scholarly journals IL-13-driven alterations in hepatic cholesterol handling contributes to hypercholesterolemia in a rat model of minimal change disease

2020 ◽  
Vol 134 (2) ◽  
pp. 225-237 ◽  
Author(s):  
Lauretta D. Low ◽  
Liangjian Lu ◽  
Chang-Yien Chan ◽  
Jinmiao Chen ◽  
Henry H. Yang ◽  
...  
Keyword(s):  
Total Cholesterol ◽  
Rat Model ◽  
Minimal Change Disease ◽  
Cholesterol Metabolism ◽  
Rat Hepatocytes ◽  
Minimal Change ◽  
Luciferase Assay ◽  
Hepatic Cholesterol ◽  
Plasma Total Cholesterol ◽  
Rat Primary Hepatocytes

Abstract Circulating factors have been implicated in the pathogenesis of minimal change disease (MCD), and may have direct effects on cholesterol metabolism. This study investigated the pathogenesis of hypercholesterolemia in an IL-13 overexpression rat model of MCD prior to the onset of proteinuria, so as to establish the direct contribution of IL-13, especially with regard to hepatic cholesterol handling. In this model of MCD, the temporal relationship between hypercholesterolemia and proteinuria was first identified. Plasma proprotein convertase subtilisin/kexin type 9 (Pcsk9) and liver ATP-binding cassette sub-family G member 5 (Abcg5) were measured using ELISA. Liver Ldlr and liver X receptor alpha (Lxra) were quantified with Western blot. Abcg5-mediated cholesterol efflux in IL-13-stimulated rat primary hepatocytes was measured using taurocholate as cholesterol acceptor. The role of Lxra was validated using a luciferase assay in Lxre-luciferase-transfected IL-13-stimulated hepatocytes. IL-13-transfected rats developed hypercholesterolemia prior to proteinuria, with 35% of rats hypercholesterolemic but only 11% proteinuric by Day 20 (P = 0.04). These pre-proteinuric hypercholesterolemic rats showed elevations in total and LDL-cholesterol, but not hypertriglyceridemia or hepatic steatosis. The hypercholesterolemia was associated with increased hepatic Pcsk9 synthesis and enhanced circulating Pcsk9 levels, which correlated strongly with plasma total cholesterol (r = 0.73, P<0.001). The hypercholesterolemia was also contributed by decreased Abcg5 expression and activity, due to reduced Lxra expression. Lxra expression correlated with plasma total cholesterol levels (r = −0.52, P = 0.01), and overexpression of pLxra in rat hepatocytes abrogated the IL-13-mediated down-regulation of Lxre-driven gene expression. In conclusion, we have shown that IL-13 induced changes in hepatic cholesterol handling in a cytokine-induced rat model of MCD, resulting in hypercholesterolemia which can precede the onset of proteinuria.

Gender effects of tall oil versus soybean phytosterols as cholesterol-lowering agents in hamsters

1998 ◽  
Vol 76 (7-8) ◽  
pp. 780-787 ◽  
Author(s):  
Fady Y Ntanios ◽  
Diane E MacDougall ◽  
Peter JH Jones
Keyword(s):  
Total Cholesterol ◽  
Cholesterol Level ◽  
Cholesterol Metabolism ◽  
Total Cholesterol Level ◽  
Cholesterol Biosynthesis ◽  
Gender Effects ◽  
Plasma Total Cholesterol ◽  
Tall Oil ◽  
Cholesterol Lowering ◽  
Plasma Total Cholesterol Level

To examine the effect of gender on the mechanisms of action of phytosterols extracted from tall oil (TO) and soybean (SB) on cholesterol and phytosterol metabolism, male and female hamsters were fed cholesterol-enriched diets containing 0.5 or 1% (w/w) TO or SB phytosterols for 90 days. Plasma lipoprotein cholesterol profile and tissue phytosterol and cholesterol biosynthesis levels were determined. Mean plasma total-cholesterol level in females fed 1% (w/w) SB was reduced (p < 0.05) by 44%, while in males it was lowered (p < 0.05) by 25% compared with their respective controls. Moreover, mean plasma total-cholesterol level was reduced (p < 0.05) in male hamsters by -31% and female hamsters by -32% when fed 1% (w/w) TO. Cholesterol biosynthesis was higher (p < 0.05) by twofold in groups fed TO at 0.5 and 1% (w/w) concentrations, compared with SB. Hamsters fed TO at 0.5 and 1% (w/w) levels also had higher (p < 0.05) hepatic and enterocytic campesterol contents than SB-fed animals. These findings demonstrate gender differences in cholesterol metabolism in TO- and SB-fed hamsters. The results suggest that TO, conversely to SB phytosterol, is a more effective cholesterol-lowering agent in male, but not as much in female, hamsters, over a feeding period of 90 days.Key words: phytosterols, cholesterol, sitosterol, sitostanol, gender, hamster.

