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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 325 records · Page 18
All sourcesNASA NTRSDOE OSTI
DOE OSTI2019

Metal Artifact Reduction for Orthopedic Prosthesis in Lower Extremity CT Venography: Evaluation of Image Quality and Vessel Conspicuity

Purpose: This study evaluates the image quality of lower extremity CT venography reconstructed with orthopedic metal artifact reduction (O-MAR) in patients with unilateral or bilateral metallic prostheses in the hip or knee. Methods: This retrospective study was approved by our institutional review board, and informed consent was waived. Twenty-nine patients of lower extremity CT with 51 metallic hip or knee prostheses were reconstructed to both standard CT images and O-MAR images. The subjective image quality and vessel conspicuity for both images were evaluated by two readers using five-point scales (0–4). Vessel conspicuity scores of 3 or 4 were considered diagnostically acceptable. Image noise was measured in the air and subcutaneous fat. Results: O-MAR images showed significantly higher scores of subjective image quality (p < .001) and vessel conspicuity (p = .002) than standard CT images. Diagnostic acceptance of vessel conspicuity was not significantly different between O-MAR images and standard CT images (p = 1.000). O-MAR images showed significantly less image noise than conventional CT images (p < .001 for both air and subcutaneous fat). Conclusion: O-MAR may be an effective solution for the metal artifacts in lower extremity CT venography; however, the distance between prostheses and vessels affects the diagnostic acceptance in patients with metallic hip or knee prostheses. Level of Evidence: Level 4, Case Series.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Disruption of ATP-sensitive potassium channel function in skeletal muscles promotes production and secretion of musclin

Sarcolemmal ATP-sensitive potassium (K{sub ATP}) channels control skeletal muscle energy use through their ability to adjust membrane excitability and related cell functions in accordance with cellular metabolic status. Mice with disrupted skeletal muscle K{sub ATP} channels exhibit reduced adipocyte size and increased fatty acid release into the circulation. As yet, the molecular mechanisms underlying this link between skeletal muscle K{sub ATP} channel function and adipose mobilization have not been established. Here, we demonstrate that skeletal muscle-specific disruption of K{sub ATP} channel function in transgenic (TG) mice promotes production and secretion of musclin. Musclin is a myokine with high homology to atrial natriuretic peptide (ANP) that enhances ANP signaling by competing for elimination. Augmented musclin production in TG mice is driven by a molecular cascade resulting in enhanced acetylation and nuclear exclusion of the transcription factor forkhead box O1 (FOXO1) – an inhibitor of transcription of the musclin encoding gene. Musclin production/secretion in TG is paired with increased mobilization of fatty acids and a clear trend toward increased circulating ANP, an activator of lipolysis. These data establish K{sub ATP} channel-dependent musclin production as a potential mechanistic link coupling “local” skeletal muscle energy consumption with mobilization of bodily resources from fat. Understanding such mechanisms is an important step toward designing interventions to manage metabolic disorders including those related to excess body fat and associated co-morbidities. - Highlights: • ATP-sensitive K{sup +} channels regulate musclin production by skeletal muscles. • Lipolytic ANP signaling is promoted by augmented skeletal muscle musclin production. • Skeletal muscle musclin transcription is promoted by a CaMKII/HDAC/FOXO1 pathway. • Musclin links adipose mobilization to energy use in K{sub ATP} channel deficient skeletal muscle.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Spontaneous nonalcoholic fatty liver disease and ER stress in Sidt2 deficiency mice

