Oxysterols Research Articles

Cadmium induces chondroitin sulfate synthase 1 via protein kinase Cα and elongates chondroitin/dermatan sulfate chains in cultured vascular endothelial cells.

Cadmium is an environmental pollutant and a risk factor for atherosclerosis. In the atherosclerotic intima, dermatan sulfate chains accelerate accumulation and oxidation of LDL cholesterol. The major type of dermatan sulfate proteoglycan that is synthesized by vascular endothelial cells is biglycan. In the present study, we analyzed the effect of cadmium on the biglycan synthesis using cultured bovine aortic endothelial cells. Cadmium did not induce biglycan mRNA and core protein expression; however, it elongated the chondroitin/dermatan sulfate chains of biglycan. Among elongation enzymes of the chondroitin/dermatan sulfate chain, chondroitin sulfate synthase 1 (CHSY1) mRNA and protein expression were dose- and time-dependently upregulated by cadmium depending on protein kinase Cα. This finding suggests that CHSY1-dependent elongation of chondroitin/dermatan sulfate chains of biglycan may exacerbate cadmium-induced atherosclerosis.

Glucocorticoids Impair the 7α-Hydroxycholesterol-Enhanced Innate Immune Response.

Glucocorticoids suppress the vascular inflammation that occurs under hypercholesterolemia, as demonstrated in an animal model fed a high-cholesterol diet. However, the molecular mechanisms underlying these beneficial effects remain poorly understood. Because cholesterol is oxidized to form cholesterol oxides (oxysterols) that are capable of inducing inflammation, we investigated whether glucocorticoids affect the immune responses evoked by 7α-hydroxycholesterol (7αOHChol). The treatment of human THP-1 monocytic cells with dexamethasone (Dex) and prednisolone (Pdn) downregulated the expression of pattern recognition receptors (PRRs), such as TLR6 and CD14, and diminished 7αOHChol-enhanced response to FSL-1, a TLR2/6 ligand, and lipopolysaccharide, which interacts with CD14 to initiate immune responses, as determined by the reduced secretion of IL-23 and CCL2, respectively. Glucocorticoids weakened the 7αOHChol-induced production of CCL2 and CCR5 ligands, which was accompanied by decreased migration of monocytic cells and CCR5-expressing Jurkat T cells. Treatment with Dex or Pdn also reduced the phosphorylation of the Akt-1 Src, ERK1/2, and p65 subunits. These results indicate that both Dex and Pdn impair the expression of PRRs and their downstream products, chemokine production, and phosphorylation of signaling molecules. Collectively, glucocorticoids suppress the innate immune response and activation of monocytic cells to an inflammatory phenotype enhanced or induced by 7αOHChol, which may contribute to the anti-inflammatory effects in hypercholesterolemic conditions.

Cytotoxicity of Cholesterol Oxides and the Consequences of Relative Molecular Similarity to cGMP Nucleotide

Cytotoxicity of Cholesterol Oxides and the Consequences of Relative Molecular Similarity to cGMP Nucleotide

Effect of thermal processing on the quality parameters of ghee incorporated with curry leaf (Murraya koeneigii) extract

This study examined the effect of adding antioxidants, namely curry leaf extract (CLE) and butylated hydroxyanisole (BHA), on the physicochemical properties of ghee during deep frying. The results showed that the addition of CLE to ghee resulted in significant changes in the L*, a*, and b* values, likely due to the extraction of chlorophyll molecules during CLE preparation. Deep frying caused a decrease in L* values and an increase in a* and b* values of ghee, as well as an increase in the redness and yellowness indices, with control ghee experiencing the most significant changes. The viscosity of ghee increased during frying, and the increase was less in ghee with added antioxidants. Antioxidant-added ghee showed the least increase in total polar compounds (TPC) and thiobarbituric acid reactive substances (TBARS) during frying, which are indicators of oil degradation. CLE and BHA were found to inhibit the production of Cholesterol Oxidation Products (COPs) in ghee during deep frying for up to 45 minutes. Control ghee showed the presence of both COPs (5α, 6α-epoxide and 7β-hydroxy cholesterol) after 45 minutes of frying, whereas ghee with added CLE and BHA had only 5α, 6α-epoxide after 45 minutes of frying.

