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The worldwide prevalence of obesity and obesity-associated liver diseases have attracted great attention in the past decades. Obesity is an increasing health problem, which can induce a series of metabolic syndrome associated diseases, such as fatty liver disease, type 2 diabetes. The conventional causes for obesity, such as over-eating, sedentary life-style, and genetic factors, cannot fully explain the global rapid increase of obese population in the last few decades. It was found that the production of persistent organic pollutants (POPs) in the industry was closely correlated with the prevalence of obesity. POPs are organic chemicals that are resisted to degrade by various processes and widely applied in daily products to improve the quality of our life. 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is the most abundant and toxic congener in the family of polybrominated diphenyl ethers (PBDEs), which are the commonly used flame retardants and listed as POPs in 2009. High concentration of BDE-47 has been found in indoor dust and marine fish in Hong Kong. Owing to their high lipophilic and persistent characters, BDE-47 is mainly accumulated in adipose tissue. Epidemiological data indicates that exposure to BDE-47 is associated with obesity and obesity-associated liver diseases. Therefore, based on published research, we hypothesize that BDE-47 exposure may increase the occurrence of obesity and aggravate the progression of obesity-associated fatty liver disease through promoting adipocyte differentiation and impairing lipid metabolism. To verify this hypothesis, mouse preadipocytes (3T3-L1 cells) were exposed to BDE-47 and differentiated into adipocytes. Excitedly, with BDE-47 exposure, more lipid droplets were formed and accumulated in the treated cells than that in untreated adipocytes (without BDE-47 exposure). Along with the increased content of triglyceride accumulation, augmented gene and protein levels of transcription factors (PPARγ and PGC-1α), and related genes (FABP4 and C/EBPα) were also detected in BDE-47 treated cells. In addition, the total production of reactive oxygen species (ROS), contents of lipid peroxidation and DNA oxidation were obviously increased in adipocytes treated with BDE-47 (10 μM). To explore how BDE-47 regulated the oxidative stress signal pathways, antioxidants of ROS sources were employed with BDE-47 exposure during adipocyte differentiation. Notably, mitochondrial respiration, xanthine oxidase and NADPH pathway were significantly influenced by BDE-47 exposure to generate ROS in the treated adipocytes. The effects of BDE-47 on mitochondrial respiration were also determined for further exploring the relationship between mitochondrial ROS and adipocyte differentiation. Significant elevation of mitochondrial ROS was detected in adipocytes exposed with BDE-47 (10 μM). Furthermore, to support the energy requirements for the growth of adipocytes during differentiation process, BDE-47 improved the mitochondrial metabolism for ATP production via increasing the spare mitochondrial respiration capacity. Inhibiting the mitochondrial ROS generation in BDE-47-treated adipocytes with antioxidant attenuated the generation of ROS and reduced the accumulation of lipid droplets as well. This phenomenon indicated that the ROS-induced by BDE-47 through mitochondrial chain was critical for adipocyte differentiation. Global metabolomic profiling based on high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) was performed on differentiated 3T3-L1 cells to reveal the metabolic changes induced by BDE-47. Twenty three significantly changed metabolites were identified in the adipocytes after BDE-47 exposure. The results of pathway analysis showed that purine and glutathione metabolism were the main impacted pathways and upregulated by BDE-47 treatment. In purine metabolism, increasing levels of adenosine monophosphate (AMP) and guanosine monophosphate (GMP) induced by BDE-47 led to the increment of inosine 5'-monophosphate (IMP) in adipocytes. These increases forwarded the pathway and caused high production of uric acid along with hydrogen peroxide, which contributed to the elevation of ROS after exposure to BDE-47. Inhibiting the synthesis of uric acid with antioxidant could significantly decrease the production of ROS, the levels of adipogenesis-related genes, and the accumulation of lipid droplets in BDE-47 exposed adipocytes. These results further demonstrated that exposure to BDE-47 promoted adipocyte differentiation via causing oxidative stress, upregulating purine metabolism, and increasing production of uric acid. Subsequently, C57BL/6J mouse model with diet interaction was employed to explore the obesogenic effects of BDE-47. Male C57BL/6J mice were fed with either a low-fat diet (LFD, 10% fat) or high-fat diet (HFD, 60% fat) for 15 weeks and subcutaneously injected with BDE-47 (7mg/kg [Low dose, L] or 70mg/kg [High dose, H]) or the vehicle weekly. It was found that exposure to BDE-47 (H) significantly led to the elevation of body weight and serum triglyceride content in HFD fed mice. Besides, the combination of BDE-47 and HFD also significantly increased the weight of white adipose tissue (WAT) and augmented the size of adipocytes in WAT. These have confirmed the obesogenic effects of BDE-47 in vivo. Additionally, BDE-47 (H) exposure significantly increased the accumulation of hepatic triglyceride content and lipid droplets accompanying with elevated inflammation in HFD fed mice, indicating the deterioration of hepatic steatosis in BDE-47 treated mice. Moreover, the integration analysis of lipidomic and gene expression revealed that BDE-47 up-regulated triglyceride synthesis but suppressed lipid exportation and β oxidation to impair the lipid metabolism and worsen the accumulation of hepatic lipid in HFD fed mice. In