Sidt2 is a newly discovered lysosomal membrane protein that is closely related to glucose metabolism. In the present study, we found that Sidt2 is also closely related to lipid metabolism. Gradual increases in serum triglyceride (TG) and free fatty acid, as well as elevated aspartate transaminase and alanine transaminase levels were observed in Sidt2{sup −/−} mice fed a normal diet from the age of 3 months, suggesting the presence of lipid metabolism disorders and impaired liver function in these mice. In the liver slices of 6-month-old Sidt2{sup −/−} mice, there were obvious fat degeneration and inflammatory changes. Almost all of the liver cells demonstrated different levels of lipid droplet accumulation and cell swelling, and some of the cells demonstrated balloon-like changes. Infiltration of inflammatory cells was observed in the portal area and hepatic lobule. Electron microscopy showed that macrophages tended to be attached to the endothelial cells, and a large number of lipid droplets were present in the liver cells. Oil red O staining showed that there were significantly increased number of deep straining particles in the liver cells of Sidt2{sup −/−} mice, and the TG content in liver tissue was also significantly increased. Detection of key genes and proteins related to fat synthesis showed that mRNA and protein levels of the SREBP1c in the liver of Sidt2{sup −/−} mice were significantly elevated, and the downstream genes acetyl-CoA carboxylase, fatty acid synthase, and mitochondrial glycerol 3-phosphate acyltransferase were significantly upregulated. In addition, there was severe endoplasmic reticulum stress (ERS) in the liver of Sidt2{sup −/−} mice, which had significantly increased levels of markers specific for unfolded protein response activation, Grp78 and CHOP, as well as significant elevation of downstream p-PERK, p-eIF2a, p-IRE1a, along with ER damage. These results suggest that Sidt2{sup −/−} mice had spontaneous nonalcoholic fatty liver disease (NAFLD) accompanied by ERS. In summary, as a lysosomal membrane protein, Sidt2 plays an important role in the pathogenesis of NAFLD, and ERS may mediate the occurrence and development of this disease in Sdit2 deficiency mice.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Activation of the Wnt/β-catenin pathway in pancreatic beta cells during the compensatory islet hyperplasia in prediabetic mice

The Wnt/β-catenin signaling pathway, also known as the canonical Wnt pathway, plays a role in cell proliferation and differentiation in several tissues/organs. It has been recently described in humans a relationship between type 2 diabetes (T2DM) and mutation in the gene encoding the transcription factor TCF7L2 associated to the Wnt/β-catenin pathway. In the present study, we demonstrated that hyperplastic pancreatic islets from prediabetic mice fed a high-fat diet (HFD) for 60 d displayed nuclear translocation of active β-catenin associated with significant increases in protein content and gene expression of β-catenin as well as of cyclins D1, D2 and c-Myc (target genes of the Wnt pathway) but not of Tcf7l2 (the transcription factor). Meanwhile, these alterations were not observed in pancreatic islets from 30 d HFD-fed mice, that do not display significant beta cell hyperplasia. These data suggest that the Wnt/β-catenin pathway is activated in pancreatic islets during prediabetes and may play a role in the induction of the compensatory beta cell hyperplasia observed at early phase of T2DM. - Highlights: • Exposure to high-fat diet for 60 days induced prediabetes and beta cell mass expansion. • Hyperplastic pancreatic islets displayed nuclear translocation of active β-catenin. • Hyperplastic islets showed increased expression of target genes of the Wnt/β-catenin pathway. • Wnt/β-catenin pathway is activated during compensatory beta cell hyperplasia in mice.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Zinc alpha2 glycoprotein promotes browning in adipocytes

Recent studies have highlighted recruiting and activating brite adipocytes in WAT (so-called “browning”) would be an attractive anti-obesity strategy. Zinc alpha2 glycoprotein (ZAG) as an important adipokine, is reported to ameliorate glycolipid metabolism and lose body weight in obese mice. However whether the body reducing effect mediated by browning programme remains unclear. Here, we show that overexpression of ZAG in 3T3-L1 adipocytes enhanced expression of brown fat-specific markers (UCP-1, PRDM16 and CIDEA), mitochondrial biogenesis genes (PGC-1α, NRF-1/2 and mtTFA) and the key lipid metabolism lipases (ATGL, HSL, CPT1-A and p-acyl-CoA carboxylase). Additionally, those effects were dramaticlly abolished by H89/SB203580, revealing ZAG-induced browning depend on PKA and p38 MAPK signaling. Overall, our findings suggest that ZAG is a candidate therapeutic agent against obesity via induction of brown fat-like phenotype in white adipocytes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Soluble dietary fiber improves energy homeostasis in obese mice by remodeling the gut microbiota

Intervention with dietary fibers is an important strategy to combat the global epidemic of obesity which is a consequence of energy imbalance. However, a possible role of the gut microbiota in effects of dietary fibers on energy homeostasis remains unclear. Here, we treated a high fat diet-induced obese (DIO) mouse model with soluble dietary fiber. Our results showed that soluble dietary fiber reduced body weight gain and the excessive accumulation of white fat tissue in DIO mice. Notably, soluble dietary fiber increased energy expenditure, but not change energy intake in DIO mice. In accordance, 16S rRNA sequencing revealed that the diversity of the gut microbiota was restored by soluble dietary fiber. Moreover, compared with controls, soluble dietary fiber resulted in a decreased ratio of Firmicutes/Bacteroidetes at the phylum level, and an increased relative abundance of the genera Roseburia at the genus level. Taken together, these findings indicate that soluble dietary fiber improves energy homeostasis and prevents obesity by increasing the diversity of the gut microbiota and the colonization of beneficial bacteria.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

