Expression Of Lipid Metabolism Genes Research Articles

AdipoRon Effect on Expression of Lipid Metabolism Genes in Cultured Human Primary Macrophages

AdipoRon Effect on Expression of Lipid Metabolism Genes in Cultured Human Primary Macrophages

Effect of supplementation with a mixture of <i>Curcuma longa</i> and <i>Rosmarinus officinalis</i> extracts on growth performance, meat quality and lipid metabolism gene expressions in young castrated Polish White Improved bucks

Effect of supplementation with a mixture of <i>Curcuma longa</i> and <i>Rosmarinus officinalis</i> extracts on growth performance, meat quality and lipid metabolism gene expressions in young castrated Polish White Improved bucks

F-box only protein 2 exacerbates non-alcoholic fatty liver disease by targeting the hydroxyl CoA dehydrogenase alpha subunit.

Non-alcoholic fatty liver disease (NAFLD) is a major health burden with an increasing global incidence. Unfortunately, the unavailability of knowledge underlying NAFLD pathogenesis inhibits effective preventive and therapeutic measures. To explore the molecular mechanism of NAFLD. Whole genome sequencing (WGS) analysis was performed on liver tissues from patients with NAFLD (n = 6) and patients with normal metabolic conditions (n = 6) to identify the target genes. A NAFLD C57BL6/J mouse model induced by 16 wk of high-fat diet feeding and a hepatocyte-specific F-box only protein 2 (FBXO2) overexpression mouse model were used for in vivo studies. Plasmid transfection, co-immunoprecipitation-based mass spectrometry assays, and ubiquitination in HepG2 cells and HEK293T cells were used for in vitro studies. A total of 30982 genes were detected in WGS analysis, with 649 up-regulated and 178 down-regulated. Expression of FBXO2, an E3 ligase, was upregulated in the liver tissues of patients with NAFLD. Hepatocyte-specific FBXO2 overexpression facilitated NAFLD-associated phenotypes in mice. Overexpression of FBXO2 aggravated odium oleate (OA)-induced lipid accumulation in HepG2 cells, resulting in an abnormal expression of genes related to lipid metabolism, such as fatty acid synthase, peroxisome proliferator-activated receptor alpha, and so on. In contrast, knocking down FBXO2 in HepG2 cells significantly alleviated the OA-induced lipid accumulation and aberrant expression of lipid metabolism genes. The hydroxyl CoA dehydrogenase alpha subunit (HADHA), a protein involved in oxidative stress, was a target of FBXO2-mediated ubiquitination. FBXO2 directly bound to HADHA and facilitated its proteasomal degradation in HepG2 and HEK293T cells. Supplementation with HADHA alleviated lipid accumulation caused by FBXO2 overexpression in HepG2 cells. FBXO2 exacerbates lipid accumulation by targeting HADHA and is a potential therapeutic target for NAFLD.

Medium-chain fatty acids modify macrophage expression of metabolic and inflammatory genes in a PPAR β/δ-dependent manner

There is great interest on medium chain fatty acids (MCFA) for cardiovascular health. We explored the effects of MCFA on the expression of lipid metabolism and inflammatory genes in macrophages, and the extent to which they were mediated by the nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPAR β/δ). J774A.1 murine macrophages were exposed to octanoate or decanoate as MCFA, a long-chain fatty acid control (palmitate), or the PPAR β/δ agonist GW501516, with or without lipopolysaccharide (LPS) stimulation, and with or without an siRNA-induced knockdown of PPAR β/δ. MCFA increased the expression of Plin2, encoding a lipid-droplet associated protein with anti-inflammatory effects in macrophages, in a partially PPAR β/δ-dependent manner. Both MCFA stimulated expression of the cholesterol efflux pump ABCA1, more pronouncedly under LPS stimulation and in the absence of PPAR β/δ. Octanoate stimulated the expression of Pltp, encoding a phospholipid transfer protein that aids ABCA1 in cellular lipid efflux. Only palmitate increased expression of the proinflammatory genes Il6, Tnf, Nos2 and Mmp9. Non-stimulated macrophages exposed to MCFA showed less internalization of fluorescently labeled lipoproteins. MCFA influenced the transcriptional responses of macrophages favoring cholesterol efflux and a less inflammatory response compared to palmitate. These effects were partially mediated by PPAR β/δ.

