BDE-99 stimulates generation of aberrant brown/beige adipocytes.

Adipose tissue compromises one of the principal depots where brominated flame retardants (BFR) accumulate in vivo, yet whether BFR disturb thermogenic brown/beige adipocytes is still not referred to date. Herein, effects of BDE-99, a major congener of polybrominated diphenyl ethers (PBDEs) detected in humans, on brown/beige adipocytes were explored for the first time, aiming to provide new knowledge evaluating the obesogenic and metabolic disrupting effects of BFR. Our results firstly demonstrated that exposure to BDE-99 during the lineage commitment period significantly promoted C3H10T1/2 MSCs differentiating into brown/beige adipocytes, evidenced by the increase of brown/beige adipocyte marker UCP1, Cidea as well as mitochondrial membrane potential and basal respiration rate, which was similar to pharmacological PPARγ agonist rosiglitazone. Unexpectedly, the mitochondrial maximal respiration rate of BDE-99 stimulated brown/beige adipocytes was not synchronously enhanced and resulted in a significant reduction of mitochondrial spare respiration capacity (SRC) compared to control or rosiglitazone stimulated adipocytes, indicating a deficient energy-dissipating capacity of BDE-99 stimulated thermogenic adipocytes. Consistently with compromised mitochondrial SRC, lipidomic analysis further revealed that the lipids profile of mitochondria derived from BDE-99 stimulated brown/beige adipocytes were quite different from control or rosiglitazone stimulated cells. In detail, BDE-99 group contains more free fatty acid (FFA) and lyso-PE in mitochondria. In addition to energy metabolism, our results also demonstrated that BDE-99 stimulated brown/beige adipocytes were deficient in endocrine, which secreted more adverse adipokine named resistin, coinciding with comparable beneficial adipokine adiponectin compared with that of rosiglitazone. Taken together, our results showed for the first time that BDE-99 stimulated brown/beige adipocytes were aberrant in energy metabolism and endocrine, which strongly suggests that BDE-99 accumulated in human adipose tissue could interfere with brown/beige adipocytes to contribute to the occurrence of obesity and relevant metabolic disorders.

2,2',4,4'-Tetrabromodiphenyl Ether (PBDE 47) Selectively Stimulates Proatherogenic PPARγ Signatures in Human THP-1 Macrophages to Contribute to Foam Cell Formation.

2,2',4,4'-Tetrabromodiphenyl ether (PBDE 47) is one of the most prominent PBDE congeners detected in the human body, suggesting that the potential health risks of PBDE 47 should be thoroughly considered. However, the cardiovascular toxicity of PBDE 47 remains poorly understood. Here, toxic outcomes of PBDE 47 in human THP-1 macrophages concerning foam cell formation, which play crucial roles in the occurrence and development of atherosclerosis, were elucidated. First, our results indicated that PBDE 47 affected the PPARγ pathway most efficiently in THP-1 macrophages by transcriptomic analysis. Second, the PPARγ target genes CD36 and FABP4, responsible for lipid uptake and accumulation in macrophages, were consistently upregulated both at transcriptional and translational levels in THP-1 macrophages upon PBDE 47. Unexpectedly, PBDE 47 failed to activate the PPARγ target gene LXRα and PPARγ-LXRα-ABCA1/G1 cascade, which is activated by the PPARγ full agonist rosiglitazone and enables cholesterol efflux in macrophages. Thus, coincident with the selective upregulation of the PPARγ target genes CD36 and FABP4, PBDE 47, distinct from rosiglitazone, functionally resulted in more lipid accumulation and oxLDL uptake in THP-1 macrophages through high-content analysis (HCA). Moreover, these effects were markedly abrogated by the addition of the PPARγ antagonist T0070907. Mechanistically, the structural basis of selective activation of PPARγ by PBDE 47 was explored by molecular docking and dynamics simulation, which indicated that PBDE 47 interacted with the PPARγ ligand binding domain (PPARγ-LBD) distinctively from that of rosiglitazone. PBDE 47 was revealed to interact with helix 3 and helix 5 but not helix 12 in the PPARγ-LBD. Collectively, these results unraveled the potential cardiovascular toxicity of PBDE 47 by selective activation of PPARγ to facilitate foam cell formation for the first time.

