Obesity is a serious metabolic syndrome characterized by high levels of cholesterol, lipids in the blood, and intracellular fat accumulation in adipose tissues. It is known that the suppression of adipogenic protein expression is an effective approach for the treatment of obesity, and regulates fatty acid storage and transportation in adipose tissues. The 60% ethanol extract of Grateloupia elliptica (GEE), a red seaweed from Jeju Island in Korea, was shown to exert anti-adipogenic activity in 3T3-L1 cells and in mice with high-fat diet (HFD)-induced obesity. GEE inhibited intracellular lipid accumulation in 3T3-L1 cells, and significantly reduced expression of adipogenic proteins. In vivo experiments indicated a significant reduction in body weight, as well as white adipose tissue (WAT) weight, including fatty liver, serum triglycerides, total cholesterol, and leptin contents. The expression of the adipogenic proteins, SREBP-1 and PPAR-γ, was significantly decreased by GEE, and the expression of the metabolic regulator protein was increased in WAT. The potential of GEE was shown in WAT, with the downregulation of PPAR-γ and C/EBP-α mRNA; in contrast, in brown adipose tissue (BAT), the thermogenic proteins were increased. Collectively, these research findings suggest the potential of GEE as an effective candidate for the treatment of obesity-related issues via functional foods or pharmaceutical agents.

This study aimed to demonstrate the anti-obesity effect of Plocamium telfairiae (PT), a red seaweed.

Background:Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation and imbalances in lipid metabolism in the liver. Although nuclear receptors (NRs) play a crucial role in hepatic lipid metabolism, the underlying mechanisms of NR regulation in NAFLD remain largely unclear. Methods:Using network analysis and RNA-seq to determine the correlation between NRs and microRNA in human NAFLD patients, we revealed that MIR20B specifically targets PPARA. MIR20B mimic and anti-MIR20B were administered to human HepG2 and Huh-7 cells and mouse primary hepatocytes as well as high fat diet (HFD)- or methionine-deficient diet (MCD)-fed mice to verify the specific function of MIR20B in NAFLD. We tested the inhibition of the therapeutic effect of a PPARα agonist, fenofibrate, by Mir20b and the synergic effect of combination of fenofibrate with anti-Mir20b in NAFLD mouse model. Results:We revealed that MIR20B specifically targets PPARA through miRNA regulatory network analysis of nuclear receptor genes in NAFLD. The expression of MIR20B was upregulated in free fatty acid (FA)-treated hepatocytes and the livers of both obesity-induced mice and NAFLD patients. Overexpression of MIR20B significantly increased hepatic lipid accumulation and triglyceride levels. Furthermore, MIR20B significantly reduced FA oxidation and mitochondrial biogenesis by targeting PPARA. In Mir20b-introduced mice, the effect of fenofibrate to ameliorate hepatic steatosis was significantly suppressed. Finally, inhibition of Mir20b significantly increased FA oxidation and uptake, resulting in improved insulin sensitivity and a decrease in NAFLD progression. Moreover, combination of fenofibrate and anti-Mir20b exhibited the synergic effect on improvement of NAFLD in MCD-fed mice. Conclusions:Taken together, our results demonstrate that the novel MIR20B targets PPARA, plays a significant role in hepatic lipid metabolism, and present an opportunity for the development of novel therapeutics for NAFLD. Funding:This research was funded by Korea Mouse Phenotyping Project (2016M3A9D5A01952411), the National Research Foundation of Korea (NRF) grant funded by the Korea government (2020R1F1A1061267, 2018R1A5A1024340, NRF-2021R1I1A2041463, 2020R1I1A1A01074940), and the Future-leading Project Research Fund (1.210034.01) of UNIST.

The endoplasmic reticulum (ER) stress response is an adaptive mechanism that is activated upon disruption of ER homeostasis and protects the cells against certain harmful environmental stimuli. However, critical and prolonged cell stress triggers cell death. In this study, we demonstrate that Flightless-1 (FliI) regulates ER stress-induced apoptosis in colon cancer cells by modulating Ca 2+ homeostasis. FliI was highly expressed in both colon cell lines and colorectal cancer mouse models. In a mouse xenograft model using CT26 mouse colorectal cancer cells, tumor formation was slowed due to elevated levels of apoptosis in FliI-knockdown (FliI-KD) cells. FliI-KD cells treated with ER stress inducers, thapsigargin (TG), and tunicamycin exhibited activation of the unfolded protein response (UPR) and induction of UPRrelated gene expression, which eventually triggered apoptosis. FliI-KD increased the intracellular Ca 2+ concentration, and this upregulation was caused by accelerated ER-to-cytosolic efflux of Ca 2+. The increase in intracellular Ca 2+ concentration was significantly blocked by dantrolene and tetracaine, inhibitors of ryanodine receptors (RyRs). Dantrolene inhibited TG-induced ER stress and decreased the rate of apoptosis in FliI-KD CT26 cells. Finally, we found that knockdown of FliI decreased the levels of sorcin and ER Ca 2+ and that TG-induced ER stress was recovered by overexpression of sorcin in FliI-KD cells. Taken together, these results suggest that FliI regulates sorcin expression, which modulates Ca 2+ homeostasis in the ER through RyRs. Our findings reveal a novel mechanism by which FliI influences Ca 2+ homeostasis and cell survival during ER stress.