AIM2 accelerates the atherosclerotic plaque progressions in ApoE−/− mice

Highlights: • Our study demonstrated that AIM2 plays an important role in atherosclerosis. • We found that AIM2 could mediate GSDMD-N and pyroptosis in VSMCs for the first time. • We first found that AIM2 could affect ICAM-1 and macrophage recruitment in atherosclerosis. • We first found that ox-LDL can promote AIM2 expression through NF-κB signaling. Plaque formation is initiated and triggered by cell death in the vascular wall, which gradually leads to the progression of atherosclerosis. Pyroptosis is a newly discovered form of programmed cell death. Absent in melanoma 2 (AIM2), a member of the HIN-200 protein family, plays an important role in activating inflammasomes. However, the role and mechanism of AIM2 in atherosclerotic plaque progression has not been thoroughly elucidated to date. The effect of pyroptosis and the mechanism for this effect were investigated in apolipoprotein E-deficient (ApoE−/−) mice. AIM2 overexpression and inhibition were studied in ApoE−/− mice that were fed a high-fat diet. The specific role of AIM2 in vascular smooth muscle cells (VSMCs) was explored in vitro. The results showed that high fat diet increases the expression of AIM2, ICMA-1, GSDMD-N, which could be mediated by AIM2 expression. The plaque lesion area is lager with AIM2 overexpression. Moreover, TUNEL-positive cells were increased when AIM2 was overexpressed. With increased AIM2, macrophages were enhanced. In vitro studies showed that AIM2 and GSDMD-N expression correlated with ox-LDL levels in a concentration dependent manner. AIM2 expression is associated with NF-κB signaling activity and can be inhibited by NF-κB inhibitor. AIM2 mediated GSDMD activity through ASC, caspase1 pathway. EthD-III and TUNEL staining showed that AIM2 mediates pyroptosis in VSMCs. Our study suggests that AIM2 is not only a regular of inflammasome but also an active participant in atherosclerosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

GSK126 alleviates the obesity phenotype by promoting the differentiation of thermogenic beige adipocytes in diet-induced obese mice

Highlights: • GSK126, a chemical inducer of beige adipocytes, was identified in mice. • GSK126 induced the browning phenotype in subcutaneous and visceral WAT in mice. • Ezh2 and H3K27me3 promoted the differentiation of white adipocytes in mice. • Ezh2 and H3K27me3 inhibited the differentiation of beige adipocytes in mice. • Ezh2 and H3K27me3 played complex roles in brown adipocytes differentiation in mice. A close relationship between epigenetic regulation and obesity has been demonstrated in several recent studies. Histone methyltransferase enhancer of Zeste homolog 2 (Ezh2), which mainly catalyzes trimethylation of histone H3K27 to form H3K27me3 was found to be required for the differentiation of white and brown adipocytes in vitro. Here, we investigated the effects of the Ezh2-specific inhibitor GSK126 in a mouse model of obesity induced by a high-fat diet (HFD). We found that GSK126 treatment reduced body fat, improved glucose tolerance, increased lipolysis and improved cold tolerance in mice by promoting the differentiation of thermogenic beige adipocytes. Moreover, we discovered that GSK126 inhibited the differentiation of white adipocytes, and the decrease of Ezh2 enzymatic activity and H3K27me3 also changed the morphology of brown adipocytes but did not alter the expression of thermogenic genes in these cells. Our results indicated that GSK126 was a novel chemical inducer of beige adipocytes and may be a potential therapeutic agent for the management of obesity. Furthermore, they also prompted that Ezh2 and H3K27me3 play different roles in the differentiation of the white, brown, and beige adipocytes in vivo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Ifi27 is indispensable for mitochondrial function and browning in adipocytes