scholarly journals Two Weeks Of Western Diet Disrupts Liver Molecular Markers Of Cholesterol Metabolism In Rat

2020 ◽  
Author(s):  
Roxane St-Amand ◽  
Emilienne T. Ngo Sock ◽  
Samantha Quinn ◽  
Jean-Marc Lavoie ◽  
David H. St-Pierre
Keyword(s):  
Total Cholesterol ◽  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Plasma Total Cholesterol ◽  
Cholesterol Levels ◽  
Density Lipoprotein Receptor ◽  
Element Binding Protein

Abstract Background: The present study was designed to test the hypothesis that in the liver, excessive fat accumulation impairs cholesterol metabolism mainly by altering the low-density lipoprotein-receptor (LDL-R) pathway. Method: Young male Wistar rats were fed standard (SD), high fat (HFD; 60% kcal) or Western (WD; 40% fat + 35% sucrose (17.5% fructose)) diets for 2 or 6 weeks. Results: Weight gain (~ 40g) was observed only following 6 weeks of the obesogenic diets (P < 0.01). Compared to the 2-week treatment, obesogenic diets tripled fat pad weight (~ 20 vs 7 g) after 6 weeks. Hepatic triglyceride (TG) levels were greater in response to both the WD and HFD compared to the SD (P < 0.01) at 2 and 6 weeks and their concentrations were greater (P < 0.05) in WD than HFD at 2 weeks. Plasma total cholesterol levels were higher (P < 0.05) in animals submitted to WD. After 2 and 6 weeks, liver expression of LDL-R, proprotein convertase subtilisin/kexin 9 (PCSKk9) and sterol regulatory element binding protein 2 (SREBP2), involved in LDL-cholesterol uptake, was lower in animals submitted to WD than in others treated with HFD or SD (P < 0.01). Similarly, low-density lipoprotein-receptor-related protein 1 (LRP1) and acyl-CoA cholesterol acyltransferase-2 (ACAT-2) mRNA levels were lower (P < 0.01) among WD compared to SD-fed rats. Expression of the gene coding the main regulator of endogenous cholesterol synthesis, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR) was reduced in response to WD compared to SD and HFD at 2 (P < 0.001) and 6 (P < 0.05) weeks. Being enriched in fructose, the WD strongly promoted the expression of carbohydrate-response element binding protein (ChREBP) and acetyl-CoA carboxylase (ACC), two key regulators of de novo lipogenesis. Conclusion: These results show that the WD promptly increased TG levels in the liver by potentiating fat storage. This impaired the pathway of hepatic cholesterol uptake via the LDL-R axis, promoting a rapid increase in plasma total cholesterol levels. These results indicate that liver fat content is a factor involved in the regulation of plasma cholesterol.

scholarly journals Two Weeks Of Western Diet Disrupts Liver Molecular Markers Of Cholesterol Metabolism In Rat

2020 ◽  
Author(s):  
Roxane St-Amand ◽  
Emilienne T. Ngo Sock ◽  
Samantha Quinn ◽  
Jean-Marc Lavoie ◽  
David H. St-Pierre
Keyword(s):  
Total Cholesterol ◽  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Plasma Total Cholesterol ◽  
Cholesterol Levels ◽  
Density Lipoprotein Receptor ◽  
Element Binding Protein

Abstract Background: The present study was designed to test the hypothesis that in the liver, excessive fat accumulation impairs cholesterol metabolism mainly by altering the low-density lipoprotein-receptor (LDL-R) pathway. Method: Young male Wistar rats were fed standard (SD), high fat (HFD; 60% kcal) or Western (WD; 40% fat + 35% sucrose (17.5% fructose)) diets for 2 or 6 weeks. Results: Weight gain (~ 40g) was observed only following 6 weeks of the obesogenic diets (P < 0.01). Compared to the 2-week treatment, obesogenic diets tripled fat pad weight (~ 20 vs 7 g) after 6 weeks. Hepatic triglyceride (TG) levels were greater in response to both the WD and HFD compared to the SD (P < 0.01) at 2 and 6 weeks and their concentrations were greater (P < 0.05) in WD than HFD at 2 weeks. Plasma total cholesterol levels were higher (P < 0.05) in animals submitted to WD. After 2 and 6 weeks, liver expression of LDL-R, proprotein convertase subtilisin/kexin 9 (PCSKk9) and sterol regulatory element binding protein protein 2 (SREBP2), involved in LDL-cholesterol uptake, was lower in animals submitted to WD than in others treated with HFD or SD (P < 0.01). Similarly, low-density lipoprotein-receptor-related protein 1 (LRP1) and acyl-CoA cholesterol acyltransferase-2 (ACAT-2) mRNA levels were lower (P < 0.01) among WD compared to SD-fed rats. Expression of the gene coding the main regulator of endogenous cholesterol synthesis, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR) was reduced in response to WD compared to SD and HFD at 2 (P < 0.001) and 6 (P < 0.05) weeks. Being enriched in fructose, the WD strongly promoted the expression of carbohydrate-response element binding protein (ChREBP) and acetyl-CoA carboxylase (ACC), two key regulators of de novo lipogenesis. Conclusion: These results show that the WD promptly increased TG levels in the liver by potentiating fat storage. This impaired the pathway of hepatic cholesterol uptake via the LDL-R axis, promoting a rapid increase in plasma total cholesterol levels. These results indicate that liver fat content is a factor involved in the regulation of plasma cholesterol.

