Abstract
Purpose: N 6-methyladenosine (m6A) mRNA methylation is affected by dietary factors and associated with lipid metabolism; however, whether the regulatory role of resveratrol in lipid metabolism is involved in m6A mRNA methylation remains unknown. Here, the objective of this study was to investigate the effect of resveratrol on hepatic lipid metabolism and m6A RNA methylation in the liver of mice. Methods: A total of 24 male mice were randomly allocated to LFD (low-fat diet), LFDR (low-fat diet + resveratrol), HFD (high-fat diet), and HFDR (high-fat diet + resveratrol) groups for 12 weeks (n = 6/group). Final body weight of mice was measured before sacrificing. Perirhemtric fat, abdominal and epididymal fat, liver tissues, and serum were collected at sacrifice and analyzed. Briefly, mice phenotype, lipid metabolic index, and m6A modification in the liver were assessed. Results: Compared to the HFD group, dietary resveratrol supplementation reduced the body weight and relative abdominal, epididymal, and perirhemtric fat weight in high-fat-exposed mice; however, resveratrol significantly increased average daily feed intake in mice given HFD. The amounts of serum low-density lipoprotein cholesterol (LDL), liver total cholesterol (TC), and triacylglycerol (TAG) were significantly decreased by resveratrol supplementation. In addition, resveratrol significantly enhanced the levels of peroxisome proliferator-activated receptor alpha (PPARα), peroxisome proliferator-activated receptor beta/delta (PPARβ/δ), cytochrome P450, family 4, subfamily a, polypeptide 10/14 (CYP4A10/14), acyl-CoA oxidase 1 (ACOX1), and fatty acid-binding protein 4 (FABP4) mRNA and inhibited acyl-CoA carboxylase (ACC) mRNA levels in the liver. Furthermore, the resveratrol in HFD increased the transcript levels of methyltransferase like 3 (METTL3), alkB homolog 5 (ALKBH5), fat mass and obesity associated protein (FTO), and YTH domain family 2 (YTHDF2), whereas it decreased the level of YTH domain family 3 (YTHDF3) and m6A abundance in mice liver. Conclusion: The beneficial effect of resveratrol on lipid metabolism disorder under HFD may be due to decrease of m6A RNA methylation and increase of PPARα mRNA, providing mechanistic insights into the function of resveratrol in alleviating the disturbance of lipid metabolism in mice.
Highlights
Lipids are critical nutrients and energy substances in both human and animals, whereas long-term high-fat diet (HFD) could result in defective nutritional metabolism, in hepatic lipid metabolism (Feltenberger et al, 2013)
After 3 weeks of acclimation, mice were randomly distributed into four groups of six mice each as follows: 10% LFD and dietary supplemented with 276 mg/kg of resveratrol (LFDR), 60% HFD and dietary supplemented with 400 mg/kg of resveratrol (HFDR) (Kopec and Piatkowska 2013; Tomayko et al, 2014; Sun et al, 2015)
We found that resveratrol in a HFD significantly reduced the average daily gain in mice compared with the HFD group (p < 0.05, Figure 1C)
Summary
Lipids are critical nutrients and energy substances in both human and animals, whereas long-term high-fat diet (HFD) could result in defective nutritional metabolism, in hepatic lipid metabolism (Feltenberger et al, 2013). Further developing the effective investigation in the regulation of hepatic lipid metabolism is necessary and could offer potential theory to prevent and treat metabolic diseases. It is well known that resveratrol has antioxidative (Fu et al, 2018; Truong et al, 2018), antiinflammatory (Xu et al, 2018; Zhou et al, 2018), anticarcinogenic (Kisková et al, 2014; Zheng et al, 2018), and antibacterial (Kukric and Topalic-Trivunovi, 2006; Duarte et al, 2015) effects and exhibits protective nature in the regulation of liver injury (Ajmo et al, 2008). Resveratrol improves serum lipid characters and reverses body fat deposition in a pig model (Zhang et al, 2015). Sun et al (2015) suggested that resveratrol could restore clock-mediated dysfunctional lipid metabolism in high-fat-fed mice via the activation of clock machinery. The potential molecular network of resveratrol in regulating lipid metabolism is unclear
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