The effect of tempeh flour on LDL (low-density lipoprotein)-level lowering in Rattus norvegicus fed a high-fat diet

Tempeh is an antioxidant-rich food that can prevent LDL cholesterol oxidation in the arteries. The primary antioxidants from tempeh are isoflavone aglycones, which potently lower cholesterol levels in the blood. This research aimed to determine the effect of tempeh flour on the LDL levels of rats fed a high-fat diet. The experimental design included a completely randomized design (CRD) and pretest-posttest control group design. In this study, twenty-four male Rattus Norvegicus rats were divided into four groups. The rats were acclimatized for seven days and then supplied with a high-fat diet in the form of pork oil for 14 days. The pork oil was administered at 2 mL/kg body weight/ day. In addition, tempeh flour was also administered at three doses as an intervention for 14 days. The dosage groups were as follows: P1 with 50 g, P2 with 75 g, and P3 with 100 g. All the dosages were converted with a dose conversion table for rats so that the final dosages were P1 1.9 g, P2 1.35 g, and P3 1.8 g. The positive control group was given 0.18 mg simvastatin. The LDL level was measured by using the CHOD-PAP method. In addition, the data were analyzed by using one-way ANOVA. The results indicated that the implementation of Tempeh flour intervention significantly altered the LDL levels of rats. There was a significant decrease in LDL levels after the administration of Tempeh flour at all three (0.9 g, 1.35 g, and 1.8 g) doses for 14 days. Moreover, the most effective dosage compared to the control group was the 1.35 g dosage.

Antioxidant addition improves cholesterol and astaxanthin stability in dry salted shrimp.

Traditional production of dry salted shrimp enhances cholesterol oxidation and astaxanthin degradation in the product. The aim of this study was to evaluate the effect of addition of the antioxidants butylhydroxytoluene (BHT) and tert-butylhydroquinone (TBHQ) to cooked shrimp on the formation of cholesterol oxidation products (COPs) and astaxanthin degradation during solar drying of shrimp. The added antioxidants significantly inhibited COPs formation after the product was boiled in brine. Smaller amounts of COPs were formed in antioxidant-treated shrimps (~-23%) as compared to untreated samples. The antioxidants continued to significantly inhibit COPs formation (~-39%) during sun drying. Similarly, TBHQ and BHT reduced by 51.3% and 37.2%, respectively, the degradation rate of astaxanthin, favoring a higher retention of this carotenoid in the final product. The use of the antioxidants BHT and TBHQ in the preparation of dry salted shrimp significantly inhibited the formation of COPs after cooking raw shrimp and during direct solar drying. They also protected astaxanthin contained in the cooked shrimp from photodegradation. These results are technologically relevant because it is possible to prepare a product with a higher content of astaxanthin and lower the presence of hazardous COPs. © 2022 Society of Chemical Industry.

Abstract A009: ZMYND8 is an epigenetic regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells

Abstract 27-hydroxycholesterol (27-HC) is the most abundant oxysterol that increases the risk of breast cancer progression. However, little is known about epigenetic regulation of 27-HC metabolism and its role in breast tumor initiation. Using genetic mouse mammary tumor and human breast cancer models, we showed here that the histone reader ZMYND8 was selectively expressed in breast cancer stem cells (BCSCs) and promoted epithelial-mesenchymal transition (EMT), BCSC maintenance and self-renewal, and oncogenic transformation through its epigenetic functions, leading to breast tumor initiation. Mechanistically, ZMYND8 was a master transcriptional regulator of 27-HC metabolism. It increased cholesterol biosynthesis and oxidation but blocked cholesterol efflux and 27-HC catabolism leading to accumulation of 27-HC in BCSCs. Consequently, 27-HC promoted EMT, oncogenic transformation, and tumor initiation through activation of liver X receptor. These findings reveal that ZMYND8 is an epigenetic booster that drives breast tumor initiation through metabolic reprogramming. Citation Format: Weibo Luo, Maowu Luo. ZMYND8 is an epigenetic regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A009.