Aspects of hepatic cholesterol metabolism in normal and dystrophic chicken embryos

1983 ◽  
Vol 61 (6) ◽  
pp. 378-386 ◽  
Author(s):  
D. E. Kuhn ◽  
D. M. Logan
Keyword(s):  
Total Cholesterol ◽  
Free Cholesterol ◽  
Cholesterol Metabolism ◽  
Cholesterol Content ◽  
Normal Embryo ◽  
Total Protein Content ◽  
Cholesterol Esters ◽  
Hepatic Cholesterol ◽  
Chicken Embryos ◽  
Dystrophic Chicken

Several aspects of hepatic cholesterol metabolism have been studied in normal and dystrophic chicken embryos (12 days in ovo). Dystrophic embryo livers weigh the same and have the same total protein content as their normal counterparts. However, the total cholesterol content of dystrophic embryo livers is significantly decreased compared with the content of normal embryo livers. This decrease in total cholesterol is due mainly to a large decrease in the amount of cholesterol esters, although the free cholesterol content is also decreased. The proportions of free cholesterol and cholesterol esters are 43 and 57%, respectively, in normal embryo livers, but this proportion is essentially reversed in dystrophic embryo livers (i.e., 56 and 44%). The decreased total cholesterol content of dystrophic embryo livers is not apparently due to a decrease in the rate of free cholesterol de novo biosynthesis or to a decrease in the rate of free cholesterol esterification. However, the decrease in cholesterol ester content may be due to an increase in the rate of its hydrolysis, as a result of increased levels of sterol ester hydrolase in dystrophic livers. These data are consistent with the proposal that membranes in dystrophic tissues are altered as a result of altered cholesterol metabolism and utilization.

scholarly journals Two Weeks Of Western Diet Disrupts Liver Molecular Markers Of Cholesterol Metabolism In Rat

2020 ◽  
Author(s):  
Roxane St-Amand ◽  
Emilienne T. Ngo Sock ◽  
Samantha Quinn ◽  
Jean-Marc Lavoie ◽  
David H. St-Pierre
Keyword(s):  
Total Cholesterol ◽  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Plasma Total Cholesterol ◽  
Cholesterol Levels ◽  
Density Lipoprotein Receptor ◽  
Element Binding Protein

Abstract Background: The present study was designed to test the hypothesis that in the liver, excessive fat accumulation impairs cholesterol metabolism mainly by altering the low-density lipoprotein-receptor (LDL-R) pathway. Method: Young male Wistar rats were fed standard (SD), high fat (HFD; 60% kcal) or Western (WD; 40% fat + 35% sucrose (17.5% fructose)) diets for 2 or 6 weeks. Results: Weight gain (~ 40g) was observed only following 6 weeks of the obesogenic diets (P < 0.01). Compared to the 2-week treatment, obesogenic diets tripled fat pad weight (~ 20 vs 7 g) after 6 weeks. Hepatic triglyceride (TG) levels were greater in response to both the WD and HFD compared to the SD (P < 0.01) at 2 and 6 weeks and their concentrations were greater (P < 0.05) in WD than HFD at 2 weeks. Plasma total cholesterol levels were higher (P < 0.05) in animals submitted to WD. After 2 and 6 weeks, liver expression of LDL-R, proprotein convertase subtilisin/kexin 9 (PCSKk9) and sterol regulatory element binding protein 2 (SREBP2), involved in LDL-cholesterol uptake, was lower in animals submitted to WD than in others treated with HFD or SD (P < 0.01). Similarly, low-density lipoprotein-receptor-related protein 1 (LRP1) and acyl-CoA cholesterol acyltransferase-2 (ACAT-2) mRNA levels were lower (P < 0.01) among WD compared to SD-fed rats. Expression of the gene coding the main regulator of endogenous cholesterol synthesis, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR) was reduced in response to WD compared to SD and HFD at 2 (P < 0.001) and 6 (P < 0.05) weeks. Being enriched in fructose, the WD strongly promoted the expression of carbohydrate-response element binding protein (ChREBP) and acetyl-CoA carboxylase (ACC), two key regulators of de novo lipogenesis. Conclusion: These results show that the WD promptly increased TG levels in the liver by potentiating fat storage. This impaired the pathway of hepatic cholesterol uptake via the LDL-R axis, promoting a rapid increase in plasma total cholesterol levels. These results indicate that liver fat content is a factor involved in the regulation of plasma cholesterol.

