scholarly journals URI-1 Levels Are Elevated in Fatty Livers of db/db and C57BL/6 Mice Fed Trans-10, Cis-12 Conjugated Linoleic Acid

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 383-383
Author(s):  
Luis Cordero-Monroy ◽  
Carla Taylor ◽  
Peter Zahradka
Keyword(s):  
Body Weight ◽  
Fatty Acid ◽  
Linoleic Acid ◽  
Fatty Liver ◽  
Western Blotting ◽  
Weight Ratio ◽  
Fatty Acid Uptake ◽  
Acid Uptake ◽  
Body Weight Ratio ◽  
Protein Levels

Abstract Objectives This study was designed to investigate whether unconventional prefoldin RPB5 interactor (URI)-1 mediates hepatic accumulation of triglyceride (TG) in response to a diet with trans-10,cis-12 conjugated linoleic acid (t10,c12 CLA) in lean or genetically obese mice. URI-1 belongs to the prefoldin family of proteins that have been shown to coordinate nutrient availablility by transcriptional regulation of genes involved in glucose and lipid metabolism. Thus, it was hypothesized that URI-1 in liver is involved in increased fatty acid uptake and accumulation leading to fatty liver. Methods C57BL/6 and db/db mice were randomly assigned to two diet groups, control (CTL) and t10,c12 CLA (0.4% w/w). After 4 weeks, the mice were weighed and euthanized. Livers were dissected, weighed and stored at –80°C. Liver lysates were prepared from the tissue for Western blotting to measure hepatic protein levels of URI-1 and FABP1. The amount of lipid in the livers was determined using the LabAssay™ Triglyceride kit, a colorimetric TG assay. Results The liver to body weight ratio of db/db and C57BL/6 mice fed t10,c12 CLA increased by 90% and 52%, respectively, compared to their counterparts fed the CTL diet. Likewise, the hepatic TG concentration (mg TG/mg protein) was increased 38% and 5-fold, respectively, in CLA-fed db/db and C57BL/6 mice compared to CTL db/db and C57BL/6 mice. Western blotting showed that FABP1 levels were approximately 2-fold greater in the db/db t10,c12 CLA group relative to the db/db CTL group, and may contribute to increased fatty acid uptake. Furthermore, URI-1 protein levels were elevated 4-fold in db/db and C57BL6 mice fed t10,c12 CLA compared to their respective CTL groups. Lastly, correlation analysis revealed that URI-1 levels were significantly correlated with hepatic TG concentrations (r = 0.61) and liver/body weight ratio (r = 0.64). Conclusions This study revealed a relationship between hepatic TG accumulation and URI-1, a protein associated with hepatocellular carcinoma (HCC) and cirrhosis. This study provides a basis for in vitro experiments exploring the causative role of URI-1 in propagating hepatic TG accumulation, and ultimately the progression of fatty liver disease to HCC and cirrhosis. Funding Sources University Collaborative Research Project, NSERC Discovery, and University of Manitoba Graduate Enhancement of Tri-Council Stipends.

scholarly journals ADAMTS13/VWF Axis Potentially Contributes to Diabetic Nephropathy By Regulating PAI-1 Levels

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2240-2240
Author(s):  
Nirav Dhanesha ◽  
Anil K. Chauhan
Keyword(s):  
Body Weight ◽  
Diabetic Nephropathy ◽  
Renal Injury ◽  
Weight Ratio ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Body Weight Ratio ◽  
Renal Hypertrophy ◽  
Protein Levels ◽  
Pai 1

