Adverse effects of triclosan on kidney in mice: Implication of lipid metabolism disorders.

Triclosan (TCS) is a ubiquitous antimicrobial used in daily consumer products. Previous reports have shown that TCS could induce hepatotoxicity, endocrine disruption, disturbance on immune function and impaired thyroid function. Kidney is critical in the elimination of toxins, while the effects of TCS on kidney have not yet been well-characterized. The aim of the present study was to investigate the effects of TCS exposure on kidney function and the possible underlying mechanisms in mice. Male C57BL/6 mice were orally exposed to TCS with the doses of 10 and 100 mg/(kg•day) for 13 weeks. TCS was dissolved in dimethyl sulfoxide (DMSO) and diluted by corn oil for exposure. Corn oil containing DMSO was used as vehicle control. Serum and kidney tissues were collected for study. Biomarkers associated with kidney function, oxidative stress, inflammation and fibrosis were assessed. Our results showed that TCS could cause renal injury as was revealed by increased levels of renal function markers including serum creatinine, urea nitrogen and uric acid, as well as increased oxidative stress, pro-inflammatory cytokines and fibrotic markers in a dose dependent manner, which were more significantly in 100 mg/(kg•day) group. Mass spectrometry-based analysis of metabolites related with lipid metabolism demonstrated the occurrence of lipid accumulation and defective fatty acid oxidation in 100 mg/(kg•day) TCS-exposed mouse kidney. These processes might lead to lipotoxicity and energy depletion, thus resulting in kidney fibrosis and functional decline. Taken together, the present study demonstrated that TCS could induce lipid accumulation and fatty acid metabolism disturbance in mouse kidney, which might contribute to renal function impairment. The present study further widens our insights into the adverse effects of TCS.

Perfluorooctanoic acid-induced lipid metabolism disorder in SD rat liver and its effect on the expression of fatty acid metabolism-related proteins. / å ¨æ°Ÿè¾›é ¸å¯¹SDå¤§é¼ è‚è„‚è´¨ä»£è°¢ç´Šä¹±åŠè„‚è‚ªé ¸ä»£è°¢ç›¸å ³è›‹ç™½è¡¨è¾¾çš„å½±å“.

OBJECTIVES: Perfluorooctanoic acid (PFOA) can cause lipid metabolism disorders in animal body and affect the lipolysis and synthesis of fatty acids. Peroxisome proliferators-activated receptor (PPAR) plays an extremely important role in this process. This study aims to explore the effects of PFOA on liver lipid metabolism disorders in Sprague Dewley (SD) rats and the expression of PPAR. METHODS: A total of 40 male SD rats were randomly divided into 4 groups (n=10 in each group): a control group (ddH2O), a low-dose PFOA group [PFOA 1.25 mg/(kg·d)], a middle-dose PFOA group [PFOA 5.00 mg/(kg·d)], and a high-dose PFOA group [PFOA 20.00 mg/(kg·d)]. The rats were fed with normal diet, and PFOA exposure were performed by oral gavage for 14 days, and the rats were observed, weighted and recorded every day during the exposure. After the exposure, the blood was collected, and the livers were quickly stripped after the rats were killed. Part of the liver tissues were fixed in 4% paraformaldehyde for periodic acid-schiff (PAS) staining; the contents of HDLC, LDLC, TG, TC in serum and liver tissues, as well as the activities of their related enzymes were assayed; The expression levels of cyclic adenosine monophosphate-response element binding protein (Cbp), general control of amino acid synthesis 5-like 2 (Gcn5L2), peroxidation peroxisome proliferation factor activated receptor γ (PPAR), silent information regulator 1 (Sirt1) and human retinoid X receptor alpha 2 (Rxrα2) ) were detected by Western blotting. RESULTS: After 14 days of PFOA exposure, the PAS staining positive particles in the cytoplasm and nucleus of SD rats in the medium and high dose groups were significantly reduced compared with the control group. The serum levels of LDLC and TC in the low-dose and middle-dose groups were significantly reduced compared with the control group (all P<0.05), while the high-dose group showed an increasing tendency, without siginificant difference (P>0.05), there was no significant difference in HDLC and TG (both P>0.05). The activities of alkaline phosphatase (AKP) and alanine aminotransferase (ALT) were increased significantly (both P<0.05) compared with control group; the ratio of ALT/aspartate aminotransferase (AST) in the high-dose group was increased significantly (P<0.05), there was no significant difference in LDH and TG (both P>0.05); the HDLC content in the liver tissues in the high-dose group was significantly reduced, compared with the control group (P<0.05); the TC contents in the liver tissues in the low, medium and high-dose groups were significantly increased (all P<0.05), there was no significant difference in LDLC and TG (both P>0.05); the AKP activity in the livers in the medium and high-dose groups was significantly increased (both P<0.05), there was no siginificant difference in LDH, ALT, and the ratio of ALT/AST (all P>0.05); the protein expression levels of Ppar γ, Cbp and Rxrα2 in the liver in the high dose groups were significantly down-regulated compared with the control group (all P<0.05), while the protein expression levels of Sirt1 were significantly up-regulated (all P<0.05). CONCLUSIONS: PFOA exposure can cause lipid metabolism disorder and glycogen reduction in SD rat livers, which may be related to the activation of Sirt1 and inhibition of Ppar γ expression, leading to affecting the normal metabolism of fatty acids and promoting glycolysis.