Blood lipid profiles, fatty acid deposition and expression of hepatic lipid and lipoprotein metabolism genes in laying hens fed palm oils, palm kernel oil, and soybean oil.

The palm oil, palm kernel oil and soybean oil have unique and distinctive fatty acid chain length and saturation profiles, and how they affect lipid peroxidation, fatty acid intake and metabolism is worth exploring in poultry. This study elucidated the influence the dietary oils on lipid peroxidation, blood lipid profiles, fatty acid deposition of liver, serum and yolk and the expression of liver genes related to lipid and lipoprotein metabolism in laying hens. About 150 Hisex brown laying hens were fed diets containing crude palm oil (CPO), red palm oil (RPO), refined palm oil (RBD), palm kernel oil (PKO) or soybean oil (SBO) for 16 weeks. Serum, liver and yolk lipid peroxidation were not different between dietary oils. The PKO increased liver, serum and yolk medium-chain fatty acids (MCFA). There was no difference in liver saturated fatty acids (SFA). The CPO and RPO reduced serum SFA, but the PKO increased yolk SFA. The SBO increased polyunsaturated fatty acids (PUFA) in liver serum and yolk. No difference in liver elaidic acid (C18:1-trans), but SBO lowered elaidic acid (C18:1-trans) in serum. Higher very-low density lipoprotein (VLDL) in CPO than RPO and SBO and greater serum lipase in CPO, RBD and PKO than SBO. There was no difference in sterol regulatory element-binding protein 2 (SREBP-II) between oils. Apolipoprotein VLDL-II (APOVLDL2) was upregulated in palm oils and apolipoprotein B-100 (APOB) in RBD. Downregulation in peroxisome proliferator-activated receptor-alpha (PPAR-α), peroxisome proliferator-activated receptor gamma (PPAR-γ) and low-density lipoprotein receptor (LDLR) was observed in palm oils and PKO. In conclusion, different dietary oils greatly influence several aspects of fatty acid metabolism, deposition and lipoprotein profiles but have no influence on reducing lipid peroxidation.

Antioxidant Enzyme System Modulation by Dietary Palm Oils, Palm Kernel Oil and Soybean Oil in Laying Hens.

Palm-based oils (palm oil and kernel oil) and soybean oil have unique fatty acid and antioxidant profiles based on the compounds present in them. Hence, this study elucidated the antioxidant properties of crude palm oil (CPO), red palm oil (RPO), refined palm oil (RBD), palm kernel oil (PKO) and soybean oil (SBO) and the influence of dietary oils on blood lipid profiles, tissue fatty acid deposition and the expression of hepatic lipid and lipoprotein metabolism genes in laying hens. The oils were analyzed for color, beta-carotene, free fatty acid and acid value, phenolic content and lipid peroxidation. In an in vivo trial, 150 laying hens were allotted into five groups and supplemented with either CPO, RPO, RBD, PKO or SBO for 16 weeks. High antioxidant compounds present in palm oils help reduce the oxidation of oils. Dietary supplementation with palm oils, particularly CPO and RPO, contributed to the lower liver, serum and jejunal mucosal antioxidant enzyme activities. The antioxidant enzyme genes in the jejunal mucosa were downregulated in palm oils and PKO, but there was no difference between oils in antioxidant enzyme genes in the liver. In conclusion, dietary supplementation with oils with high antioxidant content contributed to protection against oxidation and was associated with a lower requirement for producing antioxidant enzymes.

