Resveratrol Ameliorates Lipid Droplet Accumulation in Liver Through a SIRT1/ ATF6-Dependent Mechanism

Abstract

Background/Aims: Lipid droplets (LDs) are dynamic organelles that store neutral lipids during times of energy excess, and an increased accumulation of LDs in the liver is closely linked to hepatic steatosis. Our previous studies suggested that resveratrol (RSV) supplement could improve hepatic steatosis, but the underlying mechanism, particularly which related to LD accumulation, has not yet been elucidated. Methods: A high-fat diet (HFD) and palmitic acid were used to induce hepatic steatosis in mouse liver and hepatocytes, respectively. The effects of RSV on LD accumulation were analyzed in vivo and in vitro. The effects of RSV on the expression levels of LD-associated genes (ATF6, Fsp27β/CIDEC, CREBH, and PLIN1) were measured by qRT-PCR and western blot assays, followed by KD or overexpression of SIRT1 and ATF6 with small interfering RNAs or overexpressed plasmids, respectively. The dual luciferase reporter assay, chromatin immunoprecipitation assay, coimmunoprecipitation, and proximity ligation assay were utilized to clarify the mechanism of transcriptional regulation and possible interaction between SIRT1 and ATF6. Results: There was a significant increase in the accumulation of LDs in liver and hepatocytes during the process of HFD-induced steatosis, respectively, which was significantly inhibited by RSV supplementation. RSV notably activated SIRT1 expression and decreased the expression levels of ATF6, Fsp27β/CIDEC, CREBH, and PLIN1, which are associated with LD accumulation. Interestingly, the inhibitory effects of RSV on LD accumulation and the associated expression of genes in hepatocytes were abrogated or strengthened with SIRT1 silencing or overexpression, respectively. On the contrary, the benefits of RSV in hepatocytes were eliminated or aggravated when transfected with the overexpressed ATF6 or ATF6 siRNA, respectively. Furthermore, we found that RSV stimulated SIRT1 expression significantly, which was followed by increased deacetylation and inactivation of ATF6, resulting in a positive feedback loop for SIRT1 transcription associated with ATF6 binding to the SIRT1 promoter region. Conclusion: Taken together, these findings indicate that RSV supplementation improves hepatic steatosis by ameliorating the accumulation of LDs, and this might be partially mediated by a SIRT1/ATF6-dependent mechanism.

The Role of Resveratrol in Liver Disease: A Comprehensive Review from In Vitro to Clinical Trials

“…RSV (resveratrol) supplementation in rodents fed with a highfat diet demonstrated an increased number of mitochondria and, in particular, an increase in hepatic decoupling protein 2 expression, which could be involved in the normalization of the hepatic fat content [18]. Resveratrol significantly reduced TAG (triacylglycerols) and cholesterol, as well as the number and size of lipid droplets [19,20]. It would appear that a low dose of resveratrol (0.005%) is more effective than higher doses (0.02%) at reducing the development of hepatic steatosis, along with increases in body weight, plasma TAG levels, and total cholesterol levels [21].…”

Resveratrol Metabolites Are Able to Reduce Steatosis in Cultured Hepatocytes

“…When higher concentrations were used, only 10 µM DH-R and 25 µM R-4G induced significant effects. However, several authors have reported positive effects of resveratrol at higher concentrations (10–100 µM) in in vitro assays [ 46 , 47 ]. Indeed, Ji et al (2015) reported a reduction in triglyceride levels in AML12 cells from 25 to 100 μM of resveratrol.…”

Resveratrol Modulates the Gut-Brain Axis: Focus on Glucagon-Like Peptide-1, 5-HT, and Gut Microbiota

“…Resveratrol induces the expression of adiponectin (one of the adipokines) and improves insulin resistance in adipocytes and inhibits the inflammatory response (Sadruddin and Arora, 2009;Timmers et al, 2011). Resveratrol is specifically known to activate mammalian nicotinamide adenosine dinucleotidedependent deacetylase SIRT1, which is involved in regulating glucose homeostasis, lipid metabolism, and the activation of mitochondrial function (Baur, 2010;Zhou et al, 2018). SIRT1 is a NAD+-dependent protein deacetylase that is a critical regulator of energy homeostasis-dependent nutrient metabolism (Vassilopoulos et al, 2011;Aguilar-Arnal et al, 2016).…”