Abstract Background and objective: ADAMTS13 (A Disintegrin And Metalloprotease with Thrombospondin type I repeats-13) cleaves von Willebrand factor (VWF), a large multimeric protein that plays an important role in hemostasis and thrombosis. Severe deficiency or very low levels of ADAMTS13 in presence of external stimuli results in accumulation of thrombogenic ultra large VWF multimers (which are released from activated endothelium) known to trigger thrombotic microangiopathy. Activated endothelium/dysfunction is a prominent feature of diabetic nephropathy, and advanced diabetic glomerulopathy often exhibits thrombotic microangiopathy. Significantly reduced ADAMTS13 and increased plasma VWF levels have been found in diabetic patients with nephropathy. Although major site of ADAMTS13 synthesis is liver, ADAMTS13 is also expressed by podocytes in normal renal cortex. It remains unknown, however, whether VWF and ADAMTS13 imbalance plays a causal role in development of nephropathy in diabetic patients or rather is simply an associate marker of disease status, possibly secondary to endothelial function. We performed experiments in genetic models to determine whether ADAMTS13 and VWF axis contributes to diabetic nephropathy. Methods : Male, 8-10 weeks old wild-type (WT), Adamts13-/- and Vwf-/- mice were made diabetic by injecting multiple low doses of streptozotocin (60 mg/kg, i.p. for five consecutive days). Successful diabetes induction was tested after 2 weeks by measuring blood glucose. Mice having blood glucose levels above 300 mg/dL were included in the study. Controls were nondiabetic littermate mice treated with citrate buffer. The extent of renal injury was evaluated after 28 weeks of diabetes induction by measuring albuminuria and kidney to body weight ratio. Renal hypertrophy and extracellular matrix deposition was quantified by hematoxylin and immunostaining. PAI-1 mRNA and protein levels were measured by real time quantitative RT-PCR and ELISA. Results: Adamts13- /- diabetic mice exhibited significantly increased kidney to body weight ratio (P<0.05 vs. WT diabetic mice). Urine albuminuria, an index of renal injury was significantly elevated in Adamts13-/- diabetic mice (P<0.05 vs. WT diabetic mice). Increased renal injury in Adamts13-/- diabetic mice was concomitant with increased renal hypertrophy and extracellular matrix (ECM) deposition within glomeruli (P<0.05 vs. WT diabetic mice). Murine studies have shown that PAI-1 contributes to diabetic nephropathy by regulating TGF-beta and ECM deposition. A positive association exists between increased PAI-1 levels in glomeruli and microangiopathy in patients with diabetic nephropathy. We determined whether ADAMTS13 deficiency-induced microangiopathy in glomeruli increases PAI-1 levels. Adamts13-/- diabetic mice exhibited increased PAI-1 mRNA and protein levels (P<0.05 vs. WT diabetic mice). VWF remains the only known substrate of ADAMTS13 and increased plasma VWF levels have been associated with diabetic nephropathy. We determined the role of VWF in diabetic nephropathy. Vwf-/- diabetic mice exhibited significantly decreased kidney weight/body weight ratio, less urinary albuminuria, decreased kidney PAI-1 expression levels concomitant with improved kidney morphological changes (P<0.05 vs. WT diabetic mice). Conclusion : These findings provide experimental evidence for the first time that ADAMTS13/VWF axis potentially contributes to diabetic nephropathy, most likely by regulating PAI-1 levels. Disclosures No relevant conflicts of interest to declare.

scholarly journals Hepatic Insulin Signaling Changes: Possible Mechanism in Prenatal Hypoxia-Increased Susceptibility of Fatty Liver in Adulthood

Endocrinology ◽  
2012 ◽  
Vol 153 (10) ◽  
pp. 4955-4965 ◽  
Author(s):  
Li Cao ◽  
Caiping Mao ◽  
Shigang Li ◽  
Yujuan Zhang ◽  
Juanxiu Lv ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Fatty Liver ◽  
Insulin Signaling ◽  
Weight Ratio ◽  
Glucose Transporters ◽  
Prenatal Hypoxia ◽  
Body Weight Ratio ◽  
Altered Expression ◽  
Hepatic Insulin Signaling

Abstract Nonalcoholic fatty liver disease (NAFLD) is strongly linked to insulin resistance. Prenatal hypoxia (PH) is a risk factor in programming of insulin resistance, glucose intolerance, and metabolic dysfunctions in later life, although the mechanisms are unclear. In this study, the role of metabolic and histological changes as well as the hepatic insulin signaling mechanisms were determined in increasing susceptibility of NAFLD in the fetus and offspring exposed to PH. Pregnant rats exposed to hypoxia (O2 10%) during pregnancy demonstrated decreased fetal body and liver weight as well as liver to body weight ratio, whereas these changes were not observed in the offspring. However, male liver to body weight ratio increased after PH stress. Microscopic analysis demonstrated that exposure to PH resulted in distorted architecture of the hepatic parenchyma cells with reduced cellularity in the fetus and offspring. Blood glucose and insulin levels were lower with enhanced insulin sensitivity and increased expression of hepatic insulin-signaling elements in the fetus. Furthermore, insulin resistance, impaired glucose homeostasis, and altered expression of insulin-signaling elements occurred in the offspring. Postnatal hypoxia increased hepatic lipid droplets and triglyceride in liver, whereas expressions of insulin-signaling elements were less in the offspring exposed to PH except glucose transporters 2. The results indicated that PH contributed to hepatocyte heteroplasia and metabolic changes that enhanced vulnerability for NAFLD in the offspring, probably via affecting insulin signaling pathway, including glucose transporters 2.

