Effect of rosiglitazone on HDL metabolism in subjects with metabolic syndrome and low HDL

Abstract

The metabolic syndrome consists of a cluster of abnormalities that include hypertension, abdominal obesity, impaired fasting glucose, elevated fasting triglyceride levels, and low HDL-cholesterol (HDL-C). Patients with metabolic syndrome are at increased risk of cardiovascular disease and, as a result, recommendations have been made to reduce the risk in these patients. These recommendations include therapeutic lifestyle changes and, if treatment goals are not met, pharmacological intervention ( 1 ).Currently, few drugs are available that are suitable for treating patients with two components of the metabolic syndrome, insulin resistance and low HDL-C. Among treatments available for improving insulin resistance are the thiazolidinediones (TZDs) rosiglitazone and pioglitazone, which activate the nuclear receptor peroxisome proliferatoractivated receptor ␥ (PPAR ␥ ). In addition to their insulinsensitizing effects, TZDs have been shown to increase HDL-C levels in diabetic populations ( 2 ) by up to 14% for rosiglitazone and up to 19% for pioglitazone ( 3 ). These changes in HDL-C compare favorably to HDL-C changes achieved with other drugs currently approved to treat low HDL-C levels ( 4-7 ). Although rosiglitazone and pioglitazone both activate PPAR ␥ , they each have a characteristic metabolic response in regard to plasma lipid levels, with rosiglitazone also increasing plasma triglyceride levels in the relatively short term, whereas pioglitazone does not ( 8 ).The mechanisms responsible for the HDL-C-raising effects of TZDs are currently unknown. Studies that have measured apolipoprotein A-I (apoA-I) and apoA-II levels Abstract Treatment with the peroxisome proliferator-activated receptor ␥ agonist rosiglitazone has been reported to increase HDL-cholesterol (HDL-C) levels, although the mechanism responsible for this is unknown. We sought to determine the effect of rosiglitazone on HDL apolipoprotein A-I (apoA-I) and apoA-II metabolism in subjects with metabolic syndrome and low HDL-C. Subjects were treated with placebo followed by rosiglitazone (8 mg) once daily. At the end of each 8 week treatment, subjects (n = 15) underwent a kinetic study to measure apoA-I and apoA-II production rate (PR) and fractional catabolic rate. Rosiglitazone signifi cantly reduced fasting insulin and high-sensitivity C-reactive protein (hsCRP) and increased apoA-II levels. Mean apoA-I and HDL-C levels were unchanged following rosiglitazone treatment, although there was considerable individual variability in the HDL-C response. Rosiglitazone had no effect on apoA-I metabolism, whereas the apoA-II PR was increased by 23%. The change in HDL-C in response to rosiglitazone was signifi cantly correlated with the change in apoA-II concentration but not to changes in apoA-I, measures of glucose homeostasis, or hsCRP. Treatment with rosiglitazone signifi cantly increased apoA-II production in subjects with metabolic syndrome and low HDL-C but had no effect on apoA-I metabolism. The change in HDL-C in response to rosiglitazone treatment was u...

PPARγ Represses Apolipoprotein A‐I Gene but Impedes TNFα‐Mediated ApoA‐I Downregulation in HepG2 Cells

“…Moreover, since dihydrocapsaicin upregulates both PPARg and LXRa mRNA, and protein levels and is able to block siRNA-mediated inhibition of PPARg and LXRa expression [Hu et al, 2013], it is plausible to suggest an indirect mechanism of dihydrocapsaicin action, which involves dihydrocapsaicin-mediated PPARg and LXRa mRNA stabilization rather than the role of this compound as a ligand for PPARg or LXRa. Taking into account these data and our results we suggest that PPARg effects on apoA-I gene expression might be sensitive to used PPARg ligands, which could also explain discrepancies in ApoA-I level alterations in patients treated with several PPARg agonists [Sarafidis et al, 2005;Millar et al, 2011].…”

“…There are several PPARg activating ligands, including arachidonic acid metabolites, which are produced by cyclooxygenase and lipoxygenase pathways [Forman et al, 1995;Nagy et al, 1998], and drugs, such as thiazolidinediones, including pioglitazone and rosiglitazone [Sakamoto et al, 2000]. Pioglitazone treatment results in an elevation of HDL-cholesterol (HDL-C) plasma levels [Herz et al, 2003], whereas rosiglitazone does not change HDL-C plasma levels, although considerable individual variability in the HDL-C response was observed [Millar et al, 2011]. PPARg gene expression occurs in various cell types, including hepatocytes [Kim et al, 2007] and enterocytes [Braissant et al, 1996].…”

Current and future therapies for addressing the effects of inflammation on HDL cholesterol metabolism

“…In this particular study, patients receiving aspirin, renin angiotensin system inhibitors and statins were included, which may have biased the final results. In contrast, Millar et al (2010) demonstrated that in subjects with metabolic syndrome, rosiglitazone increased the production rate of Apo-A2 with no effect on Apo-A1 metabolism. PPAR-α agonists have been shown to stimulate the synthesis of both Apo-A1 and Apo-A2 and thus increase plasma HDL-C levels (Colin et al, 2015).…”

“…In contrast, Millar et al . () demonstrated that in subjects with metabolic syndrome, rosiglitazone increased the production rate of Apo‐A2 with no effect on Apo‐A1 metabolism. PPAR‐α agonists have been shown to stimulate the synthesis of both Apo‐A1 and Apo‐A2 and thus increase plasma HDL‐C levels (Colin et al ., ).…”

Enhancement of HDL Formation and Normalization of Intravascular HDL Remodeling

“…Specifically, pioglitazone increases apoA-I production by directly enhancing PPAR-response element-dependent transcription, resulting in the generation of apoA-I-containing HDL particles with improved anti-inflammatory properties [457]. In contrast, treatment with rosiglitazone increases apoA-II production in subjects with metabolic syndrome and low HDL-C, but has no effect on apoA-I metabolism [458].…”