Evaluation of the Anti-Obesity Effect of Zeaxanthin and Exercise in HFD-Induced Obese Rats

Obesity is a worldwide epidemic associated with many health problems. One of the new trends in health care is the emphasis on regular exercise and a healthy diet. Zeaxanthin (Zea) is a carotenoid with many beneficial effects on human health. The aim of this study was to investigate whether the combination of Zea and exercise had therapeutic effects on obesity induced by an HFD in rats. Sixty male Wistar rats were randomly divided into five groups of twelve: rats fed a standard diet; rats fed a high-fat diet (HFD); rats fed an HFD with Zea; rats fed an HFD with Exc; and rats fed an HFD with both Zea and Exc. To induce obesity, rats were fed an HFD for twelve weeks. Then, Zea and exercise were introduced with the HFD for five weeks. The results showed that the HFD significantly increased visceral adipose tissue, oxidative stress, and inflammation biomarkers and reduced insulin, high-density lipoprotein, and antioxidant parameters. Treatments with Zea, Exc, and Zea plus Exc reduced body weight gain, triacylglycerol, glucose, total cholesterol, and nitric oxide levels and significantly increased catalase and insulin compared with the HFD group. This study demonstrated that Zea administration and Exc performance appeared to effectively alleviate the metabolic alterations induced by an HFD. Furthermore, Zea and Exc together had a better effect than either intervention alone.

Production and statistical optimization of cholesterol-oxidase generated by Streptomyces sp. AN strain

BackgroundCholesterol oxidases (CHOs) have attracted enormous attention because of their wide biotechnological potential. The present study explores the production of CHOs by Streptomyces sp. AN. Evaluation of culture conditions affecting enzyme production, medium optimization and released metabolite characteristics were also investigated. ResultsThe current work reports the isolation of 37 colonies (bacteria/actinobacteria) with different morphotypes from different soil/water samples. The isolate-coded AN was selected for its high potency for CHO production. Morphological characteristics and the obtained partial sequence of 16srRNA of AN showed 99.38% identity to Streptomyces sp. strain P12–37. Factors affecting CHO production were evaluated using Plackett-Burman (PB) and Box-Behnken (BB) statistical designs to find out the optimum level of the most effective variables, namely, pH, starch, NH4NO3 and FeSO4.7H2O with a predicted activity of 6.56 U/mL. According to this optimization, the following medium composition was considered to be optimum (g/L): cholesterol 1, starch 6, MgSO4.7H2O 0.1, CaCl2 0.01, FeSO4.7H2O 0.1, NH4NO3 23.97, yeast extract (YE) 0.2, K2HPO4 0.01, KH2PO4 0.1, NaCl 0.01, Tween 20 0.01, pH 6.36 and incubation temperature (30 °C) for 9 days. Spectophotometric analysis for released metabolites against cholesterol (standard) via Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) was carried out. FTIR spectrum showed the appearance of new absorption peaks at 1644 and 1725cm−1; this confirmed the presence of the Keto group (C=O) stretch bond. Besides, fermentation caused changes in thermal properties such as melting temperature peak (99.26; 148.77 °C), heat flow (− 8; − 3.6 Mw/mg), capacity (− 924.69; − 209.77 mJ) and heat enthalpy (− 385.29; 69.83 J/g) by comparison to the standard cholesterol as recognized through DSC thermogram. These changes are attributed to the action of the CHO enzyme and the release of keto derivatives of cholesterol with different properties. ConclusionStreptomyces sp. AN was endowed with the capability to produce CHO. Enzyme maximization was followed using a statistical experimental approach, leading to a 2.6-fold increase in the overall activity compared to the basal condition. CHO catalyzed the oxidation of cholesterol; this was verified by the appearance of a new keto group (C=O) peak at 1644 and 1725 cm−1 observed by FTIR spectroscopic analysis. Also, DSC thermogram demonstrates the alteration of cholesterol triggered by CHO.