addition, the increase of liver fibrosis scars (the protein level of αSMA and collagens), serum transaminase levels, as well as lipid peroxidation have been detected in the mice with co-treatment of BDE-47 and HFD. BDE-47 exposure also increased the production of ROS and the levels of fibrotic genes in hepatocytes. However, in LFD with BDE-47 exposed mouse liver, we cannot observe such changes compared with the control (LFD-DMSO). Interestingly, the application of antioxidants reversed the BDE-47-induced fibrotic responses (the expression of αSMA and col3) in hepatocytes, which indicated that the increase of liver fibrosis scars was tightly associated with the level of oxidative stress. In conclusion, these results offered a new insight of lipid toxicities and underlying mechanism of BDE-47 induced obesity-related liver fibrosis. As far as we know, this is the first systematic study of the obesogenic effects and underlying mechanisms of BDE-47 in diet-induced mouse model. These results have showed the pathological roles of BDE-47 in the development of obesity and related liver diseases by an integration analysis of omics study and biological analysis in vivo and in vitro. Meanwhile, inhibitors were applied to investigate the mechanism of BDE-47-induced toxicity. Taken together, our results indicated that BDE-47 exposure could accelerate the development of obesity and aggravate the progression of fatty liver in obese mice via causing oxidative stress. This study may shed a light for an explanation for the worldwide prevalence of obesity and related liver diseases. Furthermore, this work reflects the potential of omics study and biological methods for toxicity assessment of environmental pollutants on human health. It would be helpful for the clinical diagnose and treatment.

Fatty acid intercalated layered double hydroxides were used as additives for Jojoba oil and polymer matrices. The first phase of the study was to intercalate carboxylic acids (C14 to C22). These were successfully intercalated into layered double hydroxides (LDHs), with the formula [Mg0.7Al0.3 (OH) 2](CO3)0. 15•0.5H2O. The one-pot synthesis consistently yielded a bilayer intercalated product for the range of acids employed. The intercalated anions had an orientation tilt angle of 55–63°, depending on the length of the fatty acid chain. However, there is an indication that the anion exchange process employed in this study is accompanied by probable dissolution and recrystallisation of the LDH. This is supported by the different growth habits and sizes of platelets observed through scanning electron microscopy (SEM). Moreover, the organo-LDH platelets were found to have varying MII/MIII compositions, ranging from 1.65 to 6, indicating that the one-pot synthesis yields an array of mixed metal hydroxides. Polymer composites, containing 5% and 10 wt.% of stearate intercalated layered double hydroxides (LDH-stearate) and neat layered double hydroxides (LDH-CO3), were prepared via melt-compounding to explore the use of LDHs as an additive. The stearate modified starting material was bilayer-intercalated clay. During melt compounding, excess stearates were released and the clay reverted to a monolayer-intercalated form. Comprehensive characterisation and study of the fatty acid-intercalated LDH showed that these organoclay hybrids exhibit thermotropic behaviour. This behaviour ultimately leads to the exudation of excess fatty acid. The exuded stearates were found to have lubricating and plasticising effects on the poly(ethylene-co-vinyl acetate) (EVA) and linear low density polyethylene (LLDPE) matrices. Strong hydrogen bond interactions between the chains of poly(ethyleneco- vinyl alcohol) (EVAL) and the clay platelet surfaces overwhelmed the lubrication effect and caused an increase in the melt viscosity of this matrix. The notched Charpy impact strength of this composite was almost double that of the neat polymer. It appears that this can be attributed to the ability of the highly dispersed and randomly oriented nanosized clay platelets to promote extensive internal microcavitation during impact loading. The creation of a large internal surface area provided the requisite energy dissipation mechanism. The study also considered fatty acid-intercalated LDH as an argillaceous mineral for potential use as a rheological additive in Jojoba oil. A minimum of 20 wt.% LDH in Jojoba oil formulation was found to be stable, i.e. it did not form separate layers on standing. The viscosity of the neat Jojoba oil demonstrated Newtonian behaviour, whereas the modified LDH/Jojoba oil formulation shear thinned, which is a typical non-Newtonian behaviour. Viscosity as a function of temperature showed complex rheological behaviour for the long chain fatty acids C16 to C22. The viscosity increase is assumed to be due to a combination of three events, which include the formation and changes of LDH microstructures within the oil, the loss of excess fatty acids into the oil matrix, and the formation of fatty acid crystal networks. Shear action also induced some delamination of the clay platelets. / Thesis (PhD(Eng))--University of Pretoria, 2012. / Chemical Engineering / unrestricted

The boundaries between freshwater and terrestrial ecosystems can be areas of important subsidy transfers. These subsidies, such as leaf litter inputs to streams or aquatic emerging insects into riparian zones, link food webs and provide benefits to consumers in the form of nutrients and energy. Subsidies from aquatic systems tend to have high levels of essential long chain polyunsaturated fatty acids (LC-PUFAs), such as eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) that are only produced by certain forms of aquatic algae. These LC-PUFAs are highly important in growth, development, and other metabolic functions across animal groups (Brett and Muller-Navarra 1997, Gladyshev et al. 2009).