Polybrominated diphenyl ether congener 99 (PBDE 99) promotes adipocyte lineage commitment of C3H10T1/2 mesenchymal stem cells.

Obesogens are defined as chemicals that trigger obesity partially by stimulating adipogenesis. Adipogenesis consists of two successive processes: the adipocyte lineage commitment of pluripotent stem cells and the differentiation of preadipocytes. Compared with the differentiation of preadipocytes, the effects of most environmental obesogens on adipocyte lineage commitment remain largely unknown. In this study, investigations are performed to explore the influences of PBDE 99 on the adipocyte lineage commitment based on C3H10T1/2, which has been widely used as a mesenchymal stem cell (MSC) model. Our results indicated that exposure to PBDE 99 during commitment stage resulted in significant up-regulation of subsequent adipogenesis in C3H10T1/2 MSCs. Interestingly, PBDE 99 did not affect the osteogenesis of C3H10T1/2 MSCs, although the adipogenesis and osteogenesis of MSCs are typically reciprocal. PBDE 99 was further demonstrated to significantly decrease the expression of Pref1, the marker of very early adipose mesenchymal precursor, and its downstream effector, Sox9. This result strongly suggested that PBDE 99 facilitated adipocyte commitment to exert adipogenic effect on C3H10T1/2 MSCs. Mechanistic studies revealed that PBDE 99 efficiently inhibited Hedgehog signaling transduction, a conserved negative regulator of the adipocyte lineage commitment. Furthermore, the effects of PBDE 99 on adipogenesis were abrogated by the co-treatment with SAG, a specific Hedgehog signaling activator, suggesting inhibition of Hedgehog signaling is responsible for the effect of PBDE 99 on adipocyte commitment. Taking together, these results strongly suggested enhanced adipocyte lineage commitment was involved in potential obesogenic effect of PBDE 99, presumably through repressing Hedgehog signalling during commitment stage. Moreover, the results of this study indicated that C3H10T1/2 can be used as a feasible MSCs cell model to evaluate the capabilities of potential obesogens on adipocyte commitment.

Polychlorinated biphenyl congener 180 (PCB 180) regulates mitotic clonal expansion and enhances adipogenesis through modulation of C/EBPß SUMOylation in preadipocytes.

PCB 180 is a typical non-dioxin-like polychlorinated biphenyl (NDL-PCB). It is one of the most prevalent PCB-congeners found in human adipose tissue. However, the role of PCB 180 in obesity remains poorly understood. The aim of this study was to explore the adipogenic effect and mechanism of PCB 180. Significant enhancement in adipogenesis was observed when differentiating murine 3T3-L1 preadipocytes or human preadipocytes-visceral (HPA-v) that were exposed to PCB 180. Furthermore, exposure to PCB 180 during the first two days was critical to the adipogenic effect. According to results from sequential cell cycle analyses, cell counting, BrdU incorporation, and cyclin D1, cyclin B1, and p27 protein quantification, PCB 180 was found to enhance mitotic clonal expansion (MCE) during early adipogenic differentiation. Molecular mechanistic investigation revealed that PCB 180 promoted accumulation of the C/EBPß protein, a key regulator that controls MCE. Finally, it was found that PCB 180 mitigated degradation of the C/EBPß protein by repressing the SUMOylation and subsequent ubiquitination of C/EBPß by the upregulation of SENP2. In summary, it was shown for the first time that PCB 180 facilitated adipogenesis by alleviating C/EBPß protein SUMOylation. This result provides novel evidence regarding obesogenic effect of PCB 180.

Methyl tertiary-butyl ether inhibits THP-1 macrophage cholesterol efflux in vitro and accelerates atherosclerosis in ApoE-deficient mice in vivo.