Folic acid oversupplementation during pregnancy disorders lipid metabolism in male offspring via regulating arginase 1-associated NOS3-AMPKα pathway.

BACKGROUND & AIMS: Folic acid supplementation is widely accepted during pregnancy, as it exerts a protective effect on neural tube defects. However, the long-term underlying effects of folic acid supplementation during pregnancy (FASDP) on offspring remain unclear. METHODS: Thirty pregnant female rats were randomly divided into normal control group, folic acid appropriate supplementation group (2.5 × FA group) and folic acid oversupplementation group (5 × FA group) and fed with corresponding folic acid concentration AIN93G diet. UPLC-Q-TOF-MS, UPLC-TQ-MS and GC-MS were performed to detect the serum metabolites profiles in adult male offspring and explore the effects of FASDP. Moreover, molecular biology technologies were used to clarify the underlying mechanism. RESULTS: We demonstrate that 2.5-folds folic acid leads to dyslipidemic-diabetic slightly in male offspring, while 5-folds folic acid aggravates the disorder and prominent hepatic lipid accumulations. Using untargeted and targeted metabolomics, total 63 differential metabolites and 12 significantly differential KEGG pathways are identified. Of note, arginine biosynthesis, arginine and proline metabolism are the two most significant pathways. Mechanistic investigations reveal that the increased levels of arginase-1 (Arg1) causes the lipid metabolism disorder by regulating nitric oxide synthase-3 (NOS3)-adenosine monophosphate activated protein kinase-α (AMPKα) pathway, resulting in lipid accumulation in hepatocytes. CONCLUSIONS: Our data suggest that maternal folic acid oversupplementation during pregnancy contributes to lipid metabolism disorder in male offspring by regulating Arg1-NOS3-AMPKα pathway.

DHA-enriched phospholipids from large yellow croaker roe regulate lipid metabolic disorders and gut microbiota imbalance in SD rats with a high-fat diet.

Large yellow croaker roe phospholipids (LYCRPLs) have great nutritional value because they are rich in docosahexaenoic acid (DHA), which is an n-3 polyunsaturated fatty acid (n-3 PUFA). In previous research, we studied the effect of LYCRPLs on the inhibition of triglyceride accumulation at the cellular level. However, its lipid regulation effect in rats on a high-fat diet and its influence on the gut microbiota has not yet been clarified. In this study, a high-fat diet was used to induce the lipid metabolism disorder in SD rats, and simvastatin, low-dose, medium-dose and high-dose LYCRPLs were given by intragastric administration for 8 weeks. The rats' body weight, food intake, organ index, blood biochemical indicators, epididymal fat tissue and liver histopathology were compared and analyzed. High-throughput 16S rRNA gene sequencing technology and bioinformatics analysis technology were also used to analyze the diversity of gut microbiota in rats. We found that LYCRPLs can significantly regulate lipid metabolism, and improve the gut microbiota disorder induced in rats by a high-fat diet. These results can lay a foundation for the study of the regulation mechanism of LYCRPLs lipid metabolism, and also provide a theoretical basis for the development of LYCRPLs as functional food additives and excipients with hypolipidemic effects.

Branched-Chain Amino Acids Exacerbate Obesity-Related Hepatic Glucose and Lipid Metabolic Disorders via Attenuating Akt2 Signaling.

Branched chain amino acids (BCAAs) are associated with the progression of obesity-related metabolic disorders, including type 2 diabetes and nonalcoholic fatty liver disease. However, whether BCAAs disrupt the homeostasis of hepatic glucose and lipid metabolism remains unknown. In this study, we observed that BCAAs supplementation significantly reduced high-fat (HF) diet-induced hepatic lipid accumulation while increasing the plasma lipid levels and promoting muscular and renal lipid accumulation. Further studies demonstrated that BCAAs supplementation significantly increased hepatic gluconeogenesis and suppressed hepatic lipogenesis in HF diet-induced obese (DIO) mice. These phenotypes resulted from severe attenuation of Akt2 signaling via mTORC1- and mTORC2-dependent pathways. BCAAs/branched-chain α-keto acids (BCKAs) chronically suppressed Akt2 activation through mTORC1 and mTORC2 signaling and promoted Akt2 ubiquitin-proteasome-dependent degradation through the mTORC2 pathway. Moreover, the E3 ligase Mul1 played an essential role in BCAAs/BCKAs-mTORC2-induced Akt2 ubiquitin-dependent degradation. We also demonstrated that BCAAs inhibited hepatic lipogenesis by blocking Akt2/SREBP1/INSIG2a signaling and increased hepatic glycogenesis by regulating Akt2/Foxo1 signaling. Collectively, these data demonstrate that in DIO mice, BCAAs supplementation resulted in serious hepatic metabolic disorder and severe liver insulin resistance: insulin failed to not only suppress gluconeogenesis but also activate lipogenesis. Intervening BCAA metabolism is a potential therapeutic target for severe insulin-resistant disease.