Thesis (D.Sc.N.S.)--Boston University, Henry M. Goldman School of Graduate Dentistry, 1993 (Nutritional Sciences). / Includes bibliography (leaves 176-187) / This dissertation has been presented in two related studies: A. Fish Oil Reduces Proteinuria and Interstitial Injury but not GIomerulosclerosis in the Milan Nomotensive Rat Rats of the Milan Normotensive strain (MNS) spontaneously develop severe Proteinuria and excessive glomemlar thromboxane (Tx)A2 PrOduction at a young age. These are accompanied by podocyte alterations and progressive focal glomerulosclerosis (FGS) and interstitial fibrosis. Since previous studies showed that pharmacologic... [TRUNCATED]

The burden of liver diseases is increasing worldwide, accounting for two million deaths annually. In the past decade, tremendous progress has been made in the basic and translational research of liver tissue engineering, which seeks to build physiologically relevant liver models to better understand liver diseases, accelerate drug development, and advance regenerative medicine. Liver microtissues are small, three-dimensional (3D) hepatocyte cultures that recapitulate liver physiology and have been used in many biomedical applications. However, sourcing of high-quality human hepatocytes for microtissue fabrication poses a significant challenge. Since the inception of induced pluripotent stem cell (iPSC) technology, iPSC-derived hepatocyte-like cells (HLCs) have demonstrated significant improvement over other hepatocyte cell sources in many studies. Despite their promising potential, HLCs face certain challenges: they resemble fetal hepatocytes rather than adult hepatocytes; they undergo dedifferentiation quickly after reaching maturity; they are produced on a small scale; and they exhibit large donor-to-donor and batch-to-batch variability. This doctoral thesis focuses on engineering patient-specific liver microtissues with prolonged phenotypic maintenance and disease modeling potential. Chapter 1 provides a review of recent advances, challenges, and future directions in liver microtissue research. 3D microtissues can be generated by scaffold-free assembly or scaffold-assisted methods using macroencapsulation, droplet microfluidics, and bioprinting. Optimization of the hepatic microenvironment entails incorporating the appropriate cell composition for enhanced cell-cell interactions and niche-specific signals, and creating scaffolds with desired chemical, mechanical and physical properties. Perfusion-based culture systems such as bioreactors and microfluidic systems are used to achieve efficient exchange of nutrients and soluble factors in the microtissues. Chapter 2 describes our efforts in optimizing methods of generating human HLCs from the peripheral blood of selected donors. Peripheral blood mononuclear cells (PBMCs) were first reprogrammed to iPSCs using Sendai viruses carrying the four Yamanaka factors. We developed an optimized protocol for hepatocyte differentiation from iPSCs, and obtained HLCs that exhibited hepatocyte-specific phenotypes and functions that were comparable to other reports. We then demonstrated the one-step generation of homogeneous, microencapsulated liver microtissues in Chapter 3. Droplet microfluidics was used to produce double emulsion droplets that served as individual microenvironments where HLCs were encapsulated in methylated collagen and alginate. The cells self-assembled in <16 hours through dynamic interactions with methylated collagen, and individual spheroids were encapsulated in polymerized alginate gel to prevent cell fusion and attachment. HLC spheroids remained viable and functional for >24 days, whereas 2D HLCs underwent dedifferentiation within 7 days of reaching maturity. The spheroids showed further maturation compared to the 2D HLCs at peak maturity. Co-culture of HLCs with human endothelial cells was also investigated in the 3D system, but no improvement was observed over monoculture spheroids with our current methods. To our knowledge, this is the first study to utilize droplet microfluidics to generate homogeneous, compartmentalized droplets that serve as optimized 3D microenvironments for HLC aggregation and maturation. It demonstrated the potential of using high-throughput droplet microfluidics to produce and encapsulate mature, functional human HLCs for long-term applications. In Chapter 4, we developed a TM6SF2 knockout and overexpression model in iPSCs to investigate its molecular function and potential role in nonalcoholic fatty liver disease (NAFLD). Transmembrane 6 superfamily member 2 (TM6SF2) is a protein of unknown function, and analysis from our model suggested that TM6SF2 dysregulation has a biphasic response. Our data showed that both knockout and overexpression can result in the upregulation of cholesterol biosynthesis and a defect in the proper processing of lipid droplets. Additionally, high expression of the TM6SF2 rs58542926 variant has an increased risk for cholesterol upregulation, compared to the major allele. Future works will focus on generating liver microtissues from the TM6SF2 knockout and transgene-expressing cells using droplet microfluidics, and validating our hypotheses with established biochemical and functional assays.