The Effect of Adiporon on Lipid Metabolism Genes Expression in Human Macrophages

Atherosclerosis is characterized by excessive uptake of cholesterol-rich low-density lipoproteins by the vascular wall macrophages. It leads to macrophage transformation into foam cells, accumulation of lipids in the intima of the arteries, atherosclerotic plaques development and following progression of cardiovascular diseases. Adiponectin, adipose tissue adipokine, has anti-atherogenic and anti-inflammatory effects that are mediated through binding to its receptors – AdipoR1 and AdipoR2. One of the mechanisms of adiponectin anti-atherogenic activity may be the participation in the regulation of reverse cholesterol transport and prevention of foam cells formation. We assumed that AdipoRon, a small-molecule adiponectin receptor agonist, could modulate the reverse cholesterol transport and inflammation genes expression in human macrophages. The aim of the present study was to investigate the effect of various concentrations of AdipoRon on the lipid metabolism ABCA1, ABCG1, APOA1, NR1H3 (LXRα), NR1H2 (LXRβ), PPARG, ACAT1 genes expression and inflammation IL6, TNFA, TLR4 genes expression in human macrophages. Primary human macrophages and THP-1 macrophages cell line were treated with various concentrations of AdipoRon. Cell viability was measured using the MTS assay. ABCA1, ABCG1, APOA1, NR1H3, NR1H2, PPARG, ACAT1, IL6, TNFA, TLR4 mRNA levels in the primary human macrophages was assessed using real-time PCR. The increase of PPARG and ABCA1 mRNA levels was shown in the primary human macrophages after 5 and 10 μM A-dipoRon treatment for 24 h. At the same time high concentration (20 μM) of AdipoRon has cytotoxic effect on macrophages, especially, on THP-1 cell line. The effect of AdipoRon on human macrophages and the investigation of potential adiponectin receptor agonists is of interest, due to the search for new approaches to the prevention and treatment of atherosclerosis.

Yellow Mealworm (Tenebrio molitor) and Lesser Mealworm (Alphitobius diaperinus) Proteins Slowed Weight Gain and Improved Metabolism of Diet-Induced Obesity Mice

BackgroundHigh-protein diets not only meet amino acid needs but also modulate satiety and energy metabolism. Insect-based proteins are sustainable, high-quality proteins. Mealworms have been studied, but limited information is known about their ability to impact metabolism and obesity. ObjectiveWe determined the effects of defatted yellow mealworm (Tenebrio molitor)- and whole lesser mealworm (Alphitobius diaperinus)-based proteins on the body weight (BW), serum metabolites, and liver and adipose tissue (AT) histology and gene expression of diet-induced obesity mice. MethodsMale C57BL/6J mice were fed a high-fat diet (HFD; 46% kcal) to induce obesity and metabolic syndrome. Obese mice were then assigned to treatments (n = 10/group) and fed for 8 wk: HFD: HFD with casein protein; B50: HFD with 50% protein from whole lesser mealworm; B100: HFD with 100% protein from whole lesser mealworm; Y50: HFD with 50% protein from defatted yellow mealworm; Y100: HFD with 100% protein from defatted yellow mealworm. Lean mice (n = 10) fed a low-fat-diet (LFD; 10% kcal) were included. Longitudinal food intake, BW, body composition, and glucose response were measured. At time of killing, serum metabolites, tissue histopathology and gene expression, and hepatic triglycerides were analyzed. ResultsAfter 8 wk, HFD, B50, and B100 had greater (P < 0.05) weight gain than LFD, whereas Y50 and Y100 did not. Y50, B100, and Y100 had a lower (P < 0.05) BW change rate than HFD. Mealworm-based diets led to increased (P < 0.05) serum high-density lipoprotein (HDL) and reduced (P < 0.05) serum low-density lipoprotein (LDL) concentrations and reduced (P<0.05) LDL/HDL ratio. Mealworm-based diets led to increased (P < 0.05) hepatic expression of genes related to energy balance, immune response, and antioxidants and reduced (P < 0.05) AT expression of genes associated with inflammation and apoptosis. Mealworm-based diets altered (P < 0.05) hepatic and AT expression of glucose and lipid metabolism genes. ConclusionsIn addition to serving as an alternative protein source, mealworms may confer health benefits to obese patients.

DHCR7 Expression Predicts Poor Outcomes and Mortality From Sepsis.

