Involvement of SIRT1-AMPK signaling in the protective action of indole-3-carbinol against hepatic steatosis in mice fed a high-fat diet.

This study addressed the effect of indole-3-carbinol (I3C) supplementation on hepatic steatosis in mice fed a high-fat diet (HFD) and clarified the underlying mechanism. Male C57BL/6N mice were divided into three groups: those who received a normal diet, those fed with HFD and those fed with 0.1% I3C-supplemented diet (I3CD). In the present study, an HFD supplemented with 0.1% I3C significantly decreased body and liver weight as well as plasma and hepatic lipid levels. The activation of the silent mating type information regulation 2 homolog 1 (SIRT1)-AMP-activated protein kinase (AMPK) signaling system by I3C correlated with decreased mRNA levels of sterol regulatory element-binding protein-1c-regulated lipogenic enzymes. In addition, I3C significantly reversed HFD-induced up-regulation of ER stress-mediated signaling molecules in the liver, which may have contributed to the protective effects of I3C against hepatic steatosis. Furthermore, HFD-induced up-regulations of inflammatory genes such as tumor necrosis factor α and interleukin 6 were significantly reversed by dietary I3C supplementation. Our study suggests that the protective action of I3C against hepatic steatosis is mediated, at least in part, through the up-regulation of a SIRT1-AMPK signaling system in the livers of HFD-fed mice. Further investigations revealed that alleviation of the ER stress response represented a critical mechanism underlying the beneficial effects of I3C on hepatic steatosis.

Choi Y ，Yanagawa Y ，Kim S ，Park T ... -  《-》

Piperine, an LXRα antagonist, protects against hepatic steatosis and improves insulin signaling in mice fed a high-fat diet.

This study investigated the role of piperine in the transcriptional regulation of liver X receptor α (LXRα) and the effects of dietary piperine on high-fat diet (HFD)-induced hepatic steatosis and insulin resistance in mice. Furthermore, we explored the potential molecular mechanisms through which the protective effects of piperine may work. In the present study, piperine significantly reduced ligand-induced LXRα activity in a dose-dependent manner and gradually disrupted the interaction between ligand-bound LXRα and GST-CBP. In mice, an HFD supplemented with 0.05% piperine (PSD) significantly decreased body and liver weight as well as plasma and hepatic lipid levels. In agreement with our in vitro study, in mice fed an HFD, dietary piperine markedly decreased LXRα mRNA expression and its lipogenic target genes (i.e., SREBP1c, ChREBPα, FAS, and CD36). Piperine also significantly decreased plasma insulin and glucose concentrations, while increasing insulin sensitivity in mice fed an HFD. In addition, piperine downregulated the expression of genes involved in ER stress, including GRP78, activating transcription factor 6, and eukaryotic translation initiation factor 2α, and upregulated GLUT2 translocation from the cytosol to the plasma membrane in the livers of PSD mice. Piperine antagonized LXRα transcriptional activity by abolishing the interaction of ligand-bound LXRα with the co-activator CBP. The effects of piperine on hepatic lipid accumulation were likely regulated via alterations in LXRα-mediated lipogenesis in mice fed an HFD. Dietary piperine also led to reduced ER stress and increased insulin sensitivity and prevented hepatic insulin resistance in mice fed the HFD.

Jwa H ，Choi Y ，Park UH ，Um SJ ，Yoon SK ，Park T ... -  《-》

Indole-3-carbinol prevents diet-induced obesity through modulation of multiple genes related to adipogenesis, thermogenesis or inflammation in the visceral adipose tissue of mice.

Indole-3-carbinol (I3C) is a compound found in high concentrations in Brassica family vegetables, including broccoli, cauliflower and cabbage, and is regarded as a promising chemopreventive agent against various cancers. This study assesses the protective effect of I3C against diet-induced obesity in mice. Mice were randomly grouped to receive either a normal diet, high-fat (40% energy as fat) diet (HFD) or I3C-supplemented diet (1 g/kg diet) for 10 weeks. I3C supplementation significantly ameliorated HFD-induced increases in body weight gain, visceral fat pad weights and plasma lipid levels. The visceral adipose tissue mRNA levels of uncoupling proteins 1 and 3, crucial factors of thermogenesis, and their regulators such as sirtuin 1, peroxisome proliferator-activated receptor (PPAR) α and PPARγ coactivator 1α, which were down-regulated by HFD, were normalized by supplementation with I3C. In contrast, I3C supplementation significantly decreased expression levels of a key adipogenic transcription factor, PPARγ2, and its target genes, such as leptin and adipocyte protein 2, in the visceral adipose tissue of mice maintained on the HFD. Furthermore, HFD-induced up-regulation in mRNA levels of inflammatory cytokines (tumor necrosis factor α, interferon β and interleukin 6) was significantly ameliorated by I3C. These findings suggest that I3C has a potential benefit in preventing obesity and metabolic disorders, and the action for I3C in vivo may involve multiple mechanisms including decreased adipogenesis and inflammation, along with activated thermogenesis.

Choi Y ，Kim Y ，Park S ，Lee KW ，Park T ... -  《-》

Oleuropein attenuates hepatic steatosis induced by high-fat diet in mice.

Oleuropein, a secoiridoid derived from olives and olive oil, has been known to possess antimicrobial, antioxidative, and anticancer activities. The purpose of the present study was to determine whether oleuropein has a protective effect against hepatic steatosis induced by a high fat diet (HFD) and to elucidate its underlying molecular mechanisms in mice. Male C57BL/6N mice were fed a normal diet (ND), HFD, or an oleuropein-supplemented diet (OSD) for 10 weeks. The plasma and hepatic lipid levels were determined, and the hepatic gene and protein expression levels were analysed via RT-PCR and Western blotting, respectively. The supplementation of HFD with oleuropein reversed the HFD-induced increases in liver weight along with plasma and hepatic lipid levels in mice. The expression of Wnt10b inhibitor genes, such as secreted firizzed-related sequence protein 5 and dickkopf homolog 2, was downregulated, whereas the β-catenin protein expression was upregulated in the liver of OSD-fed mice compared to HFD-fed mice. Fibroblast growth factor receptor 1 (FGFR1), phosphoextracellular-signal-regulated kinase 1/2, cyclin D, and E2F transcription factor 1, along with several key transcription factors and their target genes involved in adipogenesis, were downregulated by oleuropein. OSD-fed mice exhibited decreased expression of the toll-like-receptor-(TLR)-mediated signaling molecules (TLR2, TLR4, and myeloid differentiation primary-response gene 88) and proinflammatory cytokines, in their livers, as compared to HFD mice. These results suggest that the protective effects of oleuropein against HFD-induced hepatic steatosis in mice appear to be associated with the Wnt10b- and FGFR1-mediated signaling cascades involved in hepatic lipogenesis, along with the TLR2- and TLR4-mediated signaling implicated in hepatic steatosis.

Park S ，Choi Y ，Um SJ ，Yoon SK ，Park T ... -  《-》

Coumarin attenuates hepatic steatosis by down-regulating lipogenic gene expression in mice fed a high-fat diet.

Um MY ，Moon MK ，Ahn J ，Youl Ha T ... -  《-》