Microcystin-LR (MCLR) is one of the most common and most toxic members of the microcystins, which cause serious environmental disasters worldwide. Although the major toxicity of MCLR has been ascribed to its potent ability to inhibit protein phosphatase 1 and protein phosphatase 2A (PP2A), recent studies have suggested that MCLR may also perturb other important cellular processes, such as generation of ceramide. Ceramide is an essential second messenger in cells and regulates various cellular mechanisms, including PP2A activation and cytoskeleton destabilization. However, whether and how ceramide may mediate MCLR-induced cellular effects is unclear. We have previously reported that low concentrations of MCLR upregulate, rather than inhibit, PP2A activity in human embryonic kidney 293 (HEK293) cells. In this study, we provide evidence that MCLR induces ceramide generation in HEK293 cells and in mouse kidney. Furthermore, ceramide may mediate the MCLR-induced upregulation of PP2A activity and protein level of PP2A regulatory subunits in HEK293 cells. MCLR intoxication also causes the PP2A/B55α subunit to localize to the Golgi apparatus, and this process may also be mediated by ceramide. Importantly, ceramide may mediate cytoskeleton destabilization, cell detachment, and apoptosis induced by MCLR in HEK293 cells, whereas a ceramide synthase inhibitor, desipramine, protects cells from these changes. Our results suggest that ceramide may mediate MCLR-induced PP2A regulation and cytoskeleton destabilization.

The present study was conducted to investigate effects and mechanism of quercetin on lipids metabolism in broilers. 480 AA broilers were randomly allotted to four treatments (0, 0.2, 0.4, and 0.6 g/kg quercetin) for 42 days. Compared with the control, 0.6 g/kg quercetin significantly decreased percentage of abdominal fat (P < 0.05); 0.2, 0.4, and 0.6 g/kg quercetin significantly decreased relative abundance of Lachnospiraceae and Desulfovibrionaceae (P < 0.05, P < 0.05, P < 0.01; P < 0.01, P < 0.01, P < 0.01); 0.2 g/kg quercetin significantly increased mRNA expression of PI3K, AMPKα1, AMPKα2, AMPKβ2, LKB1 (P < 0.01, P < 0.01, P < 0.05, P < 0.01, P < 0.05), and significantly reduced mRNA expression of SREBP1 and PPARγ (P < 0.01, P < 0.05); 0.4 g/kg quercetin significantly increased mRNA expression of LKB1 and PKB (P < 0.05, P < 0.01) and significantly reduced mRNA expression of ACC, HMGR, PPARγ, and SREBP1 (P < 0.05, P < 0.01, P < 0.01, P < 0.01); 0.6 g/kg quercetin significantly increased mRNA expression of AMPKγ, LKB1, CPT1, PPARα, PKB (P < 0.01, P < 0.01, P < 0.01, P < 0.05, P < 0.05), and significantly reduced the mRNA expression of PI3K, ACC, HMGR, PPARγ, SREBP1 (P < 0.05, P < 0.05, P < 0.01, P < 0.01, P < 0.01); 0.2 g/kg quercetin significantly increased protein expression of AMPK (P < 0.01); 0.6 g/kg quercetin significantly increased protein expression of LKB1 (P < 0.01), 0.2 and 0.6 g/kg quercetin significantly increased protein expression of PI3K, PKB, CPT1 (P < 0.05, P < 0.01, P < 0.05, P < 0.01, P < 0.01, P < 0.01), and significantly reduced protein expression of ACC and SREBP1 (P < 0.01, P < 0.01, P < 0.01, P < 0.01). In conclusion, quercetin improved lipid metabolism by modulating gut microbial and AMPK/PPAR signaling pathway in broilers.

Quercetin, a flavonoid found in fruits and vegetables, is widely distributed as a secondary metabolite in the plant kingdom. Oxidative stress plays a role in the pathogenesis of diabetes mellitus (DM). The present study investigated the effects of quercetin dietary supplementation on streptozotocin- (STZ-) induced hyperglycemic Arbor Acre (AA) broilers by determining the levels of fasting blood glucose (FBG), fasting insulin (FINS), biochemical indicators, oxidative stress markers, inflammatory cytokines content, antioxidant enzymes activities in tissues, and mRNA expression of genes relating to the insulin signaling pathway. Three hundred one-day-old healthy AA broilers were randomly assigned into 5 treatments; A, control healthy broilers; B, STZ-induced broilers; C, STZ-induced broiler dietary supplemented with 0.02% quercetin; D, STZ-induced broiler dietary supplemented with 0.04% quercetin; and E, STZ-induced broiler dietary supplemented with 0.06% quercetin. The results showed that quercetin supplementation relieved the side effects of STZ-induced oxidative stress by changing activities of antioxidant enzymes, decreasing malondialdehyde (MDA) and nitric oxide (NO) levels, activating expression of genes relating to PI3K/PKB signaling pathway that modulate glucose metabolism and reduce oxidative damage, thereby decreasing FBG and increasing FINS levels. These findings suggest that quercetin exhibits a protective effect in STZ-induced hyperglycemic AA broilers via decreasing oxidative stress.

This study is aimed at evaluating the regulatory mechanism of quercetin on lipid metabolism in the ileum of broilers to better understand these pathways decreasing abdominal fat. 480 chickens were randomly divided into 4 groups (control, 0.02% quercetin, 0.04% quercetin, and 0.06% quercetin). Breast muscle, thigh muscle, and abdominal fat pad were removed and weighed at 42 d of age. Serum was obtained by centrifuging blood samples from the jugular vein (10 ml) to determine high-density lipoprotein (HDL), total cholesterol (TC), low-density lipoprotein (LDL), triglyceride (TG), leptin, and adiponectin using ELISA. About 5 g of the ileum was harvested and immediately frozen in liquid nitrogen for RNA-seq. Then, the confirmation of RNA-seq results by the Real-Time Quantitative PCR (RT-qPCR) method was evaluated using Pearson’s correlation. Compared with control, abdominal fat percentage was significantly decreased with increasing quercetin supplementation, and the best result was obtained at 0.06% dietary quercetin supplementation (P<0.01). Breast muscle percentage was significantly decreased at 0.02% quercetin (P<0.01), and thigh muscle percentage tended to increase (P=0.078). Meanwhile, 0.04% and 0.06% quercetin significantly decreased TG (P<0.01), TC (P<0.01), and LDL content (P<0.05) in serum. Serum leptin and adiponectin contents were significantly increased by 0.04% and 0.06% dietary quercetin supplementation, compared with the control (P<0.01). Analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) database were used to identify differently expressed genes and lipid metabolism pathways. Quercetin decreased abdominal fat percentage through regulating fat digestion and absorption, glycerophospholipid metabolism, AMPK signaling pathway, fatty acid degradation, and cholesterol metabolism.

These results suggested that in neonatal cardiomyocytes, fatty acid and glucose in combination with fatty acid induced apoptosis via NF-κB formation and activation of apoptosis pathways; glucose in combination with fatty acid induce more apoptosis rate for the more NF- κB formation, activation of the PPARα can reverse such apoptosis effect. The results also suggest that gluco-lipotoxicity may play a central role in the development of diabetic cardiomyopathy, and PPARα-agonist may be an effective drug in treating the diabetic cardiomyopathy.