Drug-induced liver steatosis and phospholipidosis: cell-based assays for early screening of drug candidates.

The liver plays a key role in fat metabolism, and excessive lipid accumulation in liver cells is characterised by a large spectrum of lesions, e.g., steatosis and phospholipidosis. Steatosis is increased lipid accumulation, mainly as triglycerides, in the liver, while phospholipidosis is a lysosomal storage disorder characterised by intracellular accumulation of phospholipids. These alterations can be induced by several factors, including exposure to certain drugs. Drug-induced steatosis is often reversible, and prolonged exposure to certain drugs can cause macrovacuolar steatosis, a benign hepatic lesion, that can evolve into steatohepatitis and cirrhosis in some patients. Some drugs may acutely induce microvesicular steatosis which, despite having a good short-term prognosis, can lead to chronic lipid peroxidation and to the development of steatohepatitis lesions with time. Over 50 marketed drugs have been reported to induce phospholipidosis in different tissues, including the liver. Although drug-induced phospholipidosis is often reversible and there is no definitive evidence for its toxicological implications, it is considered an adverse side finding by regulatory agencies. As developing new drugs is a complex, lengthy and expensive process that aims to identify pharmacologically active, low-toxicity drug candidates among closely related compounds, it could be advantageous to determine which drugs are able to induce lipid metabolic disorders in early developmental stages. To this end, in vitro predictive screening assays, particularly cell-based approaches in which many drug candidates are evaluated, have been developed to identify and rule out compounds with a strong liver steatosis and/or phospholipidosis-inducing potential.

Improvement on lipid metabolic disorder by 3'-deoxyadenosine in high-fat-diet-induced fatty mice.

This study explores the effects of 3'-deoxyadenosine, a compound from Cordyceps militaris, on lipid metabolic disorder induced by a high-fat-diet in C57BL/6 mice. These mice had an obese body, lipid metabolic disorder and insulin resistance and were treated orally with 100 mg/kg/day 3'-deoxyadenosine (DA), 15 mg/kg/day rosiglitazone and 150 mg/kg/day fenofibrate, respectively. Compared to the model mice, the body weight gain in DA-treated mice were decreased by 66.5%, serum triglyceride and total cholesterol levels were decreased by 20.7% and 16.7%, respectively, and the triglyceride content in the skeletal muscle was reduced by 41.2%. This treatment also had a significant effect on insulin resistance. In DA-treated mice, the serum insulin levels and homeostasis model assessment of the insulin resistance index were decreased by 30% and 46%, respectively, and the areas under the glucose-time curve were depressed by 18% in the insulin tolerance test and by 21.5% in the oral glucose tolerance test. Finally, the value of glucose infusion rates and insulin induced-glucose uptake into the skeletal muscle in the hyperinsulinemic-euglycemic clamp test were increased by 18% and 41%, respectively, compared to those in the model mice. This data suggests that the effects of DA on lipid metabolic disorder induced by a high-fat-diet may be linked to its improvement on insulin resistance, especially concerning the increase of insulin sensitivity in the skeletal muscle.

[Using green and black tea extracts to prevent toxic effects of acetone].

The authors demonstrated use of water-alcohol extracts of green and black tea for possible prevention of carbohydrates and lipid metabolism disorders in rats liver due to acetone intoxication. Polyphenols obtained from tea and injected into the animals before acetone intoxication resulted in preserved serum glucose level, phospholipid and neutral lipid contents, lower levels of cholesterol, triacylglycerines, saturated fatty acids in liver.

[Effect of selenium supplement on the disordered lipid metabolism induced by the overdose of iodine in mice].

OBJECTIVE: To explore the effect of selenium supplement on the disordered lipid metabolism induced by the overdose of iodine in mice. METHODS: The 80 Balb/c mice were randomly divided into eight groups, the normal control group, the high iodine group (drunk the water containing iodine 3000 microg/L) and six selenium groups (drunk the water containing iodine 3000 microg/L and selenium 0.1, 0.2, 0.3, 0.4, 0.5, 0.75 mg/L). The total cholesterol and triglyceride in serum and liver were determined. RESULTS: The total cholesterol in serum, the total cholesterol and triglyceride in liver of high-iodine group increased significantly compared with normal control group. There is no difference between normal control group and the group drunk the water contained 0.2 mg/L selenium. CONCLUSION: It suggests that it is an effective intervention dosage to drunk water containing 0.2 mg/L selenium.