Histone Demethylase KDM7A Contributes to the Development of Hepatic Steatosis by Targeting Diacylglycerol Acyltransferase 2

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. While the development of NAFLD is correlated with aberrant histone methylation, modifiers of histone methylation involved in this event remain poorly understood. Here, we studied the functional role of the histone demethylase KDM7A in the development of hepatic steatosis. KDM7A overexpression in AML12 cells upregulated diacylglycerol acyltransferase 2 (DGAT2) expression and resulted in increased intracellular triglyceride (TG) accumulation. Conversely, KDM7A knockdown reduced DGAT2 expression and TG accumulation, and significantly reversed free fatty acids-induced TG accumulation. Additionally, adenovirus-mediated overexpression of KDM7A in mice resulted in hepatic steatosis, which was accompanied by increased expression of hepatic DGAT2. Furthermore, KDM7A overexpression decreased the enrichment of di-methylation of histone H3 lysine 9 (H3K9me2) and H3 lysine 27 (H3K27me2) on the promoter of DGAT2. Taken together, these results indicate that KDM7A overexpression induces hepatic steatosis through upregulation of DGAT2 by erasing H3K9me2 and H3K27me2 on the promoter.

Torreya nucifera seed oil improves 3T3-L1 adipocyte differentiation

Background Adipose tissue is a critical regulator of lipid storage and endocrine function. Impairment of the recruitment of new adipocytes in the adipose tissue is associated with ectopic fat accumulation, diabetes and insulin resistance. Torreya nucifera, an evergreen conifer that grows in warm temperate climates, has been found to exert beneficial effects against inflammation, infection and diabetes. However, the molecular mechanisms responsible for these effects at the cellular level remain unknown. This study aimed to investigate effects of Torreya nucifera seed oil (TNSO) on 3T3-L1 adipocyte differentiation and its underlying regulatory mechanism. Methods To investigate the effects of TNSO on adipocyte differentiation, 3T3-L1 cells were induced to differentiate for 5 days in the presence of 0.75 μL/mL TNSO. Oil Red O staining and an assay for intracellular triglyceride were performed to determine the extent of lipid accumulation in 3T3-L1 cells. To elucidate the underlying mechanism of TNSO, adipogenic gene expression was analyzed using quantitative real-time PCR. Moreover, we monitored TNSO-derived activation of PPARγ and STAT3 with 3T3-L1 reporter cell lines engineered to secrete Gaussia luciferase upon the interaction of a transcription factor to its DNA binding element. Results Oil Red O staining revealed that TNSO improved the differentiation of 3T3-L1 preadipocytes into mature adipocytes. The mRNA levels of adipogenic genes, including adiponectin, fatty acid synthase (FAS) and adipocyte fatty acid-binding protein (FABP4), were upregulated and intracellular triglyceride levels increased upon TNSO treatment. We also established that adipocyte differentiation was improved by TNSO-derived activation of PPARγ and STAT3. Conclusions Our results suggest that TNSO improves adipocyte differentiation by regulating the activation of adipogenic transcription factors, indicating that it may serve as a potential treatment strategy for adipocyte dysfunction.

Antioxidant, Anti-Obesity, and Anti-Aging Activities of Jeju Citrus Blended Vinegar

Various types of vinegars have been developed as interest in their health benefits has increased. In this study, we prepared Jeju citrus blended vinegars (CBVs) by mixing premature mandarin vinegar and mandarin vinegar, with mandarin vinegar used as a control. The physicochemical properties of the vinegars, including pH, total acidity, and sugar content was determined. Moreover, antioxidant, anti-obesity, and anti-aging activities of the vinegars were investigated. Physicochemical analysis revealed that the CBVs had a pH similar to that of mandarin vinegar, whereas CBVs with relatively high premature mandarin vinegar content showed higher acidity and lower sugar content (p < 0.05). Moreover, the antioxidant activities and phenol contents of CBVs were significantly higher than those of mandarin vinegar (p < 0.05). Meanwhile, CBVs showed significantly decreased intracellular triglyceride, lipid accumulation, and anti-obesity related gene levels (p < 0.05), thereby highlighting their anti-obesity activity. In addition, CBVs showed anti-aging activity by increasing cell viability and cell lifespan, while decreasing the expression of senescence-related genes under H2O2-induced oxidative stress. Therefore, CBVs may be useful as a functional food with antioxidant, anti-obesity, and anti-aging effects in various food fields.

Adropin inhibited tilapia hepatic glucose output and triglyceride accumulation via AMPK activation

Adropin plays a role in the maintenance of energy homeostasis, insulin resistance prevention, and impaired glucose tolerance. However, the molecular mechanisms by which adropin affects hepatic glucose and lipid metabolism in vitro are not entirely understood. This study intended to examine the roles and underlying mechanisms of adropin in glucose and lipid metabolism in Nile tilapia. In primary cultured tilapia hepatocytes, adropin significantly attenuated oleic acid (OA)-induced glucose output and reduced the activities and mRNA expression of cytosolic phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), which are involved in gluconeogenesis. In contrast, adropin facilitated glucose uptake activity via glucose transporter 1 (Glut1) upregulation in OA-treated hepatocytes. One-week of adropin treatment reduced the hepatic total lipid accumulation in OA-fed tilapia without changes in body weight. Subsequent studies revealed that adropin suppressed OA-induced intracellular triglyceride accumulation and decreased the expression of genes and proteins involved in lipid metabolisms such as sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase α (ACCα) and CD36, but upregulated peroxisome proliferator-activated receptor α (PPARα) levels. In parallel studies, however, adropin had no detectable effects on fatty acid-binding protein 4 (Fabp4) and carnitine palmitoyltransferase 1α (Cpt1α) mRNA expression. Furthermore, adropin treatment dose-dependently increased the phosphorylation level of AMP-activated protein kinase (AMPK). Suppression of AMPK by compound C or AMPKα1 siRNA blocked adropin-induced decreases in the mature form of SREBP-1c expression, glucose output, and intracellular triglyceride content in OA-treated hepatocytes. These findings suggest that teleost adropin could suppress hepatic gluconeogenesis and triglyceride accumulation via a mechanism dependent on AMPK signalling.