The biosafety of methyl tertiary-butyl ether (MTBE), mainly used as a gasoline additive, has long been a contentious topic. In addition to its routine toxicities, MTBE has been demonstrated to disrupt glucose and lipid metabolism and contribute to the development of type 2 diabetes as well as obesity. As one of the morbidities related to dyslipidemia, atherosclerosis is worthy of being investigated under MTBE exposure. Since foam cells derived from macrophages play pivotal roles during atherosclerosis development, we studied the effects of MTBE on macrophages in vitro and assessed the effect of MTBE on atherosclerosis plaque formation with the ApoE-/- mouse model in vivo for the first time. Our results demonstrated that exposure to MTBE at environmentally relevant concentrations decreased the expression of ABCA1 and ABCG1, which are responsible for macrophage cholesterol efflux, at both mRNA and protein levels in THP-1 macrophages. Consequently, treatment with MTBE inhibited the transport of cholesterol from macrophages to High-density lipoprotein. ApoE-/- mice exposed to MTBE at environmentally relevant concentrations (100, 1000 µg/kg) displayed significant increases in lesion area in the aorta and aortic root compared to vehicle-treated ones. Further analysis indicated that MTBE exposure enhanced the macrophage-specific marker Mac-2 contents within plaques in the aortic root, implying that MTBE could promote macrophage-derived foam cell formation and thus accelerate atherosclerosis plaque formation. We for the first time demonstrated the pro-atherogenic effect of MTBE via eliciting disruption of macrophage cholesterol efflux and accelerating foam cell formation and atherosclerosis plaque development.

Exposure to HBCD promotes adipogenesis both in vitro and in vivo by interfering with Wnt6 expression.

Hexabromocyclododecane (HBCD) is a widely used brominated flame retardant, and a ubiquitous environmental contaminant. However, effects and mechanisms underlying HBCD and the development of obesity remain largely unknown. Here, we investigated the effects and underlying mechanisms of HBCD on adipogenesis. Our results firstly disclosed that both murine 3T3-L1 and human HPA-V preadipocyte exposed to HBCD displayed markedly enhanced adipogenesis, manifesting with increase of triglyceride accumulation and expression of adipogenic marker genes. HBCD was further identified to play roles mainly during early-stage adipogenesis and increased expression of Pparγ, a key adipogenic regulator. Interestingly, HBCD didn't affect early key event mitotic clonal expansion (MCE), expression and activation of early pivotal factor C/EBPß. In virtue of RNA sequencing, HBCD was further demonstrated to specially block Wnt6 gene expression and inhibited the Wnt/ß-catenin pathway at an early stage of adipogenesis. Consistent with cellular finding, C57BL/6 male mice chronically exposed to HBCD exhibited specially increased epididymal white adipose tissue (eWAT) weight gain, elevated expression of master adipogenic genes and down-regulated expression of Wnt6 in eWAT. Taking together, our findings firstly revealed that HBCD promotes adipogenesis in vitro and in vivo by specifically inhibiting Wnt6 expression, presumably connecting exposure of HBCD to the development of obesity.

Effect of methyl tert-butyl ether on adipogenesis and glucose metabolism in vitro and in vivo.

Methyl tert-butyl ether (MTBE), as a widely used gasoline additive, is suspected of being environmentally toxic. MTBE accumulates mainly in adipose tissue, but its effect on obesity or obesity-related metabolic disorders has not been well understood yet. Therefore, we examined the effect of MTBE on the adipose function and the related metabolic processes with both 3T3-L1 cell line and C57BL/6J mice model. We found that exposure to MTBE at the environmental relevant concentration (100 µmol/L) could significantly induce differentiation of preadipocyte and disturb insulin-stimulated glucose uptake of mature adipocyte. The in vivo observation in male mice showed a positive correlation of visceral white adipose tissue (vWAT) expansion and cell size increase with MTBE treatment in 14 weeks. Glucose tolerance and insulin sensitivity tests demonstrated that MTBE at 1000 µg/(kg·day) disturbed the systemic glucose metabolism in a gender-specific manner, which might be partly attributed to the alterations of gut microbiota community at genus level with respect to Akkermansia, Clostridium XlVb, and Megamonas. In summary, our study characterized the effect of MTBE on adipose tissue function and glucose homeostasis in vitro and in vivo, and revealed that systemic disorders of the glucose metabolism might be modulated by the related gut microbiota.

The brominated flame retardant PBDE 99 promotes adipogenesis via regulating mitotic clonal expansion and PPARγ expression.

