Effects of combined PPARgamma and PPARalpha agonist therapy on reverse cholesterol transport in the Zucker diabetic fatty rat.
OBJECTIVE
We investigated the effects of the combined therapy of PPARgamma and PPARalpha agonists on HDL metabolism, especially concerning reverse cholesterol transport (RCT), using Zucker diabetic fatty rats (ZDF/Crl-Lepr fa rats) that are the rodent model for type 2 diabetes with obesity, hyperlipidaemia and insulin resistance.


METHODS
The ZDF rats were divided into four medicated groups as follows: pioglitazone as a PPARgamma agonist (5 mg/kg/day; P group, n = 6), fenofibrate as a PPARalpha 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 alpha (L x R alpha), ATP-binding cassette A1 (ABCA1) and ABCG1 which are regulated by PPARs and are related to early stage RCT.


RESULTS
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.


CONCLUSIONS
These findings suggest the efficacy of combined therapy with PPARgamma and PPARalpha in improving lipid metabolism, partly through the enhanced RCT, and insulin resistance in type 2 diabetes mellitus.
Tanabe
J
J
Third Department of Internal Medicine, Hirosaki University School of Medicine, Hirosaki, Japan.
Tamasawa
N
N
Yamashita
M
M
Matsuki
K
K
Murakami
H
H
Matsui
J
J
Sugimoto
K
K
Yasujima
M
M
Suda
T
T
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000032:analysis; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000032:analysis; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D011345:Fenofibrate / Q000008:administration & dosage*; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000819:agonists; D007333:Insulin Resistance; D050356:Lipid Metabolism; D000071518:Liver X Receptors; D008297:Male; D009765:Obesity / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha / Q000819:agonists; D047495:PPAR gamma / Q000819:agonists; D000077205:Pioglitazone; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis; D045162:Thiazolidinediones / Q000008:administration & dosage*
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001786:Blood Glucose; D008076:Cholesterol, HDL; D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D000071518:Liver X Receptors; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D011345:Fenofibrate; D000077205:Pioglitazone