scholarly journals The hypocholesterolaemic effects of sitostanol in the guinea pig are in part related to changes in hepatic lipids and lipoprotein composition

2001 ◽  
Vol 85 (2) ◽  
pp. 165-172 ◽  
Author(s):  
Tripurasundari Ramjiganesh ◽  
Suheeta Roy ◽  
Jonathan C. McIntyre ◽  
Maria Luz Fernandez
Keyword(s):  
Total Cholesterol ◽  
Guinea Pigs ◽  
Corn Oil ◽  
Cholesterol Metabolism ◽  
Plasma Cholesterol ◽  
Dietary Cholesterol ◽  
Cholesterol Absorption ◽  
Negative Control ◽  
Control Group ◽  
Hepatic Cholesterol

To evaluate some of the mechanisms involved in the plasma cholesterol lowering of sitostanol (SI), male Hartley guinea pigs were fed diets containing cholesterol (0.25 g/100 g) and four doses of SI: either 0 (control), 0.75, 1.5 or 2.25 g/100 g. In addition a negative control (-C) group with dietary cholesterol (0.04 g/100 g) was included. Corn oil was used as the source of fat and the contribution of fat energy was 35 %. Plasma total cholesterol was 43, 49 and 53 % (P<0.0001) lower after SI intake compared to the control. Plasma LDL concentrations were 47, 53 and 61 % lower with increasing doses of SI. In addition, intake of SI resulted in 26–42 % lower hepatic total cholesterol. Hepatic esterified cholesterol and triacylglycerols were 32–60 % and 55–61 % lower after SI intake. SI intake resulted in favourable plasma and hepatic cholesterol concentrations similar to those in guinea pigs fed low levels of dietary cholesterol (-C). The LDL obtained from the control group had a higher number of molecules of free and esterified cholesterol than the SI groups. SI intake resulted in 69–71 % higher cholesterol excretion compared to the control. SI treatment enhanced the total faecal neutral sterol excretion by 54–58 % compared to control and by 70–76 % compared to the (-C) group. These results suggest that SI might have its hypocholesterolaemic effect by reducing cholesterol absorption, which results in lower concentration of cholesterol in liver. This reduction in hepatic cholesterol might possibly alter hepatic cholesterol metabolism and affect lipoprotein concentration and composition.

COMBINATION OF POTASSIUM PERCHLORATE AND PROPYLTHIOURACIL IN THE TREATMENT OF THYROTOXICOSIS

1968 ◽  
Vol 57 (4) ◽  
pp. 565-577 ◽  
Author(s):  
K. E. Røkke ◽  
J. H. Vogt
Keyword(s):  
Drug Therapy ◽  
Side Effects ◽  
Metabolic Rate ◽  
Total Cholesterol ◽  
Basal Metabolic Rate ◽  
Combined Therapy ◽  
Combined Treatment ◽  
Control Measures ◽  
Potassium Perchlorate ◽  
Plasma Total Cholesterol

ABSTRACT A report is given on 95 thyrotoxic patients treated with a combination of 400 mg propylthiouracil and 400 mg of potassium perchlorate. Perchlorate was stopped when a marked remission of symptoms was obtained, on an average after less than 7 weeks. Euthyroidism was found on an average after 7.2 weeks. The basal metabolic rate, PBI, plasma total cholesterol and weight showed a fairly rapid normalization. Thirteen of the 95 patients were given radio-iodine therapy shortly before drug therapy was started. The remaining 82 cases were grouped together with the 23 cases previously reported. Of the total of 105 cases, 96 became euthyroid on combined therapy. For the frequency of side-effects, the thirteen cases mentioned above were included, giving a total of 118 cases. Eight cases showed an increase in goitre size and 15 cases had other side-effects, of which three were granulocytopenia due to propylthiouracil. The possibility of a higher frequency of mainly minor side-effects on combined therapy has to be balanced against the seemingly rapid and reliable therapeutic effect. Combined treatment, perhaps with even smaller doses than reported here, can be recommended in selected cases of thyrotoxicosis where a shortening of the thyrotoxic state seems of importance, or possibly where difficulties due to iodine exposure may be anticipated, provided adequate control measures are taken.

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