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Title: Nuclear receptors associated with lipid metabolism and their role in the side effects associated with antiretroviral therapy
Author: Taylor-Smith, Corinne
ISNI:       0000 0004 2734 0072
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2012
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Anti-retroviral therapy comprises a combination of three or more drugs from at least two classes. Following long term therapy some patients experience metabolic side- effects including abnormal fat distribution, dyslipidaemia , lipoatrophy, hyperlipidaemia, impaired lipid and glucose metabolism. Metabolic nuclear receptors may be implicated in some of these deleterious side effects. RTV is widely implicated in the deleterious metabolic side effects of ARVs, whilst ATV has been shown to have a better lipid profile than R TV. Previous studies had not determined whether this was due to differences in intra-cellular accumulation of the two drugs. Cellular accumulation of ATV was determined to be 2 fold greater than that of RTV in the hepatic cell line, Huh7. This confirmed that the metabolic disruption and the deleterious side effects associated with RTV were not due to its higher intracellular accumulation. LXRα was significantly up-regulated by RTV, and it was determined to be a regulator of key downstream target gene expression, including SREBP-lc, PPARα, ApoA- I, VLDLR, ApoC-II and ApoC-III. Inhibition of LXRa by 22(S)-hydroxycholesterol and by siRNA knockdown ofLXRa was used to confirm these findings. Biological knockdown of LXRα by siRNA resulted in down-regulation of LXRα gene expression in the presence of RTV, which could provide a potential future therapeutic mechanism for inhibition of LXRa in vivo. LXRα was involved in the regulation of gene expression of bile acid and cholesterol transporters including: ABCAl, ABCB2, ABCGl, ABCG4, ABCG5, ABCG8 and the glucose transporter GLUT4, which were up-regulated by RTV. LXRa was involved in the regulation of ABCB 11 and ABCC2 but data suggested that LXRα was not the master regulator. Gene expression of these metabolic transporters differs in response to R TV and ATV. The actions of R TV can be blocked through modulation of LXRa gene expression. LXRα was also involved with the regulation of ABCB 1 and ABCC 1 gene expression. A polymorphism in LXRα, rs2279238C/T, could influence the risk of HADL development in Caucasian HIV+ populations. The results indicate further investigation would be required in a larger HIV cohort to substantiate this association. Elevated LDL-c levels were observed in HIV+ Caucasians homozygous GG genotype for the ApoB rs7575840GT SNP and with at least one copy of the A allele for the ABCAl rs2230806G/A SNP. The C allele in the LDLR rs1529729C/T SNP was associated with elevated total cholesterol, LDL-c and TG levels. Elevated total cholesterol and increased LDL-c levels were observed when this SNP was combined with the GG genotype for ApoB rs7575840GT and the C allele for the LDLR SNP rs2228671C/T. Decreased HDL-c was observed in HIV+ patients with the T allele of the SCARB 1 SNP rs2278986C/T when associated with a combination of demographic factors and the following SNPs: ABCAl rs2230806G/A, A allele; LDLR rs1529729C/T, C allele; ABCGl rs1893590AlC, C allele; ABCG8 rs6544713C/T, T allele; and ApoB rs693A/G, G allele. In summary the data in this thesis indicates LXRa is a regulator of metabolic target genes involved in cholesterol homeostasis, bile acid metabolism and the response to RTV in a hepatic cell line. The role of RTV as an agonist of LXRα was confirmed. The contrasting lipid profiles ofRTV and ATV are not due to higher intracellular concentration of the former. This thesis has also identified a potential therapeutic use for LXRα modulation. SNPs in LXRa and key cholesterol transporters have correlated with metabolic complications in HIV+ cohorts which merit further investigation in larger patient cohorts to validate the associations.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral