate these observations and predict pharmacokinetic interactions in NAFLD. This research characterized three diet-induced and one drug-induced NAFLD model in a humanized OATP1B mouse model. Additionally, a multifactorial pharmacokinetic interaction was observed between silymarin and NAFLD.

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High levels of homocysteine downregulate apolipoprotein E expressionvianuclear factor kappa B

Abstract: Hcy-induced stress negatively modulates apoE expression via MEK1/2 and NF-κB activation. The decreased apoE expression in peripheral tissues may aggravate atherosclerosis, neurodegenerative diseases and renal dysfunctions.

Cited by 7 publications

References 52 publications

m6A mRNA Methylation Regulates Epithelial Innate Antimicrobial Defense Against Cryptosporidial Infection

m6A mRNA Methylation Regulates Epithelial Innate Antimicrobial Defense Against Cryptosporidial Infection

Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers

Pharmacokinetic Effects of Different Models of Nonalcoholic Fatty Liver Disease in Transgenic Humanized OATP1B Mice

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