Regulation of Lipoprotein Metabolism by Thiazolidinediones Occurs through a Distinct but Complementary Mechanism Relative to Fibrates

Abstract

Thiazolidinediones are antidiabetic agents, which not only improve glucose metabolism but also reduce blood triglyceride concentrations. These compounds are synthetic ligands for PPAR gamma, a transcription factor belonging to the nuclear receptor subfamily of PPARs, which are important transcriptional regulators of lipid and lipoprotein metabolism. The goal of this study was to evaluate the influence of a potent thiazolidinedione, BRL49653, on serum lipoproteins and to determine whether its lipid-lowering effects are mediated by changes in the expression of key genes implicated in lipoprotein metabolism. Treatment of normal rats for 7 days with BRL49653 decreased serum triglycerides in a dose-dependent fashion without affecting serum total and HDL cholesterol and apolipoprotein (apo) A-I and apo A-II concentrations. The decrease in triglyceride concentrations after BRL49653 was mainly due to a reduction of the amount of VLDL particles of unchanged lipid and apo composition. BRL49653 treatment did not change triglyceride production in vivo as analyzed by injection of Triton WR-1339, indicating a primary action on triglyceride catabolism. Analysis of the influence of BRL49653 on the expression of LPL and apo C-III, two key players in triglyceride catabolism, showed a dose-dependent increase in mRNA levels and activity of LPL in epididymal adipose tissue, whereas liver apo C-III mRNA levels remained constant. Furthermore, addition of BRL49653 to primary cultures of differentiated adipocytes increased LPL mRNA levels, indicating a direct action of the drug on the adipocyte. Simultaneous administration of BRL49653 and fenofibrate, a hypolipidemic drug that acts primarily on liver through activation of PPAR alpha both decreased liver apo C-III and increased adipose tissue LPL mRNA levels, resulting in a more pronounced lowering of serum triglycerides than each drug alone. In conclusion, both fibrates and thiazolidinediones exert a hypotriglyceridemic effect. While fibrates act primarily on the liver by decreasing apo C-III production, BRL49653 acts primarily on adipose tissue by increasing lipolysis through the induction of LPL expression. Drugs combining both PPAR alpha and gamma activation potential should therefore display a more efficient hypotriglyceridemic activity than either compound alone and may provide a rationale for improved therapy for elevated triglycerides.

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

“…Of note, we observed an additive effect of combined PIO plus FENO therapy on the reduction in plasma triacylglycerol concentration in the present study, suggesting that the mechanisms responsible for triacylglycerol lowering may be complementary [49,50]. Further, the results of the present study suggest that a combination of PPAR-γ and PPAR-α therapy (dual PPAR therapy) may be an effective means to lower elevated plasma triacylglycerol concentrations in type 2 diabetic patients [51].…”

Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin

“…Since rosiglitazone can increase LPL expression [34], it is possible that rosiglitazone increased hydrolysis of triglyceride, but the lower plasma fatty acid levels argue against this. Another possibility is that TZDs inhibited Apo C-III expression [35], which could perhaps lead to enhanced removal of triglyceride-rich particles without lipolysis [36]. These speculative possibilities do not invalidate the methodology used here for studying tissue-specific NEFA clearance.…”

Developmental and Pharmacological Regulation of Apolipoprotein C-II Gene Expression

“…In contrast to fibrates, however, BRL49653 acts primarily by inducing LPL expression in adipose tissue. 29,40 Interestingly, BRL49653 treatment does not influence apo C-II or apo C-III gene expression, nor does it change the lipid and apolipoprotein composition of the secreted VLDL particles. 40 This may explain why, in contrast to fibrates, the triglyceride lowering after thiazolidinedione treatment is accompanied by an increased accumulation of remnant particles in plasma.…”

“…Because both PPAR␣ and PPAR␥ activators decrease plasma triglycerides, 29,40 we next investigated whether apo C-II expression was also under control of PPAR␥ activators. Therefore, rats were treated with the thiazolidinedione BRL49653, a high-affinity PPAR␥ ligand, at a concentration previously shown to reduce plasma triglycerides, 40 and its effects were compared with those of fenofibrate.…”

“…Therefore, rats were treated with the thiazolidinedione BRL49653, a high-affinity PPAR␥ ligand, at a concentration previously shown to reduce plasma triglycerides, 40 and its effects were compared with those of fenofibrate. BRL49653 treatment did not change rat liver apo C-II or apo C-III gene expression, whereas fenofibrate decreased the expression of both genes (Figure 4).…”