"Obesogens" have been widely accepted as chemicals that promote obesity, and there are many environmental pollutants that were functionally identified as obesogens. PBDE 99 is one of the most abundant PBDE congeners detected in human. However, its obesogenic effects are poorly understood. Here, we explore the in vitro effects of PBDE 99 on adipogenesis, which is a key process in obesogenesis. We observed an increase in adipogenesis when differentiating cells were exposed to PBDE 99. Further, the promoting effects of PBDE 99 on adipogenesis were most efficient during the first 4 days of 3T3-L1 differentiation. Consistent with this, early transcriptional factor CCAAT/enhancer-binding proteins ß (C/EBPß) was upregulated at Days 1 and 2 during differentiation, which is accompanied with the acceleration of mitotic clonal expansion (MCE) and the upregulation of terminal transcriptional factors C/EBPα and PPARγ2 from Day 2 or Day 4. Additionally, bisulfite genomic sequencing analysis revealed that PBDE 99 decreased methylation status of the CpG sites at PPARγ promoter region. Collectively, these findings demonstrate that PBDE 99 may be a potential environmental obesogen by promoting adipogenesis through facilitating MCE progression at early differentiation stage and upregulating key adipogenic factor PPARγ2 expression both in direct transcriptional and epigenetic regulation dependent manner.

Synthesis and biological activities of petrosiols B and D.

A divergent total synthesis of natural diacetylenic tetraols, petrosiol B and petrosiol D, was accomplished by taking advantage of a carbohydrate chiral template. In particular, petrosiol B, which is the first total synthesis so far, was achieved in 13 linear steps with a 10% overall yield applying Ohira-Bestmann homologation, NaH-mediated dehydrobromination, and Cu(i)-catalyzed Cadiot-Chodkiewicz coupling as the key reaction steps. The synthetic petrosiols B and D were subjected to the study on differentiation activities toward neuronal progenitor PC12 cells. Our results suggested that both petrosiol B and petrosiol D could induce the differentiation of neuronal progenitor PC12 cells via the enhancement of Nrf2 activity. By comparing petrosiols B, D and their natural homologue E, petrosiol B displayed the most intensive cell differentiation activity and the highest Nrf2 activity enhancement as well.

PPARγ agonist rosiglitazone switches fuel preference to lipids in promoting thermogenesis under cold exposure in C57BL/6 mice.

Brown and beige adipose tissues play key roles in adaptive thermogenesis, which is essential for homoiotherms to maintain core temperature under cold exposure. PPARγ is a transcriptional regulator critical for brown adipose tissue (BAT) recruitment and white adipose tissue (WAT) browning. Here we evaluated the impact of PPARγ activation on thermogenic activity in C57BL/6 mice under thermo-neutral and 4 °C cold environment, and revealed the regulating mechanism and metabolic basis. Rosiglitazone slowed body temperature loss in cold environment in C57BL/6 mice, suppressed cold-induced decreases in blood glucose, reversed cold-promoted 18F-FDG uptake, and increased lipid consumption in BAT. Serum/adipose tissue metabolomic and transcriptomic analyses revealed that cold exposure and rosiglitazone affect metabolism in different way, especially in terms of free fatty acid/lipid metabolism. While all tested treatments stimulated stored-substance mobilization in epididymal WAT, in heat-generating adipose tissues (BAT and subcutaneous WAT), rosiglitazone-only treatment promoted the storage of substances such as lipids for subsequent thermogenic activation; conversely, cold exposure favoured glucose consumption and mobilization/transport of extracellular lipids. When combined with cold exposure, rosiglitazone treatment preferentially triggered BAT lipid consumption, mobilized and transported lipids from epididymal to subcutaneous WAT, and reduced glucose usage. Thus, rosiglitazone might promote thermogenesis under cold exposure by switching fuel preference. SIGNIFICANCE: In current study, for the first time, PPARγ agonism by rosiglitazone was proved to promote thermogenesis under near-freezing conditions and enhance the heat generating response against cold-induced hypothermia in mice by switching the fuel preference from carbohydrates to lipids. The lipid substrates stored in BAT in response to PPARγ activation are spared for eventual thermogenic activation. These findings thus underline the remarkable actions of PPARγ in the control of energy metabolism in adipose tissues, especially the BAT.

DBZ (Danshensu Bingpian Zhi), a Novel Natural Compound Derivative, Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice.