scholarly journals Dietary Fructose During the Suckling Period Increases Body Weight and Fatty Acid Uptake Into Skeletal Muscle in Adult Rats

Obesity ◽  
2008 ◽  
Vol 16 (8) ◽  
pp. 1755-1762 ◽  
Author(s):  
Minh Huynh ◽  
Joost J.J.P. Luiken ◽  
Will Coumans ◽  
Rhonda C. Bell
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Fatty Acid ◽  
Fatty Acid Uptake ◽  
Acid Uptake ◽  
Suckling Period ◽  
Adult Rats ◽  
Dietary Fructose

Lipid Metabolism and Liver Inflammation. I. Hepatic fatty acid uptake: possible role in steatosis

2006 ◽  
Vol 290 (2) ◽  
pp. G194-G198 ◽  
Author(s):  
Michael W. Bradbury
Keyword(s):  
Lipid Peroxidation ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Liver ◽  
Type Ii Diabetes ◽  
Fatty Acid Uptake ◽  
Health Concern ◽  
Acid Uptake ◽  
Public Health Concern ◽  
Nonalcoholic Fatty Liver

Hepatic steatosis is a growing public health concern. Nonalcoholic fatty liver is increasingly common in Western societies and may lead to steatohepatitis, fibrosis, and cirrhosis, possibly triggered by lipid peroxidation. The relation of fatty liver to obesity, type II diabetes, and/or metabolic syndrome is significant. One aspect these related disorders share is increased serum-free fatty acids, which may be taken up by hepatocytes. Uptake of fatty acids in excess of metabolic requirements will lead to storage as triglycerides, resulting in steatosis and providing substrate for lipid peroxidation. Fatty acid uptake may be crucial to understanding steatosis.

Differences in transport of fatty acids and expression of fatty acid transporting proteins in adipose tissue of obese black and white women

2006 ◽  
Vol 290 (1) ◽  
pp. E87-E91 ◽  
Author(s):  
Joseph F. Bower ◽  
Julianne M. Davis ◽  
Enhui Hao ◽  
Hisham A. Barakat
Keyword(s):  
Fatty Acids ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
African American Women ◽  
White Women ◽  
De Novo ◽  
Fatty Acid Uptake ◽  
Acid Uptake ◽  
Omental Adipose Tissue ◽  
Protein Levels

We have reported that the rate of de novo triglyceride (TG) synthesis by omental, but not subcutaneous, adipose tissue was higher in African-American women (AAW) than in Caucasian women (CAW). The purpose of this study was to explore the potential mechanisms underlying this increase. Toward that end, we determined the activities of key enzymes in the pathway of TG synthesis, the rates of uptake of fatty acids by adipocytes, mRNA and protein levels of the fatty acid-transporting proteins FAT/CD36 and FATP, and mRNA and protein levels of PPARγ in omental fat of AAW and CAW. The results showed 1) no difference in the activity of phosphofructokinase, glycerol-3-phosphate dehydrogenase, or diacylglycerol acyltransferase; 2) a higher rate of fatty acid uptake by adipocytes of the AAW; 3) an increase in the mRNA and protein levels of CD36 and FATP4 in the fat of the AAW; and 4) an increase in the mRNA and protein levels of PPARγ, which can stimulate the expression of CD36 and FATP. These results suggest that the increase in the transport of fatty acid, which is mediated by the overexpression of the transport proteins in the omental adipose tissue of the AAW, might contribute to the higher prevalence of obesity in AAW.

Mechanism of oleoylethanolamide on fatty acid uptake in small intestine after food intake and body weight reduction

2007 ◽  
Vol 292 (1) ◽  
pp. R235-R241 ◽  
Author(s):  
Yingkui Yang ◽  
Min Chen ◽  
Keith E. Georgeson ◽  
Carroll M. Harmon
Keyword(s):  
Body Weight ◽  
Small Intestine ◽  
Fatty Acid ◽  
Food Intake ◽  
Mrna Level ◽  
Fatty Acid Uptake ◽  
Peroxisome Proliferator ◽  
Acid Uptake

