Sub-chronic exposure to hexaconazole affects the lipid metabolism of rats through mTOR-PPAR-γ/SREBP1 signaling pathway mediated by oxidative stress.

Hexaconazole (Hex) is a widely used and high frequency detected triazole fungicide in agricultural products and environment which may pose potential toxicity to the nontargeted organisms. Hex had been reported to affect lipid homeostasis while the mechanism was undefined. This study aims to explore the characteristic lipidomic profiles and clarify the underlying signaling pathways of Hex-induced lipid metabolism disorder in rat liver. The results showed that sub-chronic exposure to environmental related concentrations of Hex caused histopathological changes, oxidative stress, fat accumulation, lipid biochemical parameter increase in rats. Moreover, the untargeted lipidomic analysis showed that the levels of TAG, PC, and PE and the pathway of glycerophospholipid metabolism were heavily altered by Hex. We further analyzed the lipid metabolism related genes and proteins which revealed that Hex exposure increased amount of lipogenesis by activating oxidative stress-mediated mTOR-PPAR-γ/SREBP1 signaling pathways. The imbalance of lipid homeostasis induced by Hex exposure might further lead to obesity, cardiovascular diseases (CVDs), and hyperlipidemia. Our results provided systematic and comprehensive evidence for the mechanism of Hex-induced lipid metabolism disorder at environmental concentrations and supplied a certain basis for its health risks assessment.

Sclareol ameliorates liver injury by inhibiting nuclear factor-kappa B/NOD-like receptor protein 3-mediated inflammation and lipid metabolism disorder in diabetic mice.

Objectives: Sclareol (SCL) is a natural diterpene with anti-inflammation and antioxidant properties. This study aimed to assess the hepatoprotective effects of SCL in diabetic mice. Methods: SCL (10 mg/kg) was administered intragastrically to C57BL/6 mice with streptozotocin-induced diabetes daily for 5 weeks to evaluate its beneficial effects in liver injury. Body and liver weight and blood glucose levels were measured. Liver histopathology, fibrosis, and lipid accumulation were evaluated using hematoxylin and eosin, Masson's trichrome, and Oil Red O staining, respectively. Serum hepatic enzyme and lipid levels were measured using an automatic biochemical analyzer. Hepatocellular apoptosis was measured using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. Oxidative stress markers and reactive oxygen species (ROS) were measured using appropriate assay kits. The effects of sclareol on inflammation and lipid metabolism was evaluated by enzyme-linked immunosorbent assay (ELISA), immunohistochemical analysis, and Western blot assays. Results: SCL significantly decreased serum liver enzymes and lipids levels, and alleviated adipogenesis and fibrosis. Moreover, the protein levels of acetyl-CoA carboxylase and sterol response element-binding protein 1 were downregulated, whereas the expression of carnitine palmitoyl transferase 1 was upregulated. SCL increased the antioxidant activity, and decreased ROS levels. SCL alleviated hepatic mitochondrial damage. Furthermore, SCL inhibited Kupffer cell infiltration and reduced serum inflammatory cytokine levels. SCL significantly downregulated the protein expression of nuclear factor-kappa B (NF-κB) P65, NOD-like receptor protein 3 (NLRP3), caspase 1, and interleukin-1ß. Conclusions: Our findings suggest that SCL improves diabetes-induced liver injury by alleviating the NF-κB/NLRP3-mediated inflammation and lipid metabolism disorder.

Hepatic lipid metabolism disorders and immunotoxicity induced by cysteamine in early developmental stages of zebrafish.