Estrogen Abolishes the Repression Role of gga-miR-221-5p Targeting ELOVL6 and SQLE to Promote Lipid Synthesis in Chicken Liver

Few studies have been conducted regarding the biological function and regulation role of gga-miR-221-5p in the liver. We compared the conservation of miR-221-5p among species and investigated the expression pattern of gga-miR-221-5p, validating the direct target genes of gga-miR-221-5p by dual luciferase reporter assay, the biological function of gga-miR-221-5p in the liver was studied by gga-miR-221-5p overexpression and inhibition. Furthermore, we explored the regulation of gga-miR-221-5p and its target genes by treatment with estrogen and estrogen antagonists in vivo and in vitro. The results showed that miR-221-5p was highly conserved among species, expressed in all tested tissues and significantly downregulated in peak-laying hen liver compared to pre-laying hen liver. Gga-miR-221-5p could directly target the expression of elongase of very long chain fatty acids 6 (ELOVL6) and squalene epoxidase (SQLE) genes to affect triglyceride and total cholesterol content in the liver. 17β-estradiol could significantly inhibit the expression of gga-miR-221-5p but promote the expression of ELOVL6 and SQLE genes. In conclusion, the highly conservative gga-miR-221-5p could directly target ELOVL6 and SQLE mRNAs to affect the level of intracellular triglyceride and total cholesterol. Meanwhile, 17β-estradiol could repress the expression of gga-miR-221-5p but increase the expression of ELOVL6 and SQLE, therefore promoting the synthesis of intracellular triglyceride and cholesterol levels in the liver of egg-laying chicken.

Hypolipidemic Activities of Two Pentapeptides (VIAPW and IRWWW) from Miiuy Croaker (Miichthys miiuy) Muscle on Lipid Accumulation in HepG2 Cells through Regulation of AMPK Pathway

In this work, the hypolipidemic activities of two pentapeptides (VIAPW and IRWWW) from miiuy croaker (Miichthys miiuy) muscle on oleic acid (OA)-induced lipid accumulation in HepG2 cells were investigated. VIAPW and IRWWW could significantly inhibit lipid accumulation induced by OA and decreased intracellular levels of intracellular triglyceride (TG) and total cholesterol (TC) in a dose-effect dependence manner. At the concentration of 100 μm, the TG levels of VIAPW (0.201 ± 0.006 mm) and IRWWW (0.186 ± 0.005 mm) were very (p < 0.01) and extremely (p < 0.001) significantly lower than those (0.247 ± 0.004 mm) of the OA model group; the levels of TC of VIAPW (45.88 ± 0.74 μg/mg protein) and IRWWW (41.02 ± 0.14 μg/mg protein) were very (p < 0.01) and extremely (p < 0.001) significantly lower than that (53.45 ± 0.10μg/mg protein) of the OA model group (p < 0.01). The hypolipidemic mechanisms of VIAPW and IRWWW were to down-regulate the expression levels of genes of SREBP-1c, SREBP-2, FAS, ACC, and HMGR in lipid synthesis and to up-regulate the expression levels of genes of PPARα, ACOX-1, and CPT-1 in lipid oxidation. These results suggested that VIAPW and IRWWW could play their hypolipidemic activities in HepG2 cells through regulation of AMPK pathway and act as hypolipidemic nutrient ingredients applied in public healthy and functional foods.

Up-Regulated MicroRNA-27b Promotes Adipocyte Differentiation via Induction of Acyl-CoA Thioesterase 2 Expression

Nonalcoholic fatty liver disease (NAFLD) is characterized by a spectrum of liver pathologies, from simple steatosis to steatohepatitis. Recent studies have increasingly noted the aberrant expression of microRNAs closely related to NAFLD pathologies. We have previously shown the presence of increased levels of microRNA-27b (miR-27b) in patients with NAFLD. In this study, we investigated the role of miR-27b in NAFLD by examining the impact of up-regulated miR-27b on the differentiation of preadipocytes into mature adipocytes. We found that miR-27b-3p remarkably enhances the adipocyte differentiation of 3T3-L1 cells associated with lipid accumulation and intracellular triglyceride contents. Furthermore, we have demonstrated not only that miR-27b-3p induces acyl-CoA thioesterase 2 (ACOT2) expression in 3T3-L1 cells, but also that the knockdown of ACOT2 suppresses lipid accumulation and adipocyte differentiation in both the presence and absence of miR-27b-3p treatment. Our data strongly suggest that the miR-27b-ACOT2 axis is an important pathway in adipocyte differentiation and may play a role in the pathogenesis of NAFLD.