BACKGROUND: DBZ (Danshensu Bingpian Zhi), a synthetic derivative of a natural compound found in traditional Chinese medicine, has been reported to suppress lipopolysaccharide-induced macrophage activation and lipid accumulation in vitro. The aim of this study was to assess whether DBZ could attenuate atherosclerosis at early and advanced stages. METHODS AND RESULTS: The effects of DBZ on the development of atherosclerosis were studied using apolipoprotein E-deficient (apoE-/-) mice. For early treatment, 5-week-old apoE-/- mice were fed a Western diet and treated daily by oral gavage with or without DBZ or atorvastatin for 10 weeks. For advanced treatment, 5-week-old apoE-/- mice were fed a Western diet for 10 weeks to induce atherosclerosis, and then they were randomly divided into 4 groups and subjected to the treatment of vehicle, 20 mg/kg per day DBZ, 40 mg/kg per day DBZ, or 10 mg/kg per day atorvastatin for the subsequent 10 weeks. We showed that early treatment of apoE-/- mice with DBZ markedly reduced atherosclerotic lesion formation by inhibiting inflammation and decreasing macrophage infiltration into the vessel wall. Treatment with DBZ also attenuated the progression of preestablished diet-induced atherosclerotic plaques in apoE-/- mice. In addition, we showed that DBZ may affect LXR (liver X receptor) function and that treatment of macrophages with DBZ suppressed lipopolysaccharide-stimulated cell migration and oxidized low-density lipoprotein-induced foam cell formation. CONCLUSIONS: DBZ potentially has antiatherosclerotic effects that involve the inhibition of inflammation, macrophage migration, leukocyte adhesion, and foam cell formation. These results suggest that DBZ may be used as a therapeutic agent for the prevention and treatment of atherosclerosis.

Selective Tissue Distribution Mediates Tissue-Dependent PPARγ Activation and Insulin Sensitization by INT131, a Selective PPARγ Modulator.

The mechanisms underlying the enhancement of insulin sensitivity by selective peroxisome proliferator-activated receptor γ modulators (sPPARγMs) are still not completely known. Here, the representative sPPARγM, INT131, was used as a probe to investigate the insulin-sensitizing mechanisms of sPPARγM in the context of tissue selective compound distribution and PPARγ regulation. First, 30 mg kg-1 INT131 was observed to produce an insulin-sensitizing effect comparable to that of 10 mg kg-1 rosiglitazone (RSG) in both db/db and DIO mice using the oral glucose and insulin tolerance tests. Similar to RSG, INT131 significantly increased brown adipose tissue (BAT) mass and adipocyte size and up-regulated the expression of BAT-specific genes. Compared with RSG, INT131 exhibited greater potency in inducing white adipose tissue (WAT) browning, decreasing adipocyte size, and increasing BAT-specific and function-related gene expression in subcutaneous WAT (sWAT). However, it did not induce hepatomegaly or hepatic steatosis, which is associated with lower levels of lipogenic genes expression. Pharmacokinetic analysis reveals that in contrast with RSG, INT131 shows higher Cmax, and much longer residency time (AUC0-12h), as well relatively lower elimination rate in adipose tissues and skeletal muscle, this demonstrated INT131 distributed predominantly in adipose tissue. Whereas, INT131 was less abundant in the liver. These results thus suggest that the tissue-selective distribution underlies INT131's selective PPARγ modulation. Compounds favoring adipose tissue may aid in development of better, safer sPPARγM to address the insulin resistance of diabetes.

A metabolomic study of the PPARδ agonist GW501516 for enhancing running endurance in Kunming mice.

Exercise can increase peroxisome proliferator-activated receptor-δ (PPARδ) expression in skeletal muscle. PPARδ regulates muscle metabolism and reprograms muscle fibre types to enhance running endurance. This study utilized metabolomic profiling to examine the effects of GW501516, a PPARδ agonist, on running endurance in mice. While training alone increased the exhaustive running performance, GW501516 treatment enhanced running endurance and the proportion of succinate dehydrogenase (SDH)-positive muscle fibres in both trained and untrained mice. Furthermore, increased levels of intermediate metabolites and key enzymes in fatty acid oxidation pathways were observed following training and/or treatment. Training alone increased serum inositol, glucogenic amino acids, and branch chain amino acids. However, GW501516 increased serum galactose and ß-hydroxybutyrate, independent of training. Additionally, GW501516 alone raised serum unsaturated fatty acid levels, especially polyunsaturated fatty acids, but levels increased even more when combined with training. These findings suggest that mechanisms behind enhanced running capacity are not identical for GW501516 and training. Training increases energy availability by promoting catabolism of proteins, and gluconeogenesis, whereas GW501516 enhances specific consumption of fatty acids and reducing glucose utilization.