Cysteamine, a sulfhydryl compound, is an intermediate in the metabolism of coenzyme A to taurine in living organisms. However, the potential side effects of cysteamine such as hepatotoxicity in pediatric patients have been reported in some studies. To evaluate the impact of cysteamine on infants and children, larval zebrafish (a vertebrate model) were exposed to 0.18, 0.36 and 0.54 mM cysteamine from 72 hpf to 144 hpf. Alterations in general and pathological evaluation, biochemical parameters, cell proliferation, lipid metabolism factors, inflammatory factors and Wnt signaling pathway levels were examined. Increased liver area and lipid accumulation were observed in liver morphology, staining and histopathology in a dose-dependent manner with cysteamine exposure. In addition, the experimental cysteamine group exhibited higher alanine aminotransferase, aspartate aminotransferase, total triglyceride and total cholesterol levels than the control group. Meanwhile, the levels of lipogenesis-related factors ascended whereas lipid transport-related factors descended. Oxidative stress indicators such as reactive oxygen species, MDA and SOD were upregulated after cysteamine exposure. Afterwards, transcription assays revealed that biotinidase and Wnt pathway-related genes were upregulated in the exposed group, and inhibition of Wnt signaling partially rescued the abnormal liver development. The current study found that cysteamine-induced hepatotoxicity in larval zebrafish is due to inflammation and abnormal lipid metabolism, which is mediated by biotinidase (a potential pantetheinase isoenzyme) and Wnt signaling. This provides a perspective on the safety of cysteamine administration in children and identifies potential targets for protection against adverse reactions.

MC-LR Aggravates Liver Lipid Metabolism Disorders in Obese Mice Fed a High-Fat Diet via PI3K/AKT/mTOR/SREBP1 Signaling Pathway.

Obesity, a metabolic disease caused by excessive fat accumulation in the body, has attracted worldwide attention. Microcystin-LR (MC-LR) is a hepatotoxic cyanotoxin which has been reportedly to cause lipid metabolism disorder. In this study, C57BL/6J mice were fed a high-fat diet (HFD) for eight weeks to build obese an animal model, and subsequently, the obese mice were fed MC-LR for another eight weeks, and we aimed to determine how MC-LR exposure affects the liver lipid metabolism in high-fat-diet-induced obese mice. The results show that MC-LR increased the obese mice serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), indicating damaged liver function. The lipid parameters include serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and liver TG, which were all increased, whilst the high-density lipoprotein cholesterol (HDL-c) was decreased. Furthermore, after MC-LR treatment, histopathological observation revealed that the number of red lipid droplets increased, and that steatosis was more severe in the obese mice. In addition, the lipid synthesis-related genes were increased and the fatty acid ß-oxidation-related genes were decreased in the obese mice after MC-LR exposure. Meanwhile, the protein expression levels of phosphorylation phosphatidylinositol 3-kinase (p-PI3K), phosphorylation protein kinase B (p-AKT), phosphorylation mammalian target of rapamycin (p-mTOR), and sterol regulatory element binding protein 1c (SREBP1-c) were increased; similarly, the p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, and SREBP1/ß-actin were significantly up-regulated in obese mice after being exposed to MC-LR, and the activated PI3K/AKT/mTOR/SREBP1 signaling pathway. In addition, MC-LR exposure reduced the activity of superoxide dismutase (SOD) and increased the level of malondialdehyde (MDA) in the obese mice's serum. In summary, the MC-LR could aggravate the HFD-induced obese mice liver lipid metabolism disorder by activating the PI3K/AKT/mTOR/SREBP1 signaling pathway to hepatocytes, increasing the SREBP1-c-regulated key enzymes for lipid synthesis, and blocking fatty acid ß-oxidation.

Combined exposure to PM2.5 and high-fat diet facilitates the hepatic lipid metabolism disorders via ROS/miR-155/PPARγ pathway.

Environmental fine particulate matter (PM2.5), which has attracted worldwide attention, is associated with the progression of metabolic-associated fatty liver disease (MAFLD). However, it is unclear whether dietary habit exacerbate liver damage caused by PM2.5. The current study aimed to investigate the combined negative effects of PM2.5 and high-fat diet (HFD) on liver lipid metabolism in C57BL/6J mice. Histopathological and Oil-Red O staining analysis illustrated that PM2.5 exposure resulted in increased liver fat content in HFD-fed C57BL/6J mice, but not in standard chow diet (STD)-fed mice. And there was a synergistic effect between PM2.5 and HFD on hepatic lipotoxicity. The increased ROS levels and augmented oxidative damage were evaluated in liver tissue of mice treated with PM2.5 and HFD together. In addition, excessive ROS production could activate the miR-155/peroxisome proliferator-activated receptor gamma (PPARγ) pathway, including up-regulation of lipid accumulation-related protein expressions of recombinant liver X receptor alpha (LXRα), sterol regulatory element binding protein-1 (SREBP-1), stearoyl-CoA desaturase-1 (SCD1), fatty acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC1).The use of miR-155 inhibitors demonstrated the indispensable role of miR-155 in the activation of lipid-regulated proteins by PM2.5 and palmitic acid (PA). Collectively, altering high-fat dietary habits could protect against MAFLD motivated by air pollution, and miR-155 might be an effective preventive and therapeutic target for this process.