Sepsis patients experience poor outcomes including chronic critical illness (CCI) or early death (within 14 d). We investigated lipid metabolic gene expression differences by outcome to discover therapeutic targets. Secondary analysis of samples from prospectively enrolled sepsis patients (first 24 hr) and a zebrafish endotoxemia model for drug discovery. Patients were enrolled from the emergency department or ICU at an urban teaching hospital. Enrollment samples from sepsis patients were analyzed. Clinical data and cholesterol levels were recorded. Leukocytes were processed for RNA sequencing and reverse transcriptase polymerase chain reaction. A lipopolysaccharide zebrafish endotoxemia model was used for confirmation of human transcriptomic findings and drug discovery. The derivation cohort included 96 patients and controls (12 early death, 13 CCI, 51 rapid recovery, and 20 controls) and the validation cohort had 52 patients (6 early death, 8 CCI, and 38 rapid recovery). The cholesterol metabolism gene 7-dehydrocholesterol reductase (DHCR7) was significantly up-regulated in both derivation and validation cohorts in poor outcome sepsis compared with rapid recovery patients and in 90-day nonsurvivors (validation only) and validated using RT-qPCR analysis. Our zebrafish sepsis model showed up-regulation of dhcr7 and several of the same lipid genes up-regulated in poor outcome human sepsis (dhcr24, sqlea, cyp51, msmo1, and ldlra) compared with controls. We then tested six lipid-based drugs in the zebrafish endotoxemia model. Of these, only the Dhcr7 inhibitor AY9944 completely rescued zebrafish from lipopolysaccharide death in a model with 100% lethality. DHCR7, an important cholesterol metabolism gene, was up-regulated in poor outcome sepsis patients warranting external validation. This pathway may serve as a potential therapeutic target to improve sepsis outcomes.

Differential expression of lipid metabolic genes in hypercholesterolemic rabbit placenta predisposes the offspring to develop atherosclerosis in early adulthood

AimsMaternal hypercholesterolemia (MHC) is a pathological condition that may cause atherosclerosis in the adulthood of the offspring. The study aims to identify the role of in-utero programming by the placenta in atherogenesis and associated liver pathology in offspring. Main methodsFemale New Zealand white rabbits with normal lipid profiles were fed a 0.3 % HFD after mating. Lipid levels were monitored, and pregnant rabbits were sacrificed at the end of trimester 1, trimester 2, and trimester 3. Placental histology and expression of lipid metabolism genes were studied. Lipid levels, aortic lesions, and mRNA expression of cholesterol synthesis genes were investigated in fetuses at the end of gestation. A group of fetuses was allowed to attain early adulthood to investigate the liver lipid metabolism and atherogenesis with and without an HFD. Key findingsElevated maternal lipid levels and placental gene expression were differentially modulated in HFD-fed mothers. HFD-fed rabbits demonstrated differential expression of the placental genes involved in receptor-mediated endocytosis of cholesterol, lipogenesis, and lipolysis in all three trimesters. It resulted in significant lipid depositions in the placenta, hyperlipidemia, and a decrease in hepatic cholesterol synthesis in fetuses at the end of gestation. There was no atherogenesis in the aorta of offspring at trimester 3, but such offspring of HFD-fed mothers developed atherosclerosis and non-alcoholic fatty liver (NAFL) with profound steatosis in their early adulthood with and without HFD. SignificanceDiet-induced MHC differentially expressed placental lipid genes that may program the offspring to develop atherosclerosis and associated NAFL in early adulthood.

2,4-Dinitrotoluene (2,4-DNT) exposure induces liver developmental damage and perturbs lipid metabolism and oxygen transport gene expression in zebrafish (Danio rerio).

2,4-Dinitrotoluene (2, 4-DNT) is a common environmental pollutant. The toxic effect on mammals of 2,4-DNT has been well studied, but its toxicity on aquatic organisms is little known. In this study, 126 healthy female zebrafish (Danio rerio) were exposed to different concentrations of 2,4-DNT (0, 2, 4, 8, 12 and 16mg/L) to determine 96-h semi-lethal concentrations (LC50). And then, 90 female zebrafish were exposed to 0, 2, 4 and 8mg/L 2,4-DNT for 5days to study liver toxicity. Exposed zebrafish developed hypoxia features, such as floating head and breathing rapidly, and then died. 96-h LC50 of 2,4-DNT in zebrafish was 9.36mg/L. Histological data revealed that 2,4-DNT severely damaged the liver tissues, following with the round nucleus, dense interstitial tissue, dense arranged hepatocyte cords and more inflammatory cells. Additionally, the further result showed that the lower levels of lipid transport and metabolism (apoα2, mtp, ppar-α and acox) were noticed. But, exposed to 2,4-DNT for 5days significantly upregulated the expression levels of genes involved in respiration (hif1a, tfa and ho1, p < 0.05). These results indicated that 2,4-DNT exposure disturbed lipid transport and metabolism and oxygen supply in zebrafish, which could contribute to severe damage in liver and death.