Highlights: • Ifi27 is a brown fat-enriched gene and localizes to mitochondria. • The expression of Ifi27 is induced by β3-adrenergic agonist in adipose tissues. • Interferon-α signaling decreases Ifi27 level. • Ifi27 is physiologically required to maintain mitochondrial function and undergo browning. Brown adipose tissue (BAT) is specialized for energy expenditure, but the signaling pathways that regulate BAT metabolism and activity are incompletely understood. Interferon (IFN) signaling is a sophisticated defense mechanism to counteract viral infection. IFNs and interferon-stimulated genes (ISGs) are reported to exert profound effects on adipocytes. IFN-α inducible protein 27 (Ifi27/ISG12a) is a BAT-enriched gene, yet no any studies on its roles in BAT have been reported. Here, we show that Ifi27 protein localizes to mitochondria and the expression of Ifi27 can be induced by β3-adrenergic activation in adipose tissues. Knockdown of Ifi27 leads to reduced expression of key enzymes of tricarboxylic acid cycle (TCA), the subunits of electron transport chain (ETC) and uncoupling protein 1 (Ucp1) in brown and beige adipocytes. Moreover, the browning of subcutaneous white fat induced by β3-adrenergic agonist is also dramatically blocked. Ectopic expression of Ifi27 in brown adipocytes has the opposite effects. Together, these data indicate that Ifi27 regulates mitochondrial function and browning in adipocytes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Leptin regulates the expression of angiopoietin-like 6

Highlights: • High-fat diet results in increased hepatic ANGPTL6 expression. • Leptin treatment upregulates ANGPTL6 expression in hepatocytes. • Exercise training decreases serum ANGPTL6 as well as leptin. Angiopoietin-like 6 (ANGPTL6) is a hepatokine that antagonizes obesity and insulin resistance by increasing energy expenditure. Despite its beneficial effects on metabolism, human studies have shown a paradoxical increase in ANGPTL6 level in the serum of patients with metabolic diseases, which has been interpreted as a compensatory upregulation. However, the regulatory mechanism of ANGPTL6 remains unclear. Since upregulation of ANGPTL6 is induced on metabolic stress, we investigated the hepatic expression of ANGPTL6 by leptin, a representative adipokine of obesity. Mice on a high-fat diet showed increased serum leptin levels and hepatic Angptl6 expression, which were attenuated by exercise training. A single leptin injection also induced hepatic ANGPTL6 expression and increased serum ANGPTL6 levels. In an in vitro model using primary hepatocytes, leptin treatment significantly upregulated ANGPTL6 expression at the mRNA and protein levels, as well as the amount of secreted ANGPTL6 protein in conditioned media. Similarly, exercise training on human participants also showed diminished serum levels of leptin and ANGPTL6. Altogether, these results strongly indicated that hepatic ANGPTL6 expression was determined by leptin.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

DNA-binding activity of STAT3 increased in hypothalamus of DIO mice; the reduction of STAT3 phosphorylation may facilitate leptin signaling

Highlights: • The DNA-binding activity of STAT3 significantly increased, POMC expression decreased in the hypothalamus of DIO mice. • The reduction of STAT3 phosphorylation facilitated leptin-mediated POMC expression in cultured cells. • The DNA-binding activity of STAT3 and the proximal SBE of POMC promoter was essential to leptin-mediated POMC transcription. Leptin-mediated DNA-binding activity of STAT3 in hypothalamus plays crucial roles in the maintenance of energy homeostasis in lean mice; however its effects still remains unclear in case of leptin resistance in mice with diet induced obesity (DIO). In this study significant elevation of both basal and exogenously leptin-treated DNA-binding activity of STAT3 was detected using EMSA in the hypothalamus of male C57BL/6J mice fed high-fat diet for 10 wks, in concomitant with hyperleptinemia, high body weight, high fat mass, and hyperphagia as well as decreased POMC expression. The studies in vitro showed that both DNA binding activity and the proximal SBE of POMC promoter was essential to leptin-mediated POMC expression. However, the diminution of STAT3 phosphorylation, achieved by S3I-201 or a FoxO1 mutant, facilitated leptin-mediated POMC expression. The findings here demonstrated excess STAT3 activity negatively regulated POMC expression in hypothalamus of DIO mice, and suggested the limitation of STAT3 activity may promote leptin signaling.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Biomass supply chain equipment for renewable fuels production: A review

