Effects of combined PPARγ and PPARα agonist therapy on reverse cholesterol transport in the Zucker diabetic fatty rat

We investigated the effects of the combined therapy of PPARγ and PPARα agonists on HDL metabolism, especially concerning reverse cholesterol transport (RCT), using Zucker diabetic fatty rats (ZDF/Crl-Leprfa rats) that are the rodent model for type 2 diabetes with obesity, hyperlipidaemia and insulin resistance. The ZDF rats were divided into four medicated groups as follows: pioglitazone as a PPARγ agonist (5 mg/kg/day; P group, n = 6), fenofibrate as a PPARα agonist (30 mg/kg/day; F group, n = 6), both these medications (P + F group, n = 6) and no treatment (UNT group, n = 6). Non-diabetic rats (ZDF/GmiCrl-lean, CON group, n = 6) served as controls. We evaluated HDL particle size and messenger RNA (mRNA) levels of the following factors: liver X receptor α (L x R α), ATP-binding cassette A1 (ABCA1) and ABCG1 which are regulated by PPARs and are related to early stage RCT. The significant increase in HDL particle size was demonstrated in rats of the F and P + F groups, although changes in plasma HDL-cholesterol levels were not significant. In accordance with this finding, mRNA levels of ABCG1 in the liver increased significantly. These findings suggest the efficacy of combined therapy with PPARγ and PPARα in improving lipid metabolism, partly through the enhanced RCT, and insulin resistance in type 2 diabetes mellitus.