Docosahexaenoic Acid Alters Lipid Metabolism Processes via H3K9ac Epigenetic Modification in Dairy Goat.

Goat milk is increasingly recognized by consumers due to its high nutritional value, richness in short- and medium-chain fatty acids, and richness in polyunsaturated fatty acids (PUFA). Exogenous supplementation of docosahexaenoic acid (DHA) is an important approach to increasing the content of PUFA in goat milk. Several studies have reported benefits of dietary DHA in terms of human health, including potential against chronic diseases and tumors. However, the mechanisms whereby an increased supply of DHA regulates mammary cell function is unknown. In this study, we investigated the effect of DHA on lipid metabolism processes in goat mammary epithelial cells (GMEC) and the function of H3K9ac epigenetic modifications in this process. Supplementation of DHA promoted lipid droplet accumulation increased the DHA content and altered fatty acid composition in GMEC. Lipid metabolism processes were altered by DHA supplementation through transcriptional programs in GMEC. ChIP-seq analysis revealed that DHA induced genome-wide H3K9ac epigenetic changes in GMEC. Multiomics analyses (H3K9ac genome-wide screening and RNA-seq) revealed that DHA-induced expression of lipid metabolism genes (FASN, SCD1, FADS1, FADS2, LPIN1, DGAT1, MBOAT2), which were closely related with changes in lipid metabolism processes and fatty acid profiles, were regulated by modification of H3K9ac. In particular, DHA increased the enrichment of H3K9ac in the promoter region of PDK4 and promoted its transcription, while PDK4 inhibited lipid synthesis and activated AMPK signaling in GMEC. The activation of the expression of fatty acid metabolism-related genes FASN, FADS2, and SCD1 and their upstream transcription factor SREBP1 by the AMPK inhibitor was attenuated in PDK4-overexpressing GMEC. In conclusion, DHA alters lipid metabolism processes via H3K9ac modifications and the PDK4-AMPK-SREBP1 signaling axis in goat mammary epithelial cells, providing new insights into the mechanism through which DHA affects mammary cell function and regulates milk fat metabolism.

Leucine Supplementation Ameliorates Early-Life Programming of Obesity in Rats.

Early-weaned adult rats showed excess lipid accumulation and metabolic defects. Early weaning disrupts lipid metabolism and secretion of neuropeptide Y and insulin. The altered lipid metabolic gene expression in this study is vital in programming. Leucine mitigates metabolic disorders and hampers programmed obesity development.

O098 Diclofenac alters expression of genes regulating muscle lipid metabolism during resistance exercise training in humans, but does not change IMCL content

Abstract Introduction Diclofenac is an NSAID commonly used off-label to reputedly enhance athletic training adaptation. Diclofenac activates PPAR-γ and upregulates the expression of lipid metabolism genes in vitro. This study investigated the impact of diclofenac administration on IMCL content and muscle genes regulating lipid metabolism during resistance exercise training in healthy volunteers. Methods Following informed consent and screening, 17 healthy, young, exercise-trained males matched for leg strength were allocated to Diclofenac (75mg diclofenac sodium daily, n=9) or Placebo (n=8) groups. Participants performed 5×30 sets of maximal isokinetic (90°/s) knee extensions with the non-dominant leg 3× weekly over 12 weeks. Vastus lateralis biopsies were obtained in the fasted state at baseline and 1, 7, 28, and 84 days of training for histochemical determination of IMCL content and muscle mRNA expression using microfluidic gene cards. IPA identified gene networks altered from baseline. Results There were significant changes in muscle mRNA expression levels associated with the upregulation of muscle lipid metabolism at all time points compared to baseline in Diclofenac. This was not evident in Placebo, where the inhibition of lipid metabolism was predicted by day 84. Mean (±SEM) IMCL content was no different between groups at baseline (7.4±3.8% Placebo vs. 6.9±2.6% Diclofenac), and no time/treatment interactions with resistance exercise training were observed (ηp2=0.07). Conclusion Diclofenac administration had a rapid, robust impact on genes regulating muscle lipid metabolism during 12 weeks of exercise training in humans. However, these responses were not associated with changes in IMCL content and further investigation is warranted.