The production of renewable fuels is a critical component of global strategies to reduce greenhouse gas (GHG) emissions. Moreover, the collection of raw materials for its production can provide added benefits such as reduction of wildfire risk, additional income for farmers, and decreased disposal costs. Although there is substantial literature on design and modeling of supply chains, the authors were unable to find a single reference with the information needed for the selection and cost estimation of each type of equipment involved in the supply chain. Therefore, the goal of this research is to gather information necessary for the construction and utilization of models that might drive the identification of a feasible supply chain to produce renewable fuels at a commercial scale. The primary objectives are to 1) understand the supply chain of critical feedstocks for renewable fuels production; 2) identify the equipment commercially available for collection and adequation of feedstock; and 3) consolidate information regarding equipment cost, energy consumption, and efficiency, as well as feedstock storage and transportation systems. This paper provides a compilation for five feedstock types studied for sustainable aviation fuel production: 1) agricultural residues and grasses, 2) forest residues, 3) urban wood waste, 4) oilseeds, 5) fats, oils & greases. All the technologies involved from the field to the gate of the preprocessing or conversion unit were reviewed. The information on fats, oils & greases supply chains and equipment purposely designed for forest thinning and pruning was very limited.

: Feedstock, Collection and Adequation, Renewable ↗
DOE OSTI2015

Examining confounding by diet in the association between perfluoroalkyl acids and serum cholesterol in pregnancy

Background: Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) have consistently been associated with higher cholesterol levels in cross sectional studies. Concerns have, however, been raised about potential confounding by diet and clinical relevance. Objective: To examine the association between concentrations of PFOS and PFOA and total cholesterol in serum during pregnancy taking into considerations confounding by diet. Methods: 854 Danish women who gave birth in 1988–89 and provided a blood sample and reported their diet in week 30 of gestation. Results: Mean serum PFOS, PFOA and total cholesterol concentrations were 22.3 ng/mL, 4.1 ng/mL and 7.3 mmol/L, respectively. Maternal diet was a significant predictor of serum PFOS and PFOA concentrations. In particular intake of meat and meat products was positively associated while intake of vegetables was inversely associated (P for trend <0.01) with relative difference between the highest and lowest quartile in PFOS and PFOA concentrations ranging between 6% and 25% of mean values. After adjustment for dietary factors both PFOA and PFOS were positively and similarly associated with serum cholesterol (P for trend ≤0.01). For example, the mean increase in serum cholesterol was 0.39 mmol/L (95%CI: 0.09, 0.68) when comparing women in the highest to lowest quintile of PFOA concentrations. In comparison the mean increase in serum cholesterol was 0.61 mmol/L (95%CI: 0.17, 1.05) when comparing women in the highest to lowest quintile of saturated fat intake. Conclusion: In this study associations between PFOS and PFOA with serum cholesterol appeared unrelated to dietary intake and were similar in magnitude as the associations between saturated fat intake and serum cholesterol. - Highlights: • PFOS and PFOA have consistently been linked with raised serum cholesterol • Clinical relevance remains uncertain and confounding by diet has been suggested • The aim of this study was to address these issues in a cohort of 854 pregnant women • With detailed dietary information we found no indication of such confounding • As predictors cholesterol PFOSA and PFOA were similar to other known risk factors.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2016

Evaluation of Functional Marrow Irradiation Based on Skeletal Marrow Composition Obtained Using Dual-Energy Computed Tomography

Purpose: To develop an imaging method to characterize and map marrow composition in the entire skeletal system, and to simulate differential targeted marrow irradiation based on marrow composition. Methods and Materials: Whole-body dual energy computed tomography (DECT) images of cadavers and leukemia patients were acquired, segmented to separate bone marrow components, namely, bone, red marrow (RM), and yellow marrow (YM). DECT-derived marrow fat fraction was validated using histology of lumbar vertebrae obtained from cadavers. The fractions of RM (RMF = RM/total marrow) and YMF were calculated in each skeletal region to assess the correlation of marrow composition with sites and ages. Treatment planning was simulated to target irradiation differentially at a higher dose (18 Gy) to either RM or YM and a lower dose (12 Gy) to the rest of the skeleton. Results: A significant correlation between fat fractions obtained from DECT and cadaver histology samples was observed (r=0.861, P<.0001, Pearson). The RMF decreased in the head, neck, and chest was significantly inversely correlated with age but did not show any significant age-related changes in the abdomen and pelvis regions. Conformity of radiation to targets (RM, YM) was significantly dependent on skeletal sites. The radiation exposure was significantly reduced (P<.05, t test) to organs at risk (OARs) in RM and YM irradiation compared with standard total marrow irradiation (TMI). Conclusions: Whole-body DECT offers a new imaging technique to visualize and measure skeletal-wide marrow composition. The DECT-based treatment planning offers volumetric and site-specific precise radiation dosimetry of RM and YM, which varies with aging. Our proposed method could be used as a functional compartment of TMI for further targeted radiation to specific bone marrow environment, dose escalation, reduction of doses to OARs, or a combination of these factors.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