Di-2-ethylhexyl phthalate (DEHP) induced lipid metabolism disorder in liver via activating the LXR/SREBP-1c/PPARα/γ and NF-κB signaling pathway.

Di-2-ethylhexyl phthalate (DEHP) has been widely used in many fields (agricultural products, medical instruments, and food packing). As an environmental contaminant, DEHP has a negative impact on human and animal health, and thus toxicity caused by DEHP is increasingly serious health concern. Nevertheless, DEHP-induced liver damage in quail remains unclear. To investigate the mechanism of liver damage caused by DEHP, male quail were treated with DEHP (250, 500, and 750 mg/kg) by gavage. Notably, DEHP exposure results in increased blood lipids and the accumulation of triglycerides (TG), total cholesterol (TC), and non-esterified fatty acid (NEFA) in the liver. Histopathological analysis showed that steatosis and inflammatory cell infiltration were observed in the liver tissue of quails exposed to DEHP. The results of Oil Red O staining displayed that DEHP induced lipid storage in the liver. Moreover, DEHP induced lipid metabolism disorders by activating the LXR/SREBP-1c and PPARα/γ signaling pathway. DEHP exposure obviously caused the up-regulation of pro-inflammatory cytokines (NF-κB, IL-6, IL-8, IL-1ß, and TNF-a). This study showed that DEHP could induce lipid metabolism disorders and inflammatory response via LXR/SREBP-1c/PPARα/γ and NF-κB signaling pathways.

Chronic exposure to low concentration of MC-LR caused hepatic lipid metabolism disorder.

Microcystin-LR (MC-LR), a potent hepatotoxin can cause liver damages. However, research on hepatic lipid metabolism caused by long-term exposure to environmental concentrations MC-LR is limited. In the current study, mice were exposed to various low concentrations of MC-LR (0, 1, 30, 60, 90, 120 µg/L in the drinking water) for 9 months. The general parameters, serum and liver lipids, liver tissue pathology, lipid metabolism-related genes and proteins of liver were investigated. The results show that chronic MC-LR exposure had increased the levels of triglyceride (TG) and total cholesterol (TC) in serum and liver. In addition, histological observation revealed that hepatic lobules were disordered with obvious inflammatory cell infiltration and lipid droplets. More importantly, the mRNA and proteins expression levels of lipid synthesis-related nuclear sterol regulatory element binding protein-1c (nSREBP-1c), SREBP-1c, cluster of differentiation 36 (CD36), acetyl-CoA-carboxylase1 (ACC1), stearoyl-CoA desaturase1 (SCD1) and fatty acid synthase (FASN) were increased in MC-LR treated groups, the expression levels of fatty acids ß-oxidation related genes peroxisomal acyl-coenzyme A oxidase 1 (ACOX1) was decreased after exposure to 60-120 µg/L MC-LR. Furthermore, the inflammatory factors interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) were higher than that in the control group. All the findings indicated that mice were exposed to chronic low concentrations MC-LR caused liver inflammation and hepatic lipid metabolism disorder .

Fluorene-9-bisphenol exposure decreases locomotor activity and induces lipid-metabolism disorders by impairing fatty acid oxidation in zebrafish.

