Aliskiren Reduces Hepatic steatosis and Epididymal Fat Mass and Increases Skeletal Muscle Insulin Sensitivity in High-Fat Diet-Fed Mice.

Kuei-Chuan Lee,Yi-Hsiang Huang,Yun-Cheng Hsieh,Che-Chang Chan,Han-Chieh Lin,Ying-Ying Yang

doi:10.1038/srep18899

Abstract

Aliskiren has been found to reduce chronic injury and steatosis in the liver of methionine-choline-deficient (MCD) diet-fed mice. This study investigated whether aliskiren has an anti-steatotic effect in HFD-fed mice, which are more relevant to human patients with non-alcoholic fatty liver disease than MCD mice. Mice fed with 4-week normal chow or HFD randomly received aliskiren (50 mg/kg/day) or vehicle via osmotic minipumps for further 4 weeks. Aliskiren reduced systemic insulin resistance, hepatic steatosis, epididymal fat mass and increased gastrocnemius muscle glucose transporter type 4 levels with lower tissue angiotensin II levels in the HFD-fed mice. In addition, aliskiren lowered nuclear peroxisome proliferator-activated receptor gamma and its down-signaling molecules and increased cytochrome P450 4A14 and carnitine palmitoyltransferase 1A (CPT1a) in liver. In epididymal fat, aliskiren inhibited expressions of lipogenic genes, leading to decrease in fat mass, body weight, and serum levels of leptin and free fatty acid. Notably, in the gastrocnemius muscle, aliskiren increased phosphorylation of insulin receptor substrate 1 and Akt. Based on these beneficial effects on liver, peripheral fat and skeletal muscle, aliskiren is a promising therapeutic agent for patients with NAFLD.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is rapidly emerging as the most prevalent hepatic disorder in the Western world[1]
The hematoxylin and eosin (H&E) and Oil Red O stains show that aliskiren decreased hepatic steatosis in the high-fat diet (HFD)-Ali group compared to the HFD-V group (Fig. 1a,c)
The HFD-Ali mice had a significant improvement in the glucose tolerance test and a trend of improvement in insulin tolerance test when compared with the HFD-V mice (Fig. 2b)

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is rapidly emerging as the most prevalent hepatic disorder in the Western world[1]. The rate-determining enzyme for the generation of angiotensin, has been shown to result in resistance to diet-induced obesity and a reduction in fatty liver in mice[5]. Aliskiren, the first renin inhibitor to be approved for clinical use, has been reported to reduce hepatic steatosis. Kishina et al.[9] reported that aliskiren reduced hepatic steatosis in Shionogi-ob/ob mice, the underlying mechanism to reduce steatosis was not elucidated and insulin resistance was not measured. We recently found that aliskiren attenuated hepatic steatosis by up-regulating fatty acid oxidation-related genes with increasing systemic insulin sensitivity in methionine-choline-deficient (MCD) diet-fed mice[10]. This study aimed to evaluate the possible anti-steatotic effects and mechanisms of the chronic administration of aliskiren in a mouse model with hepatic steatosis and systemic insulin resistance which is relevant to clinical patients. We examined the epididymal fat and gastrocnemius muscle to investigate whether there was any effect of aliskiren on these two important tissues which contribute important roles to lipid metabolism

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Conclusion