Pancreatic stellate cell activation is regulated by fatty acids and ER stress

Introduction: Pancreatic pathologies are characterized by a progressive fibrosis process. Pancreatic stellate cells (PSC) play a crucial role in pancreatic fibrogenesis. Endoplasmic reticulum (ER) stress emerges as an important determinant of fibrotic remodeling. Overload of fatty acids (FA), typical to obesity, may lead to lipotoxic state and cellular stress. Aim: To study the effect of different lipolytic challenges on pancreatic ER stress and PSC activation. Methods: Primary PSCs were exposed to different FAs, palmitate (pal) and oleate (ole), at pathophysiological concentrations typical to obese state, and in acute caerulein-induced stress (cer). PSC activation and differentiation were analyzed by measuring fat accumulation (oil-red staining and quantitation), proliferation (cells count) and migration (wound- healing assay). PSC differentiation markers (α-sma, fibronectin, tgf-β and collagen secretion), ER stress unfolded protein response and immune indicators (Xbp1, CHOP, TNF-α, IL-6) were analyzed at the transcript and protein expression levels (quantitative RT-PCR and western blotting). Results: PSC exposure to pal and ole FAs (500 µM) increased significantly fat accumulation. Proliferation and migration analysis demonstrated that ole FA retained PSC activation, while exposure to pal FA significantly halted proliferation rate and delayed migration. Cer significantly augmented PSC differentiation markers α- sma, fibronectin and collagen, and ER stress and inflammation markers including Xbp1, CHOP, TNF-α and IL-6. The ole FA treatment significantly elevated PSC differentiation markers α-sma, fibronectin and collagen secretion. PSC ER stress was demonstrated following pal treatment with significant elevation of Xbp1 splicing and CHOP levels. Conclusion: Exposure to pal FA halted PSC activation and differentiation and elevated ER stress markers, while cer and ole exposure significantly induced activation, differentiation and fibrosis. Thus, dietary FA composition should be considered and optimized to regulate PSC activation and differentiation in pancreatic pathologies. - Highlights: • Pancreatic stellate cells (PSC) play a crucial role in pancreatic fibrogenesis. • Endoplasmic reticulum (ER) stress is an important determinant of fibrotic remodeling. • Overload of fatty acids, typical to obesity, may lead to lipotoxicity and cellular stress. • Exposure to pal FA halts PSC activation, differentiation and elevated ER stress. • Cer and ole exposure significantly induced activation, differentiation and fibrosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Silencing of RSPO1 mitigates obesity-related renal fibrosis in mice by deactivating Wnt/β-catenin pathway

Highlights: • Renal RSPO1 expression was increased in mice fed on high-fat diet for 12 weeks. • Silencing RSPO1 remitted kidney dysfunction and renal fibrosis in obesity mice. • Silencing RSPO1 inhibited LGR4 expression and Wnt/β-catenin pathway activation. • RSPO1/LGR4 axis was involved in obesity-related renal fibrosis. Obesity, a global epidemic, is one of the critical causes of chronic kidney disease (CKD). R-spondin1 (RSPO1) possessing the potential to activate Wnt/β-catenin pathway was reported to be elevated in circulation of obesity objects. However, the function of RSPO1 and the latent mechanism in obesity-related CKD are still left to be revealed. In the present study, renal RSPO1 expression was increased in mice fed on high-fat diet (HFD) for 12 weeks. Lentivirus-mediated RSPO1 knockdown partly recovered obesity-related metabolic symptoms, while distinctly remitted kidney dysfunction and renal fibrosis in obesity mice. In vitro, recombinant RSPO1 was found to elevate leucine-rich repeat-containing G protein coupled receptor 4 (LGR4) expression, promote Wnt/β-catenin signaling pathway activation, facilitate epithelial-mesenchymal transition (EMT) and increase collagen deposition in HK2 renal tubular cells. Such pro-fibrotic effect of RSPO1 was diminished by LGR4 siRNA in HK2 cells. In summary, we demonstrate that RSPO1/LGR4 axis is involved in obesity-related renal fibrosis at least through activating Wnt/β-catenin signaling pathway, providing a potential therapeutic target for this disease.

60 APPLIED LIFE SCIENCES↗