AIMS: Fluorene-9-bisphenol (BHPF), as a substitute for bisphenol A, is used in many industries in daily life. Many studies have clarified its effects as an endocrine disruptor on organisms, but its effect on lipid metabolism of zebrafish larvae is not clear. Patients with non-alcoholic fatty liver disease (NAFLD) are more susceptible to external pollutants. It is not clear how BHPF perturbs lipid metabolism or promotes NAFLD progression. MAIN METHODS: We explored the biological effects of BHPF on locomotor activity, inflammatory response, endoplasmic reticulum (ER) stress and lipid metabolism in zebrafish, especially in the mechanism of lipid homeostasis disorder. In addition, the role of BHPF in the progression of non-alcoholic fatty liver disease (NAFLD) was further explored. KEY FINDINGS: We found that high concentration (100 nmol/L) BHPF caused retarded growth, mild lipid accumulation and reduced the locomotive activity of zebrafish larvae, accompanied by a decrease in endogenous cortisol level. At the same time, it caused the full activation of inflammation and ER stress. Rescue experiments by 25(OH)D3 demonstrated that high concentration of BHPF caused defects in 1,25(OH)2D3 metabolic pathway through downregulation of cyp2r1, which further damaged pgc1a-mediated fatty acid oxidation and mitochondrial function, resulting in lipid accumulation. In summary, exposure to BHPF could damage lipid homeostasis and worsen the diet-induced NAFLD. SIGNIFICANCE: Our findings provide new insights into the role of BHPF in development of overweight and obesity and also improve understanding of its toxicological mechanism. Our results play a warning role in the administration of environmental pollutants.

Morroniside Promotes PGC-1α-Mediated Cholesterol Efflux in Sodium Palmitate or High Glucose-Induced Mouse Renal Tubular Epithelial Cells.

Lipid deposition is an etiology of renal damage caused by lipid metabolism disorder in diabetic nephropathy (DN). Thus, reducing lipid deposition is a feasible strategy for the treatment of DN. Morroniside (MOR), an iridoid glycoside isolated from the Chinese herb Cornus officinalis Sieb. et Zucc., is considered to be an effective drug in inhibiting oxidative stress, reducing inflammatory response, and countering apoptosis. To explore the protective mechanism of MOR in attenuating renal lipotoxicity in DN, we investigated the effect of MOR on an in vitro model of lipid metabolism disorder of DN established by stimulating mouse renal tubular epithelial cells (mRTECs) with sodium palmitate (PA) or high glucose (HG). Oil Red O and filipin cholesterol staining assays were used to determine intracellular lipid accumulation status. Results revealed that PA or HG stimulation inhibited the expressions of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), liver X receptors (LXR), ATP-binding cassette subfamily A member 1 (ABCA1), ABCG1, and apolipoprotein E (ApoE) in mRTECs as evidenced by western blot and quantitative real-time PCR, resulting in increased intracellular lipid deposition. Interestingly, MOR upregulated expressions of PGC-1α, LXR, ABCA1, ABCG1, and ApoE, thus reducing cholesterol accumulation in mRTECs, suggesting that MOR might promote cholesterol efflux from mRTECs via the PGC-1α/LXR pathway. Of note, silencing PGC-1α reversed the promotive effect of MOR on PA- or HG-induced cellular cholesterol accumulation. In conclusion, our results suggest that MOR has a protective effect on mRTECs under high lipid or high glucose conditions, which may be related to the promotion of intracellular cholesterol efflux mediated by PGC-1α.

Case Studies in Pediatric Lipid Disorders and Their Management.

CONTEXT: Identification of modifiable risk factors, including genetic and acquired disorders of lipid and lipoprotein metabolism, is increasingly recognized as an opportunity to prevent premature cardiovascular disease (CVD) in at-risk youth. Pediatric endocrinologists are at the forefront of this emerging public health concern and can be instrumental in beginning early interventions to prevent premature CVD-related events during adulthood. AIM: In this article, we use informative case presentations to provide practical approaches to the management of pediatric dyslipidemia. CASES: We present 3 scenarios that are commonly encountered in clinical practice: isolated elevation of low-density lipoprotein cholesterol (LDL-C), combined dyslipidemia, and severe hypertriglyceridemia. Treatment with statin is indicated when the LDL-C is ≥190 mg/dL (4.9 mmol/L) in children ≥10 years of age. For LDL-C levels between 130 and 189 mg/dL (3.4-4.89 mmol/L) despite dietary and lifestyle changes, the presence of additional risk factors and comorbid conditions would favor statin therapy. In the case of combined dyslipidemia, the primary treatment target is LDL-C ≤130 mg/dL (3.4 mmol/L) and the secondary target non-high-density lipoprotein cholesterol <145 mg/dL (3.7 mmol/L). If the triglyceride is ≥400 mg/dL (4.5 mmol/L), prescription omega-3 fatty acids and fibrates are considered. In the case of triglyceride >1000 mg/dL (11.3 mmol/L), dietary fat restriction remains the cornerstone of therapy, even though the landscape of medications is changing. CONCLUSION: Gene variants, acquired conditions, or both are responsible for dyslipidemia during childhood. Extreme elevations of triglycerides can lead to pancreatitis. Early identification and management of dyslipidemia and cardiovascular risk factors is extremely important.