Impact of Dietary Fats on Cardiovascular Disease with a Specific Focus on Omega-3 Fatty Acids.

Dietary habits have major implications as causes of death globally, particularly in terms of cardiovascular disease, cancer and diabetes, but to precisely define the role of the single components of diet in terms of cardiovascular risk is not an easy task, since current epidemiological cohorts do not include sufficient information regarding all the confounding factors typical of nutritional associations. As an example, complex and multifactorial are the possible nutritional or detrimental effects of dietary fats, due to the huge variety of lipid metabolites originating from either the enzymatic or non-enzymatic oxidation of polyunsaturated fatty acids, cholesterol and phospholipids. The area of research that has allowed the benefit/risk profile of a dietary supplement to be tested with controlled studies is that of omega-3 fatty acids. Omega-3 fatty acids have showed a potential therapeutic role only in secondary cardiovascular prevention, while controlled studies in primary prevention have consistently produced neutral results. Despite some favorable evidence in patients with chronic heart failure; a treatment with n-3 PUFA in this clinical context is presently overlooked. The potential risk of atrial fibrillation, especially when n-3 PUFA are used in high doses, is still under scrutiny.

Gold bipyramids molecularly imprinted gel colorimetric device for whole blood cholesterol analysis

Simple and disposable monitoring of blood is usually the best solution for early clinical diagnosis and home self-inspection of the chronic patients. Herein, a simple point-of-care (POC) device which called molecularly imprinted membrane modified gel colorimetric device (MIMGCD) was prepared for whole blood cholesterol colorimetric detection at the first time. The convenient detection principle of this device rely on molecularly imprinted membranes for specifically separating cholesterol from whole blood firstly, following the gold bipyramids (GBPs) agarose gel system is react with the cholesterol oxidation to product hydrogen peroxide (H2O2), and the cholesterol will be quantified based on the color change. Under optimal conditions, the analytical performance of the proposed device yielded a linear range of 315.8–6000.0 μM and detection limit of 94.7 μM with 6.89% RSD for cholesterol, which can meet the needs of the detection of normal cholesterol content in the human body. Compared with the traditional whole blood detection methods, no complex sample preparation steps or precision instruments are required, endowing MIMGCD with the merits of easy to operate and low-cost. In addition, the multicolor variation of GBPs in the device allow a colorimetric card-like detection mechanism, which can be used for home self-inspection. This device has the potential to be utilized in clinical and home POC testing application for whole blood biomolecule analysis, thereby facilitating the whole blood screening and long-term monitoring in non-specialized laboratory infrastructure.

A new electrocatalytic system based on copper (II) chloride and magnetic molecularly imprinted polymer nanoparticles in 3D printed microfluidic flow cell for enzymeless and Low-Potential cholesterol detection

• A new system for the enzymeless electrocatalytic detection of cholesterol has been proposed. • CuCl 2 in acetonitrile served as an effective low potential electrocatalyst for cholesterol oxidation. • Magnetic molecularly imprinted polymer nanoparticles were synthesized and applied for selective cholesterol isolation. • The developed enzymeless electrocatalytic system was validated by using of model mixtures imitating the blood serum. • Microfluidic flow cell was fabricated by 3D printing to perform cholesterol determination. The cholesterol level in blood is an important biomarker for the early diagnosis of atherosclerosis and cardiovascular disease. This paper reports on a new enzymeless electrocatalytic system for the determination of cholesterol. Copper (II) chloride was first used for the enzymeless electrochemical oxidation of cholesterol at a low electrode potential in acetonitrile, and the mechanism for the oxidation process was proposed. Magnetic molecularly imprinted polymer nanoparticles were then synthesized and applied in a 3D printed microfluidic flow cell for selective cholesterol isolation and subsequent analysis. The proposed enzymeless electrocatalytic system allowed for the detection of cholesterol in model solutions with a detection limit of 4 µM and a degree of extraction of more than 90 %. The sensitivity, stability, and duration of the analysis were not inferior to analogs.