Dietary Coated Sodium Butyrate Ameliorates Hepatic Lipid Accumulation and Inflammation via Enhancing Antioxidative Function in Post-Peaking Laying Hens.

During the aging process of laying hens, hepatic oxidative stress damage and lipid accumulation are prone to occur, leading to the deterioration of egg quality and a decline in production properties. This research was designed to explore the effects of different levels of coated sodium butyrate (CSB) addition on oxidation resistance, inflammatory reaction, lipid metabolism and hepatic oxidative damage-related gene expression in aged laying hens. A total of 720 healthy 52 weeks old Huafeng laying hens were arbitrarily divided into 5 groups of 6 replicates with 24 birds each and fed a basal diet supplemented with 0, 250, 500, 750 and 1000 mg/kg CSB for 8 weeks, respectively. The CSB quadratically upgraded GSH-Px activities and downgraded MDA content in the liver and serum. The LDL-C, NEFA and TG contents decreased quadratically in CSB groups and significantly reduced the fatty vacuoles as well as the formation of fat granules in the liver (p < 0.05). Meanwhile, the CSB quadratically upregulated the gene expression of IL-10, Nrf2 and HO1, but downregulated the gene expression of IFN-γ, TNF-α and Keap1 in a quadratic manner (p < 0.05). Moreover, the CSB quadratically degraded the mRNA level of fatty acid synthesis but increased the gene level of key enzymes of fatty acid catabolism (p < 0.05). In conclusion, dietary CSB supplementation has a favorable effect in protecting against liver injury and alleviating lipid accumulation and inflammation by enhancing hepatic antioxidative function in aged laying hens.

Resveratrol supplementation or diet intervention effects on heart-liver axis in prediabetic female rats submitted to high-fat-high-sucrose diet

NAFLD and type 2 diabetes (T2D) share a bidirectional relationship and cardiovascular diseases (CVD) as leading death cause, but this relationship in prediabetes is still poorly known, especially for women which exhibit an exacerbated CVD risk. Here, we evaluated the effects of resveratrol supplementation (RSV) or diet intervention on the heart-liver axis of prediabetic female rats submitted to high-fat-high-sucrose diet (HFS). Forty Female Wistar rats were divided into 4 groups fed for 5 months with: a standard diet (CTRL), HFS diet (HFS), HFS diet supplemented for the last 2 months with RSV (1 mg/kg/day in water) (RSV) or HFS diet for 3 months followed by 2 months of standard diet (RSD). In vivo Magnetic Resonance Imaging was performed to study cardiac morphology/function. Then, tolerance to ischemia-reperfusion injury was investigated ex vivo by simultaneous measurement of cardiac function (RPP, EDP) and energy metabolism by 31P Magnetic Resonance Spectroscopy. Hepatic total lipid and triglycerides (TG) contents along expression of genes involved in lipid metabolism/inflammation were studied. HFS induced glucose intolerance (P < 0.01), increased diastolic left ventricular volume and thickness (P < 0.05) and heart weight to tibia length ratio (HTLR) (P < 0.01). HFS diet also altered myocardial tolerance to IR, with impaired RPP and EDP (P < 0.001) and PCr during reperfusion (P < 0.05). Both treatments improved glucose tolerance (P < 0.05). Importantly, despite maintained HFS diet, RSV restored the elevated diastolic volume and thickness in vivo (P < 0.01 CTRL, RSV vs. HFS, RSD) and HTLR level (P < 0.001 CTRL, RSV vs. HFS, RSD), conversely to RSD. Both treatments improved the tolerance to IR, with increased RPP (P < 0.05 vs. HFS) along with PCr during reperfusion (P < 0.001, P < 0.01 vs. HFS respectively). Only RSV decreased EDP during IR injury (P < 0.05). In the liver HFS diet induced total lipid and TG accumulation (P < 0.01) as well as elevated expression of lipid oxidation/peroxidation genes without effect on lipogenesis and inflammation cytokines genes. Both treatments normalized hepatic total lipid levels. RSD restored TG levels along elevated lipid metabolism gene expressions (P < 0.01) whereas RSV partially reduced the increase (P < 0.05). Despite maintained HFS and moderate hepatic lipid metabolism effects, RSV exhibited better cardioprotection than RSD, suggesting its potential to protect against early cardiac alterations associated with prediabetes and NAFLD, especially for women.