Roles of microRNAs in carbohydrate and lipid metabolism disorders and their therapeutic potential.

MicroRNAs (miRNAs) are small (∼21 nucleotides), endogenous, non-coding RNA molecules implicated in the post-transcriptional gene regulation performed through target mRNA cleavage or translational inhibition. In recent years, several investigations have demonstrated that miRNAs are involved in regulating both carbohydrate and lipid homeostasis in humans and other organisms. Moreover, it has been observed that the dysregulation of these metabolism-related miRNAs leads to the development of several metabolic disorders, such as type 2 diabetes, obesity, nonalcoholic fatty liver, insulin resistance, and hyperlipidemia. Hence, in this current review, with the aim to impulse the research arena of the micro-transcriptome implications in vital metabolic pathways as well as to highlight the remarkable potential of miRNAs as therapeutic targets for metabolic disorders in humans, we provide an overview of the regulatory roles of metabolism-associated miRNAs in humans and murine models.

Berberine alleviates lipid metabolism disorders via inhibition of mitochondrial complex I in gut and liver.

This study is to investigate the relationship between berberine (BBR) and mitochondrial complex I in lipid metabolism. BBR reversed high-fat diet-induced obesity, hepatic steatosis, hyperlipidemia and insulin resistance in mice. Fatty acid consumption, ß-oxidation and lipogenesis were attenuated in liver after BBR treatment which may be through reduction in SCD1, FABP1, CD36 and CPT1A. BBR promoted fecal lipid excretion, which may result from the reduction in intestinal CD36 and SCD1. Moreover, BBR inhibited mitochondrial complex I-dependent oxygen consumption and ATP synthesis of liver and gut, but no impact on activities of complex II, III and IV. BBR ameliorated mitochondrial swelling, facilitated mitochondrial fusion, and reduced mtDNA and citrate synthase activity. BBR decreased the abundance and diversity of gut microbiome. However, no change in metabolism of recipient mice was observed after fecal microbiota transplantation from BBR treated mice. In primary hepatocytes, BBR and AMPK activator A769662 normalized oleic acid-induced lipid deposition. Although both the agents activated AMPK, BBR decreased oxygen consumption whereas A769662 increased it. Collectively, these findings indicated that BBR repressed complex I in gut and liver and consequently inhibited lipid metabolism which led to alleviation of obesity and fatty liver. This process was independent of intestinal bacteria.

Endothelial Cell Receptors in Tissue Lipid Uptake and Metabolism.

Lipid uptake and metabolism are central to the function of organs such as heart, skeletal muscle, and adipose tissue. Although most heart energy derives from fatty acids (FAs), excess lipid accumulation can cause cardiomyopathy. Similarly, high delivery of cholesterol can initiate coronary artery atherosclerosis. Hearts and arteries-unlike liver and adrenals-have nonfenestrated capillaries and lipid accumulation in both health and disease requires lipid movement from the circulation across the endothelial barrier. This review summarizes recent in vitro and in vivo findings on the importance of endothelial cell receptors and uptake pathways in regulating FAs and cholesterol uptake in normal physiology and cardiovascular disease. We highlight clinical and experimental data on the roles of ECs in lipid supply to tissues, heart, and arterial wall in particular, and how this affects organ metabolism and function. Models of FA uptake into ECs suggest that receptor-mediated uptake predominates at low FA concentrations, such as during fasting, whereas FA uptake during lipolysis of chylomicrons may involve paracellular movement. Similarly, in the setting of an intact arterial endothelial layer, recent and historic data support a role for receptor-mediated processes in the movement of lipoproteins into the subarterial space. We conclude with thoughts on the need to better understand endothelial lipid transfer for fuller comprehension of the pathophysiology of hyperlipidemia, and lipotoxic diseases such as some forms of cardiomyopathy and atherosclerosis.

Glucocorticoid induced diabetes and lipid profiles disorders amongst lymphoid malignancy survivors.