L312, a novel PPARγ ligand with potent anti-diabetic activity by selective regulation.

BACKGROUND: Selective PPARγ modulators (sPPARγM) retains insulin sensitizing activity but with minimal side effects compared to traditional TZDs agents, is thought as a promising strategy for development of safer insulin sensitizer. METHODS: We used a combination of virtual docking, SPR-based binding, luciferase reporter and adipogenesis assays to analyze the interaction mode, affinity and agonistic activity of L312 to PPARγ in vitro, respectively. And the anti-diabetic effects and underlying molecular mechanisms of L312 was studied in db/db mice. RESULTS: L312 interacted with PPARγ-LBD in a manner similar to known sPPARγM. L312 showed similar PPARγ binding affinity, but displayed partial PPARγ agonistic activity compared to PPARγ full agonist pioglitazone. In addition, L312 displayed partial recruitment of coactivator CBP yet equal disassociation of corepressor NCoR1 compared to pioglitazone. In db/db mice, L312 (30 mg/kg·day) treatment considerably improved insulin resistance with the regard to OGTT, ITT, fasted blood glucose, HOMA-IR and serum lipids, but elicited less weight gain, adipogenesis and hemodilution compared with pioglitazone. Further studies demonstrated that L312 is a potent inhibitor of CDK5-mediated PPARγ phosphorylation and displayed a selective gene expression profile in epididymal WAT. CONCLUSIONS: L312 is a novel sPPARγM. GENERAL SIGNIFICANCE: L312 may represent a novel lead for designing ideal sPPARγM for T2DM treatment with advantages over current TZDs.

Novel PPAR pan agonist, ZBH ameliorates hyperlipidemia and insulin resistance in high fat diet induced hyperlipidemic hamster.

Effective and safe pharmacological interventions for hyperlipidemia remains badly needed. By incorporating the key pharmacophore of fibrates into the natural scaffold of resveratrol, a novel structural compound ZBH was constructed. In present study, we found ZBH reserved approximately one third of the sirtuin 1 (SIRT1) activation produced by resveratrol at in-vitro enzyme activity assay, directly bound to and activated all three peroxisome proliferator-activated receptor (PPAR) subtypes respectively in PPAR binding and transactivation assays. Moreover, ZBH (EC50, 1.75 µM) activate PPARα 21 fold more efficiently than the well-known PPAR pan agonist bezafibrate (EC50 37.37 µM) in the cellular transactivation assays. In the high fat diet induced hyperlipidemic hamsters, 5-week treatment with ZBH significantly lowered serum triglyceride, total cholesterol, LDL-C, FFA, hyperinsulinemia, and improved insulin sensitivity more potently than bezafibrate. Meanwhile, serum transaminases, creatine phosphokinase and CREA levels were found not altered by ZBH intervention. Mechanism study indicated ZBH promoted the expression of PPARα target genes and SIRT1 mRNA. Hepatic lipogenesis was markedly decreased via down-regulation of lipogenic genes, and fatty acid uptake and oxidation was simultaneously increased in the liver and skeletal muscle via up-regulation of lipolysis genes. Glucose uptake and utilization was also significantly promoted in skeletal muscle. These results suggested that ZBH significantly lowered hyperlipidemia and ameliorated insulin resistance more efficiently than bezafibrate in the hyperlipidemic hamsters primarily by activating of PPARα, and SIRT1 promotion and activation. ZBH thus presents a potential new agent to combat hyperlipidemia.

C333H ameliorated insulin resistance through selectively modulating peroxisome proliferator-activated receptor γ in brown adipose tissue of db/db mice.