Effects of Genistein on Lipid Metabolism, Antioxidant Activity, and Immunity of Common Carp (Cyprinus carpio L.) Fed with High-Carbohydrate and High-Fat Diets.

A 56-day feeding trial was conducted to investigate the effects of genistein on growth, lipid metabolism, antioxidant capacity, and immunity of common carp fed with high-carbohydrate or high-fat diets. Five diets were used to feed fish: control diet (5% fat; CO), high-fat diet (11% fat; HF), high-carbohydrate diet (45% carbohydrate; HC), and HF or HC diet with 500 mg/kg genistein (FG or CG). Results showed that final body weight (FW) and specific growth rate (SGR) were significantly reduced, but the supplementation with genistein resulted in higher values of FW and SGR than the HF or HC group. Both high carbohydrate and high fat belong to high-energy diets, which may promote lipid deposition. Genistein obviously decreased liver triglyceride (TG) content and alleviated hepatic fat vacuolation in the HF and HC groups. The expression of lipid metabolism genes (cpt-1 and atgl) was markedly higher in the FG group than in the HF group. The lipid synthesis-related genes (fas, acc, and pparγ) were elevated in high-energy diets but recovered to the control level or reduced after genistein treatments. With respect to fatty acid transporter genes, fatp increased in the FG group, and cd36 increased in the CG group. Furthermore, the antioxidant and immune indexes, such as total antioxidant capacity (T-AOC), glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), acid phosphatase (ACP), and lysozyme (LZM) activities, were decreased, while malonate aldehyde (MDA) content, activities of alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were enhanced in the HF and HC groups. The antioxidant and immunity values could be ameliorated by treatment with genistein. Moreover, the transcript levels of antioxidant-related genes (cat, gr, and nrf2) in the liver and anti-inflammatory factors (tgf-β and il-10) and lyz in the head kidney tissue were promoted, although the expression levels of proinflammatory factors (tnf-α and il-6) declined in the genistein supplementation group, which confirmed the antioxidant and immune-enhancing effects of genistein. Therefore, 500 mg/kg genistein could ameliorate the negative effects of high-energy diets on immunity.

Cell cycle, apoptosis, cell differentiation, and lipid metabolism gene expression in endometriotic tissue and exposure to parabens and benzophenones

AimTo describe the expression profile in endometriotic tissue of genes involved in four signaling pathways related to the development and progression of endometriosis (cell cycle, apoptosis, cell differentiation and lipid metabolism) and to explore its relationship with the women exposure to chemicals with hormonal activity released from cosmetics and personal care products (PCPs). MethodsThis cross-sectional study, encompassed within the EndEA study, comprised a subsample of 33 women with endometriosis. Expression levels of 13 genes (BMI1, CCNB1, CDK1, BAX, BCL2L1, FOXO3, SPP1, HOXA10, PDGFRA, SOX2, APOE, PLCG1 and PLCG2) in endometriotic tissue and urinary concentrations of 4 paraben (PB) and 3 benzophenone (BP) congeners were quantified. Bivariate linear and logistic regression analyses were performed to explore the associations between exposure and gene expression levels. ResultsA total of 8 out 13 genes (61.5 %) were expressed in >75 % of the samples. Exposure to congeners of PBs and/or BPs was associated with the overexpression of CDK1 gene (whose protein drives cells through G2 phase and mitosis), HOXA10 and PDGFRA genes (whose proteins favor pluripotent cell differentiation to endometrial cells), and APOE (whose protein regulates the transport and metabolism of cholesterol, triglycerides and phospholipids in multiple tissues) and PLCG2 genes (whose protein creates 1D-myo-inositol 1,4,5-trisphosphate and diacylglycerol, two important second messengers). ConclusionsOur findings suggest that women exposure to cosmetic and PCP-released chemicals might be associated with the promotion of cell cycle and cell differentiation as well as with lipid metabolism disruption in endometriotic tissue, three crucial signaling pathways in the development and progression of endometriosis. However, further studies should be accomplished to confirm these preliminary data.