BACKGROUND AND AIMS: Hyperglycemia and glucose test abnormalities are problems during the treatment of patients with lymphoid malignancy, caused by corticosteroid therapy. However, its long-term complications or risk of developing diabetes are not available. METHODS: Two hundred patients with lymphoid hematologic malignancy were recruited and followed up for median of 47 months. The underlying hematologic malignancy includes Hodgkin's disease (HD), Non-Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia(CLL), Multiple Myeloma (MM) and Acute Lymphocytic Leukemia (ALL). Fasting blood sugar, glucose tolerance test and lipid profiles were measured before each chemotherapy cycle and every 3 months after. This study was designed to evaluate patients for long-term follow up of glucose tests abnormalities. RESULTS: The mean age of the non-diabetic patients was significantly lower than that of diabetics and patients with fasting glucose disorder (p < 0.001). The prevalence of diabetes and impaired FBS and GTT was higher in NHL (9%), CLL (6.5%) and MM (1.5%), respectively. For lipid profiles, the highest levels of cholesterol and triglycerides were observed in multiple myeloma and the lowest in Hodgkin's lymphoma (P:0.004). CONCLUSIONS: The most important factor for steroid-induced diabetes is age, which was more prevalent with age increase (P < 0.001). Glucocorticoid-induced diabetes is common in multiple myeloma and then in chronic lymphocytic leukemia and non-Hodgkin's lymphoma in comparison with Hodgkin's lymphoma and acute lymphoblastic leukemia.

Exposure to Low Doses of Dechlorane Plus Promotes Adipose Tissue Dysfunction and Glucose Intolerance in Male Mice.

The prevalence of type 2 diabetes (T2D) continues to increase worldwide. It is well established that genetic susceptibility, obesity, overnutrition and a sedentary life style are risk factors for the development of T2D. However, more recently, studies have also proposed links between exposure to endocrine-disrupting chemicals (EDCs) and altered glucose metabolism. Human exposure to environmental pollutants that are suspected to have endocrine disruptor activity is ubiquitous. One such chemical is Dechlorane Plus (DP), a flame retardant, that is now detected in humans and the environment. Here we show that exposure of mice to low, environmentally relevant doses of DP promoted glucose intolerance in mice fed a high-fat diet independent of weight gain. Furthermore, DP had pronounced effects on the adipose tissue, where it induced the development of hypertrophied white adipose tissue (WAT), and increased serum levels of resistin, leptin, and plasminogen activator inhibitor-1. In addition, DP exposure induced "whitening" of brown adipose tissue (BAT), and reduced BAT uncoupling protein 1 expression. Importantly, some of these effects occurred even when the mice were fed a regular, low-fat, diet. Finally, WAT adipogenic markers were reduced with DP treatment in the WAT. We also show that DP directly inhibited insulin signaling in murine adipocytes and human primary subcutaneous adipocytes in vitro. Taken together, our results show that the exposure to low and environmentally relevant levels of DP may contribute to the development of T2D.

Effect of Vanadium Complex with Enzymatic Hydrolysate of Soy Protein on Carbohydrate and Lipid Metabolism Disorders in Male Wistar Rats.

The effects of vanadium complex with enzymatic hydrolysate of soy protein (V-EHSPI) were studied in male Wistar rats with induced disorders of carbohydrate and lipid metabolism. The content of vanadium (IV) in the studied complex was 15.8 mg/g dry product. High-lipid high-carbohydrate diet was used to induce disorders of lipid and carbohydrate metabolism. Addition of vanadium in three different doses to the diet over 100-day experiment reduced body weight gain and the levels of glucose, insulin, leptin, and triglycerides. V-EHSPI produced beneficial effects on carbohydrate and lipid metabolism even in a dose 5 µg/kg body weight/day (calculated from the mean food consumption over the entire treatment period). Significant inhibition of growth and changes in the weight of organs in animals treated with V-EHSPI attested to toxicity of vanadium in the studied dose range.

Undernutrition-induced lipid metabolism disorder triggers oxidative stress in maternal and fetal livers using a model of pregnant sheep.

