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

Abstract

BACKGROUND AND PURPOSEHypertriglyceridaemia 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. ) 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. EXPERIMENTAL APPROACH KEY RESULTSIn 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)a 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 PPARa expression was confirmed at the protein level. In contrast, irbesartan did not affect expression of adipose PPARg and its downstream genes or hepatic genes that mediate fatty acid synthesis. CONCLUSIONS AND IMPLICATIONSThese findings demonstrate that irbesartan treatment up-regulates PPARa 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. AbbreviationsACC, acetyl-CoA carboxylase; ACO, acyl-CoA oxidase; AT1, angiotensin II type 1 receptor; ARB, angiotensin II type 1 receptor blocker; CPT, carnitine palmitoyltransferase; DGAT, diacylglycerol acyltransferase; eWAT, epididymal white adipose tissue; FAS, fatty acid synthase; FAT, fatty acid translocase; GLUT, glucose transporter; HOMA-IR, homeostasis model assessment of insulin resistance; NEFA, non-esterified fatty acids; PPAR, peroxisome proliferator-activated receptor; SBP, systolic blood pressure; SCD, stearoyl-CoA desaturase; SREBP, sterol regulatory element-binding protein

Irbesartan Prevents Metabolic Syndrome in Rats via Activation of Peroxisome Proliferator-Activated Receptor γ

“…Therefore, the mechanism by which irbesartan reduces plasma triglyceride level may depend on PPARγ activation. In the present study, PPARα was also upregulated by irbesartan and pioglitazone, as reported in previous papers (35,36). PPARα is predominantly expressed in the liver, where it has a crucial role in regulating fatty acid oxidation, and its activators, such as fibrates, are known to reduce plasma triglyceride levels (37).…”

“…Thus, the reduction of plasma triglyceride level in the current study in response to irbesartan treatment may be mediated by the increase in adiponectin. Nevertheless, a recent study in obese hypertensive rats reported a reduction of plasma triglyceride level by irbesartan without a concomitant increase of plasma adiponectin (35). Further studies are needed to clarify the mechanism of reduction of plasma triglyceride level by irbesartan.…”

Improvement of metabolic syndrome by irbesartan via the PPARγ/HGF pathway in apolipoprotein E knockout mice

“…Irbesartan has been reported to improve hepatic steatosis and hepatic fibrosis by activating PPARα, in NASH model FLS ob/ob mice (17). Another study also demonstrated that irbesartan upregulated PPARα in obese Koletsky (fa k /fa k ) rats and improved their metabolic disorders (18). In our model, PPARα activation may also act to improve the pathological characteristics of the MS.…”

Oral Formulation of Angiotensin-(1–7) Improves Lipid Metabolism and Prevents High-Fat Diet–Induced Hepatic Steatosis and Inflammation in Mice

“…Supporting these data, HFD-induced obesity in mice was associated with increased hepatic peroxisome proliferator-activated receptor-γ, carnitine palmitoyltransferase-1, and acetyl-CoA carboxylase, and these changes were associated with decreased serum triacylglycerol. 32 Furthermore, ACE knockout mice exhibit increased wholebody energy expenditure and increased liver expression of genes involved in fatty acid oxidation, 17 supporting a direct role of Ang II in regulating fatty acid oxidation. Our study corroborate these findings once we showed that administration of Ang-(1-7) can lead to a decrease in the expression of genes related to hepaticmitochondrial fatty acid oxidation, with acetyl-CoA carboxylase and peroxisome proliferatoractivated receptor-γ.…”