Kruppel-like factor 5 enhances proliferation, lipid droplet formation and oxaliplatin resistance in colorectal cancer by promoting fatty acid binding protein 6 transcription.

Oxaliplatin (OXA) is a standard agent for colorectal cancer (CRC) adjuvant chemotherapy. However, acquired and intrinsic OXA resistance is a primary challenge for CRC treatment. This study investigates the function of the Kruppel-like factor 5/fatty acid binding proteins 6 (KLF5/FABP6) axis in CRC proliferation, lipid droplet formation and OXA resistance. OXA-resistant CRC cell lines were constructed, and FABP6 and KLF5 expression was assessed in parental and OXA-resistant CRC cells. Subsequent to gain- and loss-of-function experiments, CRC cell proliferation was assessed by cell counting kit-8 (CCK-8) and clone formation assays, the intracellular lipid synthesis by oil red O staining and the protein expression of lipid metabolism genes by western blot. OXA resistance of CRC cells was assessed by CCK-8 assay. The binding of KLF5 to FABP6 was analyzed by the dual-luciferase reporter and ChIP assays. A tumorigenicity assay in nude mice was adopted to examine the impact of KLF5 on CRC tumor growth and OXA resistance in vivo . FABP6 and KLF5 expression was high in CRC cell lines. Downregulation of FABP6 or KLF5 restrained CRC cell proliferation and lipid droplet formation in vitro . FABP6 and KLF5 expression was elevated in OXA-resistant CRC cells. Downregulation of FABP6 or KLF5 repressed the OXA resistance of OXA-resistant CRC cells. Mechanistically, KLF5 facilitated the transcription of FABP6. FABP6 overexpression counteracted the suppressive effects of KLF5 downregulation on CRC cell growth, lipid droplet formation and OXA resistance. KLF5 downregulation restrained CRC tumor growth and OXA resistance in vivo . In conclusion, KLF5 knockdown reduced FABP6 transcription to protect against proliferation, lipid droplet formation and OXA resistance in CRC.

Liver X Receptor Inverse Agonist GAC0001E5 Impedes Glutaminolysis and Disrupts Redox Homeostasis in Breast Cancer Cells.

Liver X receptors (LXRs) are members of the nuclear receptor family of ligand-dependent transcription factors which regulate the expression of lipid and cholesterol metabolism genes. Moreover, LXRs and their ligands have been shown to inhibit tumor growth in a variety of cancers. We have previously identified the small molecule compound GAC0001E5 (1E5) as an LXR inverse agonist and a potent inhibitor of pancreatic cancer cells. Transcriptomic and metabolomic studies showed that 1E5 disrupts glutamine metabolism, an essential metabolic pathway commonly reprogrammed during malignant transformation, including in breast cancers. To determine the role of LXRs and potential application of 1E5 in breast cancer, we examined LXR expression in publicly available clinical samples, and found that LXR expression is elevated in breast tumors as compared to normal tissues. In luminal A, endocrine therapy-resistant, and triple-negative breast cancer cells, 1E5 exhibited LXR inverse agonist and "degrader" activity and strongly inhibited cell proliferation and colony formation. Treatments with 1E5 downregulated the transcription of key glutaminolysis genes, and, correspondingly, biochemical assays indicated that 1E5 lowered intracellular glutamate and glutathione levels and increased reactive oxygen species. These results indicate that novel LXR ligand 1E5 is an inhibitor of glutamine metabolism and redox homeostasis in breast cancers and suggest that modulating LXR activity and expression in tumor cells is a promising strategy for targeting metabolic reprogramming in breast cancer therapeutics.