The increase in the prevalence of human obesity highlights the need to identify molecular and cellular mechanisms involved in control of feeding and energy balance. Oleoylethanolamide (OEA), an endogenous lipid produced primarily in the small intestine, has been identified to play an important role in the regulation of animal food intake and body weight. Previous studies indicated that OEA activates peroxisome proliferator-activated receptor-α, which is required to mediate the effects of appetite suppression, reduces blood lipid levels, and enhances peripheral fatty acid catabolism. However, the effect of OEA on enterocyte function is unclear. In this study, we have examined the effect of OEA on intestinal fatty acid uptake and FAT/CD36 expression in vivo and in vitro. We intraperitoneally administered OEA to rats and examined FAT/CD36 mRNA level and fatty acid uptake in enterocytes isolated from the proximal small intestine, as well as in adipocytes. Our results indicate that OEA treatment significantly increased FAT/CD36 mRNA expression in intestinal mucosa and isolated jejunal enterocytes. In addition, we also found that OEA treatment significantly increases fatty acid uptake in isolated enterocytes in vitro. These results suggest that in addition to appetite regulation, OEA may regulate body weight by altered peripheral lipid metabolism, including increased lipolysis in adipocytes and enhanced fatty acid uptake in enterocytes, both in conjunction with increased expression of FAT/CD36. This study may have important implications in understanding the mechanism of OEA in the regulation of fatty acid absorption in human physiological and pathophysiological conditions.

scholarly journals Sodium fluorocitrate having inhibitory effect on fatty acid uptake ameliorates high fat diet-induced non-alcoholic fatty liver disease in C57BL/6J mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Seung A. Hong ◽  
Ik-Rak Jung ◽  
Sung-E. Choi ◽  
Yoonjung Hwang ◽  
Soo-Jin Lee ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Fatty Acid Uptake ◽  
Acid Uptake ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

AbstractNon-alcoholic fatty liver disease (NAFLD) is excessive fat build-up in the liver without alcohol consumption and includes hepatic inflammation and damage. Excessive influx of fatty acids to liver from circulation is thought to be a pathogenic cause for the development of NAFLD. Thus, inhibition of fatty acid intake into hepatocyte would be a maneuver for protection from high fat diet (HFD)-induced NAFLD. This study was initiated to determine whether sodium fluorocitrate (SFC) as a fatty acid uptake inhibitor could prevent palmitate-induced lipotoxicity in hepatocytes and protect the mice from HFD-induced NAFLD. SFC significantly inhibited the cellular uptake of palmitate in HepG2 hepatocytes, and thus prevented palmitate-induced fat accumulation and death in these cells. Single treatment with SFC reduced fasting-induced hepatic steatosis in C57BL/6J mice. Concurrent treatment with SFC for 15 weeks in HFD-fed C57BL/6J mice prevented HFD-induced fat accumulation and stress/inflammatory signal activation in the liver. SFC restored HFD-induced increased levels of serum alanine aminotransferase and aspartate aminotransferases as hepatic injury markers in these mice. SFC treatment also improved HFD-induced hepatic insulin resistance, and thus ameliorated HFD-induced hyperglycemia. In conclusion, inhibition of fatty acid mobilization into liver through SFC treatment can be a strategy to protect from HFD-induced NAFLD.

scholarly journals Effect of Wakame and Carob Pod Snacks on Non-Alcoholic Fatty Liver Disease

Nutrients ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 86 ◽  
Author(s):  
Daniel Rico ◽  
Ana Belén Martin-Diana ◽  
Arrate Lasa ◽  
Leixuri Aguirre ◽  
Iñaki Milton-Laskibar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Fatty Acid ◽  
Fatty Liver ◽  
Acid Synthesis ◽  
Fatty Acid Uptake ◽  
Acid Oxidation ◽  
Acid Uptake ◽  
Adult Rats ◽  
Alcoholic Fatty Liver ◽  
Carob Pod

Snacks combining different functional ingredients could represent a useful therapeutic strategy against NAFLD. The present study aimed to analyze the effect of two snack formulations based on carob and wakame flour in the treatment for NAFLD in rats. For this purpose, metabolic syndrome was induced in 50 adult rats by a high-fat high-fructose diet over eight weeks. After this period, rats were fed either normal calorie diets supplemented or not with snack A (1/50 wakame/carob pod) and snack B (1/5 wakame/carob pod) for four additional weeks. After sacrifice, liver composition and serum parameters were analyzed. Different pathways of triacylglycerol metabolism in liver were studied including fatty acid oxidation, fatty acid synthesis, triglyceride assembly and release, fatty acid uptake and glucose uptake. Oxidative stress was also measured. Snack treatment, and mainly B snack, reduced liver triacylglycerol levels by increasing fat oxidation. Moreover, this snack reduced oxidative stress. Therefore, this snack formulation could represent an interesting tool useful for fatty liver treatment.

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