Irbesartan treatment up‐regulates hepatic expression of PPARα and its target genes in obese Koletsky (fak/fak) rats: a link to amelioration of hypertriglyceridaemia

• Published in: British journal of pharmacology Vol. 160; no. 7; pp. 1796 - 1807
• Main Authors: Rong, X, Li, Y, Ebihara, K, Zhao, M, Kusakabe, T, Tomita, T, Murray, M, Nakao, K
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-08-2010; Nature Publishing Group
• Subjects: angiotensin II type 1 receptor; Biological and medical sciences; Disorders of blood lipids. Hyperlipoproteinemia; irbesartan; lipid; Medical sciences; Metabolic diseases; Obesity; peroxisome proliferator‐activated receptor; Pharmacology. Drug treatments; Research Papers; Imidazole derivatives; Tetrazole derivatives; Targeting; Rat; Liver; Peptide hormone; Lipids; Hyperlipoproteinemia; Lipoprotein; Enzymopathy; lipid; PPAR-α receptor; Octapeptide; Target; Gene; Genetics; peroxisome proliferator-activated receptor; Dyslipemia; Angiotensin II; Nutritional status; Peroxisome proliferator activated receptor; Biological receptor; Obesity; Digestive system; Rodentia; Nutrition disorder; Metabolic diseases; angiotensin II type 1 receptor; Triglyceride; Renin angiotensin system; Vertebrata; Mammalia; Treatment; Irbesartan; Biphenyl derivatives; Hypertriglyceridemia; Animal; Antihypertensive agent; Sartan derivatives; Angiotensin antagonist
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2010.00835.x

BACKGROUND AND PURPOSE
Hypertriglyceridaemia is associated with an increased risk of cardiovascular disease. Irbesartan, a well‐established angiotensin II type 1 receptor (AT1) blocker, improves hypertriglyceridaemia in rodents and humans but the underlying mechanism of action is unclear.
EXPERIMENTAL APPROACH
Male obese Koletsky (fak/fak) rats, which exhibit spontaneous hypertension and metabolic abnormalities, received irbesartan (40 mg·kg−1·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 (fak/fak) 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)α 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 PPARα expression was confirmed at the protein level. In contrast, irbesartan did not affect expression of adipose PPARγ and its downstream genes or hepatic genes that mediate fatty acid synthesis.
CONCLUSIONS AND IMPLICATIONS
These findings demonstrate that irbesartan treatment up‐regulates PPARα and several target genes in liver of obese spontaneously hypertensive Koletsky (fak/fak) rats and offers a novel insight into the lipid‐lowering mechanism of irbesartan.