Oxysterols in catfish skin secretions (Arius bilineatus, Val.) exhibit anti-cancer properties

The edible catfish Arius bilineatus, (Valenciennes) elaborates a proteinaceous gel-like material through its epidermis when threatened or injured. Our on-going studies on this gel have shown it to be a complex mixture of several biologically active molecules. Anti-cancer studies on lipid fractions isolated from the gel-like materials showed them to be active against several cancer cell lines. This prompted us to investigate further the lipid composition of the catfish epidermal gel secretions (EGS). Analysis of the lipid fraction of EGS resulted in identification of 12 oxysterols including cholesterol and 2 deoxygenated steroids i.e., 7α-hydroxy cholesterol, 7β-hydroxycholesterol, 5,6 epoxycholesterol, 3β-hydroxycholest-5-ene-7-one and cholesta-3,5-dien-7-one. Progesterone, cholest-3,5-diene, cholesta-2,4-diene, cholest-3,5,6-triol and 4-cholesten-3-one were found as minor components, and were identified through their MS, 1HNMR and FTIR spectral data and were compared with those of the standards. Cholest-3,6-dione, cholesta-4,6-diene-3-one, cholesta-2,4-diene, and cholesta-5,20(22)-dien-3-ol were found only in trace amounts and were identified by GC/MS/MS spectral data. Since cholesterol is the major component of EGS, the identified oxysterols (OS) are presumably cholesterol oxidation products. Many of the identified OS are known important biological molecules that play vital physiological role in the producer and recipient organisms. We report herein the effects of these sterols on three human cancer cell lines in vitro, i.e., K-562 (CML cell line), MDA MB-231 (estrogen positive breast cancer cell line) and MCF-7 (estrogen negative breast cancer cell line). Interestingly significant (p < 0.05) dose differences were observed between tested OS on cell types used. The presence of these sterols in EGS may help explain some aspects of the physiological activities of fraction B (FB) prepared from EGS, such as enhanced wound and diabetic ulcer healing, anti-inflammatory action and cytotoxic activities reported in our previous studies. The anti-proliferative actions of some of these oxysterols especially the cholesterol 3,5,6-triol (#5) as established on selected cancer cell lines in this study support our previous studies and make them candidates for research for human application.

The Beneficial Impact of Zinc Supplementation on the Vascular Tissue of the Abdominal Aorta under Repeated Intoxication with Cadmium: A Study in an In Vivo Experimental Model.

In an in vivo rat model of human exposure to cadmium (Cd; 5 and 50 mg/L, 6 months), whether the supplementation with zinc (Zn; 30 and 60 mg/L, increasing its daily intake by 79% and 151%, respectively) protects against the unfavourable impact of this xenobiotic on the vascular tissue of the abdominal aorta was investigated. The treatment with Cd led to oxidative stress and increased the concentrations of pro-inflammatory interleukin 1β (IL-1β), total cholesterol (TC), triglycerides (TG), and endothelial nitric oxide synthase (eNOS) and decreased the concentration of anti-inflammatory interleukin 10 (IL-10) in the vascular tissue. Cd decreased the expression of intercellular adhesion molecule-1 (ICAM-1), platelet endothelial cell adhesion molecule-1 (PECAM-1), and L-selectin on the endothelial cells. The administration of Zn prevented most of the Cd-induced alterations or at least weakened them (except for the expression of adhesive molecules). In conclusion, Zn supplementation may protect from the toxic impact of Cd on the blood vessels and thus exert a beneficial influence on the cardiovascular system. The increase in the intake of Zn by 79% may be sufficient to provide this protection and the effect is related to the antioxidative, anti-inflammatory, and antiatherogenic properties of this essential element.

