Long non-coding RNA MALAT1 regulates cholesterol accumulation in ox-LDL-induced macrophages via the microRNA-17-5p/ABCA1 axis
MOLECULAR MEDICINE REPORTS
Authors: Liu, Limin; Tan, Lili; Yao, Jian; Yang, Lin
Abstract
Atherosclerosis (AS), a major cause of cardiovascular disease, has developed into a serious challenge to the health system. The long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is associated with the pathogenesis of AS. However, whether MALAT1 can affect cholesterol accumulation in macrophages during AS progression, and the potential molecular mechanism involved in this progression have not been elucidated. In the present study, the mRNA expression level of MALAT1 was measured using reverse transcription-quantitative PCR (RT-qPCR) and the protein expression level was detected via western blot analysis. Oil Red O staining was used for detecting lipid accumulation in macrophages. Bioinformatics, dual-luciferase reporter and RT-qPCR assays were used to investigate the relationship between MALAT1 and the microRNA (miR)-17-5p/ATP-binding cassette transporter A1 (ABCA1) axis. The present results suggested that the MALAT1 expression level was significantly decreased in patients with AS and in oxidized low-density lipoprotein (ox-LDL)-stimulated macrophages. Knockdown of MALAT1 increased ox-LDL uptake, lipid accumulation and the total cholesterol (T-CHO) level in ox-LDL-induced macrophages. In addition, MALAT1 inhibition significantly decreased the mRNA and protein expression levels of scavenger receptor (SR) class B member 1, apolipoprotein E (ApoE) and ABCA1. However, MALAT1 increased the expression level of SR class A. Subsequently, the present study investigated whether MALAT1 could target miR-17-5p to regulate the expression level of ABCA1, which is involved in cholesterol efflux from macrophages. The present results suggested that inhibition of miR-17-5p reversed the effects of MALAT1 knockdown on T-CHO content, and protein expression levels of ApoE and ABCA1 in ox-LDL-stimulated macrophages. In summary, knockdown of MALAT1 may promote cholesterol accumulation by regulating the miR-17-5p/ABCA1 axis in ox-LDL-induced THP-1 macrophages.
Association of single nucleotide polymorphisms with dyslipidemia in antiretroviral exposed HIV patients in a Ghanaian population: A case-control study
PLOS ONE
Authors: Obirikorang, Christian; Acheampong, Emmanuel; Quaye, Lawrence; Yorke, Joseph; Amos-Abanyie, Ernestine Kubi; Akyaw, Priscilla Abena; Anto, Enoch Odame; Bani, Simon Bannison; Asamoah, Evans Adu; Batu, Emmanuella Nsenbah
Abstract
Dyslipidemia is a potential complication of long-term usage of antiretroviral therapy (ART) and also known to be associated with genetic factors. The host genetic variants associated with dyslipidemia in HIV patients on ART in Ghana have not been fully explored. The study constituted a total of 289 HIV-infected patients on stable ART for at least a year. Fasting blood was collected into EDTA tube for lipids measurement. Lipid profiles were used to define dyslipidemia based on the NCEP-ATP III criteria. HIV-infected subjects were categorized into two groups; those with dyslipidemia (cases) (n = 90; 31.1%) and without dyslipidemia (controls)(n = 199; 68.9%). Four candidate single nucleotide polymorphism (SNP) genes (ABCA1-rs2066714, LDLR-rs6511720, APOA5-rs662799 and DSCAML1-rs10892151) were determined. Genotyping was performed on isolated genomic DNA of study participants using PCR followed by a multiplex ligation detection reaction (LDR). The percentage of the population who had the rare homozygote alleles for rs6511720 (T/T), rs2066714 (G/G), rs10892151 (T/T) and rs662799 (G/G) among case subjects were 5.5%, 14.4%, 6.6% and 10.0% whiles 2.0% 9.1%, 6.5% and 4.0% were observed among control subjects. There were statistically significant differences in the genotypic prevalence of APOA5 (p = 0.0357) and LDLR polymorphisms (p = 0.0387) between case and control subjects. Compared to the AA genotype of the APOA5 polymorphisms, individuals with the rare homozygote genotype [aOR = 2.38, 95%CI(1.06-6.54), p = 0.004] were significantly associated with an increased likelihood of developing dyslipidemia after controlling for age, gender, treatment duration, CD4 counts and BMI. Moreover, individuals with the rare homozygous genotype of ABCA1 (G/G) [aOR = 10.7(1.3-88.7), p = 0.0280] and LDLR (rs6511720) G>T [aOR = 61.2(7.6-493.4), p<0.0001) were more likely to have high levels of total cholesterol levels. Our data accentuate the presence of SNPs in four candidate genes and their association with dyslipidemia among HIV patients exposed to ART in the Ghanaian population, especially variants in APOA5-rs662799 and LDLR rs6511720 respectively. These findings provide baseline information that necessitates a pre-symptomatic strategy for monitoring dyslipidemia in ART-treated HIV patients. There is a need for longitudinal studies to validate a comprehensive number of SNPs and their associations with dyslipidemia.