This study aimed to evaluate the oxidative status and antioxidant capacity in maternal and fetal livers upon undernutrition as well as the connection between oxidative stress and lipid metabolism disorder. Ten ewes, who were pregnant for 115 days, were restricted to a 30% level of ad libitum feed intake to develop an undernourished model, while another 10 pregnant ewes were fed normally as controls. Undernutrition induced severe lipid metabolism disorder and oxidative stress in blood, maternal liver, and fetal liver. RNA-sequencing data displayed that antioxidant capacity was changed and antioxidant genes were downregulated in maternal and fetal livers of the undernourished model. Non-esterified fatty acids (NEFAs) and beta-hydroxybutyrate (BHBA) levels showed a positive correlation with oxidative indices and negative correlation with the expression of antioxidant genes both in maternal and fetal livers. Primary hepatocytes experiments confirmed that both high levels of NEFAs and BHBA could elicit oxidative stress and decrease antioxidant capacity, and the peroxisome proliferator-activated receptor alpha (PPARA)/retinoid X receptor alpha (RXRA) signaling pathway played a vital role in enhancing antioxidant capacity and relieving oxidative stress. In conclusion, maternal undernutrition induced lipid metabolism disorder, which downregulated antioxidant genes, decreased antioxidant activity, and further triggered oxidative stress both in maternal and fetal livers. Activation of PPARA/RXRA signaling could enhance antioxidant capacity and mitigate oxidative stress. Our findings contribute to protecting the pregnant mother and her fetus from oxidative stress.

Gestational hypothyroidism elicits more pronounced lipid dysregulation in mice than pre-pregnant hypothyroidism.

Thyroid hormone is crucial for regulating lipid and glucose metabolism, which plays essential role in maintaining the health of pregnant women and their offspring. However, the current literature is just focusing on the development of offspring born to the untreated mothers with hypothyroidism, rather than mothers themselves. Additionally, the interaction between hypothyroidism and pregnancy, and its impact on the women's health are still elusive. Therefore, this study was designed to compare the metabolic differences in dams with hypothyroidism starting before pregnancy and after pregnancy. Pre-pregnant hypothyroidism was generated in 5-week-old female C57/BL/6J mice using iodine-deficient diet containing 0.15% propylthiouracil for 4 weeks, and the hypothyroidism was maintained until delivery. Gestational hypothyroidism was induced in dams after mating, using the same diet intervention until delivery. Compared with normal control, gestational hypothyroidism exhibited more prominent increase than pre-pregnant hypothyroidism in plasma total cholesterol and low-density lipoprotein cholesterol, and caused hepatic triglycerides accumulation. Similarly, more significant elevations of protein expressions of SREBP1c and p-ACL, while more dramatic inhibition of CPT1A and LDL-R levels were also observed in murine livers with gestational hypothyroidism than those with pre-pregnant hypothyroidism. Moreover, the murine hepatic levels of total cholesterol and gluconeogenesis were dramatically and equally enhanced in two hypothyroid groups, while plasma triglycerides and protein expressions of p-AKT, p-FoxO1 and APOC3 were reduced substantially in two hypothyroid groups. Taken together, our current study illuminated that gestational hypothyroidism may elicit more pronounced lipid dysregulation in dams than dose the pre-pregnant hypothyroidism.

Lipid metabolism disorders contribute to hepatotoxicity of triclosan in mice.

Previous in vivo exposure studies focused mainly on nuclear receptors involved in hepatotoxicity of triclosan (TCS). As liver plays a vital role in metabolic processes, dysregulations in lipid metabolism have been identified as potential drivers of pathogenesis. Investigation of changes in lipid metabolism might widen our understanding of toxicological effects as well as the underlying mechanism occurring in the liver. In this study, we comprehensively assessed the effect of TCS exposure on hepatic lipid metabolism in mice. Our results showed that TCS induced significant changes in hepatic free fatty acid pool by upregulation of fatty acid uptake and de novo fatty acid synthesis. Besides, hepatic levels of lipids, including acyl carnitine (AcCa), ceramide (Cer), triacylglycerols (TG), phosphatidylcholine (PC), lysophosphatidylcholine (LPC), phosphatidylethanolamine (PE) were also increased, together with upreguation of genes associated to TG synthesis, fatty acid oxidation and inflammation in TCS exposure group. These changes in lipid homeostasis could contribute to membrane instability, lipid accumulation, oxidative stress and inflammation. Our results suggested that TCS exposure could induce hepatic lipid metabolism disorders in mice, which would further contribute to the liver damage effects of TCS.