Abstract
This study is aimed at elucidating how aspirin could systemically and simultaneously normalize nonalcoholic fatty liver disease (NAFLD) and atherosclerosis through both in vitro and in vivo studies in hyperlipidemic conditions. We evaluated the effects and mechanism of aspirin on the levels of various biomarkers related to NAFLD, atherosclerosis, and oxidative phosphorylation in cells and animals of hyperlipidemic conditions. The protein levels of biomarkers (PPARδ, AMPK, and PGC-1α) involved in oxidative phosphorylation in both the vascular endothelial and liver cells were elevated by the aspirin in hyperlipidemic condition. Also in the stimulation pathway of oxidative phosphorylation by aspirin, PPARδ was a superior regulator than AMPK and PGC-1α in HepG2 cells. In the vascular endothelial cells, the phosphorylated endothelial nitric oxide synthase level was increased by the treatment. The protein levels of biomarkers related to lipid synthesis were decreased by the treatment in the liver cells. In rabbits administered with cholesterol diet, the levels of triglyceride, HDL-cholesterol, and alanine amino transferase in serums were ameliorated by the aspirin treatment, the levels of ATP and TNFα were increased or decreased, respectively, by the aspirin in liver and aorta tissues, and mannose receptor and C-C chemokine receptor type 2 levels were increased or decreased by the aspirin in spleen, respectively. The elevated levels of macrophage antigen, angiotensin II type1 receptor, and lipid accumulation were decreased in both the liver and aorta tissues in the aspirin-treated group. In conclusion, aspirin can systemically and simultaneously ameliorate NAFLD and atherosclerosis by inhibiting lipid biosynthesis and inflammation and by elevating catabolic metabolism through the activation of the PPARδ-AMPK-PGC-1α pathway. Furthermore, aspirin may normalize atherosclerosis and NAFLD by modulating the mannose receptor and CCR2 in macrophages.
Highlights
A high-calorie diet and lack of exercise can induce metabolic diseases, such as obesity, hyperlipidemia, hypertension, cardiovascular disease, and nonalcoholic fatty liver disease (NAFLD)
We reported that rabbits fed a highcholesterol diet developed both early lesions of NAFLD and atherosclerosis of the aorta; subcutaneous inflammation induced systemic inflammation and accelerated the pathogenesis of lipid-induced damage, which led to advanced lesions in both the liver and aorta [7]
Based on the results of a previous study that showed inflammatory macrophage type 1 (M1) increased in NAFLD [26], we examined whether RAW 264.7 cells changed to macrophage type 2 (M2), which is a noninflammatory state, with aspirin treatment
Summary
A high-calorie diet and lack of exercise can induce metabolic diseases, such as obesity, hyperlipidemia, hypertension, cardiovascular disease, and nonalcoholic fatty liver disease (NAFLD). Atherosclerosis plays a key role in the development of cardiovascular disease, which can be fatal and is intimately correlated with the progression of NAFLD. Patients with NAFLD have low flow-mediated vasodilatation, elevated carotid-artery intimal medial thickness BioMed Research International danger factor of atherosclerosis), and a high number of carotid atherosclerotic plaques [1, 2]. The main cause of death in patients with advanced NAFLD is cardiovascular disease [3]. Excessive amounts of either triglyceride or cholesterol accumulation are linked to the development of NAFLD with atherosclerosis. Triglycerides accumulate on the artery walls as well as in the liver
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