Peroxisome proliferator-activated receptor γ (PPARγ) is a unique target for insulin sensitizer agents. These drugs have been used for the clinical treatment of type 2 diabetes for almost twenty years. However, serious safety issues are associated with the PPARγ agonist thiazolidinediones (TZDs). Selective PPARγ modulators (SPPARMs) which retain insulin sensitization without TZDs-like side effects are emerging as a promising new generation of insulin sensitizers. C333H is a novel structure compound synthesized by our laboratory. In diabetic rodent models, C333H has insulin-sensitizing and glucose-lowering activity comparable to that of TZDs, and causes no significant increase in body weight or adipose tissue weight in db/db mice. In diabetic db/db mice, C333H elevated circulating high molecular weight adiponectin isoforms, decreased PPARγ 273 serine phosphorylation in brown adipose tissue and selectively modulated the expression of a subset of PPARγ target genes in adipose tissue. In vitro, C333H weakly recruited coactivator and weakly dissociated corepressor activity. These findings suggest that C333H has similar properties to SPPARMs and may be a potential therapeutic agent for the treatment of type 2 diabetes.

DBZ blocks LPS-induced monocyte activation and foam cell formation via inhibiting nuclear factor-ĸB.

BACKGROUND/AIMS: It has been widely accepted that chronic inflammation plays important roles in the atherogenesis. Danshensu Bingpian Zhi (DBZ) is a novel synthetic compound derived from the traditional Chinese medicine (TCM) formula Fu Fang Dan Shen (FFDS), which is effective on atherosclerosis clinically. We hypothesized that DBZ possessed the anti-atherosclerosis potentials. Here, we examined the inhibitory effects of DBZ on LPS-induced monocyte activation and foam cell formation. METHODS: The effects of DBZ were assessed on LPS-induced inflammatory factors expression in monocyte/macrophage. Activation of NF-κB and AP-1 was analyzed by luciferase reporter assay and signaling pathway of NF-κB was investigated to elucidate mechanisms underlying DBZ mediated anti-inflammatory activity. Effects of DBZ on macrophage lipid accumulation were evaluated in native LDL and LPS co-incubated macrophages. RESULTS: DBZ inhibited LPS-induced inflammatory factors expression dose dependently in monocytes. DBZ inhibited NF-κB activation strongly and AP-1 slightly. DBZ suppressed the LPS-induced degradation of IκBα, thereby decreasing the translocation of p65 to nucleus. Furthermore, DBZ suppressed LPS-activated macrophages lipid accumulation, partly due to inhibiting the expression of LPS-induced aP2 and ADRP in macrophges. CONCLUSION: These results demonstrate that DBZ has potentials on anti-atherosclerosis by suppressing monocyte activation and foam cell formation.

Functional crosstalk of CAR-LXR and ROR-LXR in drug metabolism and lipid metabolism.

Nuclear receptor crosstalk represents an important mechanism to expand the functions of individual receptors. The liver X receptors (LXR, NR1H2/3), both the α and ß isoforms, are nuclear receptors that can be activated by the endogenous oxysterols and other synthetic agonists. LXRs function as cholesterol sensors, which protect mammals from cholesterol overload. LXRs have been shown to regulate the expression of a battery of metabolic genes, especially those involved in lipid metabolism. LXRs have recently been suggested to play a novel role in the regulation of drug metabolism. The constitutive androstane receptor (CAR, NR1I3) is a xenobiotic receptor that regulates the expression of drug-metabolizing enzymes and transporters. Disruption of CAR alters sensitivity to toxins, increasing or decreasing it depending on the compounds. More recently, additional roles for CAR have been discovered. These include the involvement of CAR in lipid metabolism. Mechanistically, CAR forms an intricate regulatory network with other members of the nuclear receptor superfamily, foremost the LXRs, in exerting its effect on lipid metabolism. Retinoid-related orphan receptors (RORs, NR1F1/2/3) have three isoforms, α, ß and γ. Recent reports have shown that loss of RORα and/or RORγ can positively or negatively influence the expression of multiple drug-metabolizing enzymes and transporters in the liver. The effects of RORs on expression of drug-metabolizing enzymes were reasoned to be, at least in part, due to the crosstalk with LXR. This review focuses on the CAR-LXR and ROR-LXR crosstalk, and the implications of this crosstalk in drug metabolism and lipid metabolism.