The impacts of pink pepper (Schinus terebinthifolius Raddi) on fatty acids and cholesterol oxides formation in canned sardines during thermal processing

The effect of adding pink pepper (Schinus terebinthifolius Raddi) fruits during sardines canning to minimize cholesterol oxidation were investigated. Canning resulted in an exchange of fatty acids, cholesterol and cholesterol oxides between fish muscle and liquid medium (soybean oil). It also induced lipid oxidation, which was demonstrated by the degradation of fatty acids and the formation of cholesterol oxides. Cholesterol oxides increased from 39.53 ± 2.14 μg/g (raw sardines) to 116.04 ± 0.78 μg/g (control sardines) after canning. However, lower levels were found in samples with pink pepper. Additionally, chromatographic analyses showed the migration of compounds (phenolic acids, flavonoids, tannins, terpenes) from pink pepper to sardines, indicating the constituents that could have contributed to its antioxidant properties. Thus, pink pepper may be highlighted as a suitable additive to reduce the intake of cholesterol oxides, minimizing the loss of nutritional quality in canned fish.

The Effects of Cholesterol Oxidation on Erythrocyte Plasma Membranes: A Monolayer Study.

Cholesterol plays a key role in the molecular and mesoscopic organisation of lipid membranes and it is expected that changes in its molecular structure (e.g., through environmental factors such as oxidative stress) may affect adversely membrane properties and function. In this study, we present evidence that oxidation of cholesterol has significant effects on the mechanical properties, molecular and mesoscopic organisation and lipid–sterol interactions in condensed monolayers composed of the main species found in the inner leaflet of the erythrocyte membrane. Using a combination of experimental methods (static area compressibility, surface dilatational rheology, fluorescence microscopy, and surface sensitive X-ray techniques) and atomistic molecular dynamics simulations, we show that oxidation of cholesterol to 7-ketocholesterol leads to stiffening of the monolayer (under both static and dynamic conditions), significant changes in the monolayer microdomain organisation, disruption in the van der Waals, electrostatic and hydrophobic interactions between the sterol and the other lipid species, and the lipid membrane hydration. Surface sensitive X-ray techniques reveal that, whilst the molecular packing mode is not significantly affected by cholesterol oxidation in these condensed phases, there are subtle changes in membrane thickness and a significant decrease in the coherence length in monolayers containing 7-ketocholesterol.

Oxidative stress markers as early predictors of diabetes complications in Type 2 diabetic patients

Objectives: Type 2 diabetes mellitus (T2DM) is a complex disease that affects many organs. Oxidative stress plays a key role in the pathogenesis of insulin resistance and β-cell dysfunction. Thus, the present study aimed to use oxidative stress markers as early predictors for the progression of diabetic complications. Materials and Methods: The study sample included 400 individuals (300 T2DM and 100 non-diabetic controls) aged from 35 to 59 years randomly selected from the outpatient clinic of the National Institute for Diabetes and Endocrinology. T2DM patients were divided into subgroups: Subgroup (1) patients without any complications, Subgroup (2) patients with diabetic nephropathy (DN) and Subgroup (3) patients with cardiovascular disorders (CVD). Biochemical markers of fasting blood glucose, glycated haemoglobin (HbA1C), glucose-6-phosphate dehydrogenase (G6PD), lactate, arginase, heme oxygenase-1 (HO-1), haemoglobin (Hb), triglycerides (TG), cholesterol, low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), urea, creatinine, malondialdehyde (MDA), reduced glutathione (GSH), catalase (CAT) and nitric oxide (NO) were performed. Results: DM patients showed significant increases in body mass index, systolic blood pressure, diastolic blood pressure, FBS, HbA1C, cholesterol, TG, LDL-C and glomerular filtration rate, while HDL-C decreased. Significant increases were observed in HO-1, MDA and NO, while G6PD/lactate, GSH and CAT decreased in DM patients. The DN and CVD patients exhibited a significant increase in HO-1, MDA and NO; while G6PD/lactate, GSH and CAT decreased compared with DM patients. Receiver operating characteristic analysis showed that the sensitivity and specificity of oxidative stress markers were 66.67–100%. Conclusion: Hexose monophosphate (HMP)/glycolysis pathways are shifted during DM near glycolysis rather than HMP pathway to produce energy where the amount of glucose enters the cells is low, causing oxidative stress. Oxidative stress markers could be used as early predictors of diabetes complications.

