Irbesartan treatment up-regulates hepatic expression of PPARalpha and its target genes in obese Koletsky (fa(k)/fa(k)) rats: a link to amelioration of hypertriglyceridaemia.

BACKGROUND AND PURPOSE: Hypertriglyceridaemia is associated with an increased risk of cardiovascular disease. Irbesartan, a well-established angiotensin II type 1 receptor (AT(1)) blocker, improves hypertriglyceridaemia in rodents and humans but the underlying mechanism of action is unclear.

EXPERIMENTAL APPROACH: Male obese Koletsky (fa(k)/fa(k)) rats, which exhibit spontaneous hypertension and metabolic abnormalities, received irbesartan (40 mg x kg(-1) x day(-1)) or vehicle by oral gavage over 7 weeks. Adipocyte-derived hormones in plasma were measured by ELISA. Gene expression in liver and other tissues was assessed by real-time PCR and Western immunoblotting.

KEY

RESULTS

In Koletsky (fa(k)/fa(k)) rats irbesartan lowered plasma concentrations of triglycerides and non-esterified fatty acids, and decreased plasma insulin concentrations and the homeostasis model assessment of insulin resistance index. However, this treatment did not affect food intake, body weight, epididymal white adipose tissue weight, adipocyte size and plasma leptin concentrations, although plasma adiponectin was decreased. Irbesartan up-regulated hepatic expression of mRNAs corresponding to peroxisome proliferator-activated receptor (PPAR)alpha and its target genes (carnitine palmitoyltransferase-1a, acyl-CoA oxidase and fatty acid translocase/CD36) that mediate hepatic fatty acid uptake and oxidation; the increase in hepatic PPARalpha expression was confirmed at the protein level. In contrast, irbesartan did not affect expression of adipose PPARgamma and its downstream genes or hepatic genes that mediate fatty acid synthesis.

CONCLUSIONS AND IMPLICATIONS: These findings demonstrate that irbesartan treatment up-regulates PPARalpha and several target genes in liver of obese spontaneously hypertensive Koletsky (fa(k)/fa(k)) rats and offers a novel insight into the lipid-lowering mechanism of irbesartan.