Abstract
Obesity is associated with a series of metabolic complications, including dyslipidemia and insulin resistance (IR) that lack effective therapies. In recent years, intestinal inflammation has been suggested to contribute to obesity related metabolic syndrome and targeting gut inflammation with 5-ASA improves diet induced IR, however, its role in dyslipidemia is unknown and has never been explored. In the present study, we reported for the first time that administration of 5-ASA for 12 weeks significantly improved lipid profile by repressing plasma triglycerides and free cholesterol levels in mice fed high-fat cholesterol diet (HFC). In addition, liver lipids were significantly reduced by 5-ASA treatment in HFC-fed mice. Mechanistically, anti-inflammatory genes peroxisome proliferator-activated receptor-γ (Pparγ) and M2 marker, such as Mrc1 and Ym1, were remarkably upregulated, while pro-inflammation gene monocyte chemoattractant protein-1 (Mcp-1) were downregulated in small intestine of mice treated by 5-ASA. Further, 5-ASA improved gastrointestinal barrier by increasing the expression of the tight junction marker ZO-1. 5-ASA also enhanced cholesterol translocation by elevating genes expression of Npc1l1 and Abcg5/8. Moreover, mice fed HFC 5-ASA expressed increased Pparα in small intestinal and its target genes function in lipid oxidation and hydrolysis were remarkable elevated. Taken together, we reported a novel role of 5-ASA which may serve as a therapy target intestinal inflammation induced dyslipidemia.
Highlights
Obesity is emerging as a global public health problem and is associated with a series of metabolic complications, including dyslipidemia and insulin resistance (IR) whereas the mechanism is not fully understood
Our results demonstrate that oral 5-ASA administration improve lipid profile especially when mice were fed a high-fat, cholesterol-rich diet. 5-ASA treatment brought down inflammation related genes expression, led to a shift from M1 to M2 macrophages and activated PPARα related fatty lipid oxidation in small intestine
To assess whether 5-ASA may improve plasma lipid levels in the setting of diet-induced obesity (DIO), we challenged C57BL/6J mice with either a high-fat cholesterol diet (HFC) diet or HFC incorporated with 5-ASA for 12 weeks
Summary
Obesity is emerging as a global public health problem and is associated with a series of metabolic complications, including dyslipidemia and insulin resistance (IR) whereas the mechanism is not fully understood. Numerous studies have shown that activation of intestinal inflammation is strongly associated with early on-set obesity and plays a causal role in the development of obesity related metabolic syndrome [1, 2]. A number of anti-inflammatory actions of 5-ASA have been proposed, including inhibition of the activity of nuclear factorkappa B (NF-κB) by modulating RelA/p65 phosphorylation [10], and reduction of the biosynthesis of prostaglandins and leukotrienes [11, 12]. 5-ASA was shown to exert its anti-inflammatory effects through the activation of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) [7]. PPARγ activation leads to a cascade of events that controls the expression of a large number of regulatory genes in lipid metabolism as well as insulin sensitization [14] and in recent years, PPARγ has emerged as link between lipids, metabolic diseases and innate immunity [15]
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