Distinct responses from triglyceride and cholesterol metabolism in common carp (Cyprinus carpio) upon environmental cadmium exposure

Due to high persistence and bioavailability, Cadmium (Cd) is one of the most prevalent environmental contaminants, posing an elevating threat to the ecosystems. It has been evidenced that high-dose Cd elicits deleterious effects on aquatic organisms, but the potential toxicities of Cd at environmentally relevant concentrations remains underappreciated. In this study, we used common carp to investigate how environmental Cd exposure affects triglyceride (TG) and cholesterol metabolism and underlying mechanisms. The data indicated that Cd resulted in the shift of TG from the liver to blood and the movement of cholesterol in the opposite direction, ultimately giving rise to the storage of crude lipid in liver and muscle, especially hepatic cholesterol retention. Cholesterol, instead of TG, became the principal cause during the progression of hepatic lipid accumulation. Mechanistic investigations at transcriptional and translational levels further substantiated that Cd blocked hepatic biosynthesis of TG and enhanced TG efflux out of the liver and fatty acid β-oxidation, which collectively led to the compromised TG metabolism in the liver and accelerated TG export to the serum. Additionally, strengthened synthesis, retarded export and oxidation of cholesterol detailed the hepatic prominent cholesterol retention. Taken together, our results demonstrated that environmental exposure to Cd perturbed lipid metabolism through triggering distinct responses from hepatic TG and cholesterol homeostasis. These indicated that environmental factors (such as waterborne Cd) could be a potential contributor to the prevalence of non-alcoholic fatty-liver disease in aquaculture and more efforts should be devoted to the ecological risk assessment of pollutants under environmental scenarios.

SERINC5-Mediated Restriction of HIV-1 Infectivity Correlates with Resistance to Cholesterol Extraction but Not with Lipid Order of Viral Membrane.

Serine incorporator 5 (SER5) is a protein that upon incorporation into virions inhibits HIV-1 infectivity by interfering with the ability of the Env glycoprotein to promote viral fusion. The mechanisms by which SER5 antagonizes HIV-1 fusion are not well understood. A recent study of SER5’s structure revealed a lipid-binding pocket, suggesting the ability to sequester lipids. This finding, along with the well-documented modulation of HIV-1 infectivity by viral lipids, especially cholesterol, prompted our examination of SER5′s effect on the general lipid order of the HIV-1 membrane. Pseudoviruses bearing the SER5-sensitive HXB2-Env and containing SER5 or SER2, a control protein that lacks antiviral activity, were analyzed using two distinct lipid-order probes. We show that SER5 incorporation does not noticeably affect the lipid order of pseudoviruses. Although viral cholesterol extraction reduces HIV-1 infectivity, SER5+ viruses are less sensitive to cholesterol extraction than the control samples. In contrast, the virus’ sensitivity to cholesterol oxidation was not affected by SER5 incorporation. The hydrolytic release of sphingomyelin-sequestered cholesterol had a minimal impact on the apparent resistance to cholesterol extraction. Based on these results, we propose that a subpopulation of more stable Env glycoproteins responsible for the residual infectivity of SER5+ viruses is less sensitive to the cholesterol content of the viral membrane.

ZMYND8 is a master regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells.

27-Hydroxycholesterol (27-HC) is the most abundant oxysterol that increases the risk of breast cancer progression. However, little is known about epigenetic regulation of 27-HC metabolism and its role in breast tumor initiation. Using genetic mouse mammary tumor and human breast cancer models, we showed here that the histone reader ZMYND8 was selectively expressed in breast cancer stem cells (BCSCs) and promoted epithelial-mesenchymal transition (EMT), BCSC maintenance and self-renewal, and oncogenic transformation through its epigenetic functions, leading to breast tumor initiation. Mechanistically, ZMYND8 was a master transcriptional regulator of 27-HC metabolism. It increased cholesterol biosynthesis and oxidation but blocked cholesterol efflux and 27-HC catabolism, leading to accumulation of 27-HC in BCSCs. Consequently, 27-HC promoted EMT, oncogenic transformation, and tumor initiation through activation of liver X receptor. These findings reveal that ZMYND8 is an epigenetic booster that drives breast tumor initiation through metabolic reprogramming.