scholarly journals Lithogenic diet and gallstone formation in mice: integrated response of activities of regulatory enzymes in hepatic cholesterol metabolism

1996 ◽  
Vol 76 (5) ◽  
pp. 765-772 ◽  
Author(s):  
Eva Reihnér ◽  
Dagny Ståhlberg
Keyword(s):  
Bile Acids ◽  
Cholic Acid ◽  
Cholesterol Metabolism ◽  
Gallstone Formation ◽  
Hepatic Cholesterol ◽  
Defence Mechanisms ◽  
Cholesterol Acyl Transferase ◽  
Lithogenic Diet ◽  
Acat Activity ◽  
Integrated Response

Supersaturation of bile with cholesterol is a prerequisite of the development of gallstones. With the intention to study the integrated response of enzymes regulating hepatic cholesterol metabolism during gallstone formation we used an established model for the induction of cholesterol gallstone disease in mice. Ten mice were fed on a lithogenic diet containing 10 g cholesterol/kg and 5 g cholic acid/kg for 8 weeks and were compared with ten mice fed on a standard pellet diet. Cholesterol crystals or gallstones developed in 90% of gallbladders in treated mice. The lithogenic diet had an inhibitory effect on the rate-limiting enzyme of cholesterol biosynthesis, hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC1.1.1.88) activity, 39·6 (SEM 2·8)v. 171·0 (SEM 47·3) pmol/min per mg protein. Cholesterol 7α-hydroxylase (EC1.14.13.17) activity, regulating bile acid synthesis, was decreased by 80%, and this was assumed to be due to cholic acid in the diet. The cholesterol-enriched diet also induced a tenfold increase in cholesterol esterification rate in the liver, i.e. acyl-CoA: cholesterol acyl transferase (ACAT;EC2.3.1.26) activity. The total, as well as esterified, cholesterol contents of liver homogenates were significantly higher in cholesterol- and cholic acid-treated mice and correlated well with the ACAT activity (rs0·72 (P < 0·005), and rs0·68 (P < 0·01) respectively). A significantly higher ACAT activity was obtained in mice given cholesterol and cholic acid even when the enzyme was saturated with exogenous cholesterol, thus indicating an increased amount of the enzyme. The formation of gallstones is dependent on a delicate balance between lithogenic factors (increased absorption of cholesterol and reduced secretion of bile acids) and defence mechanisms (decreased synthesis and increased esterification of cholesterol). In the specific animal model studied here the two defence mechanisms cannot compensate for the increased absorption of cholesterol and the reduced synthesis of bile acids.

Altered hepatic cholesterol metabolism compensates for disruption of phosphatidylcholine transfer protein in mice

2005 ◽  
Vol 289 (3) ◽  
pp. G456-G461 ◽  
Author(s):  
Michele K. Wu ◽  
David E. Cohen
Keyword(s):  
Cholesterol Metabolism ◽  
Hepatic Cholesterol ◽  
Wild Type ◽  
Unesterified Cholesterol ◽  
Hydroxylase Activity ◽  
Lithogenic Diet ◽  
Transfer Protein ◽  
Acat Activity ◽  
Coa Reductase ◽  
Phosphatidylcholine Transfer Protein

Phosphatidylcholine transfer protein (PC-TP) is a member of the steroidogenic acute regulatory transfer protein-related domain superfamily and is enriched in liver. To explore a role for PC-TP in hepatic cholesterol metabolism, Pctp −/− and wild-type C57BL/6J mice were fed a standard chow diet or a high-fat, high-cholesterol lithogenic diet. In chow-fed Pctp−/− mice, acyl CoA:cholesterol acyltransferase (Acat) activity was markedly increased, 3-hydroxy-3-methylglutaryl-CoA reductase activity was unchanged, and cholesterol 7α-hydroxylase activity was reduced. Consistent with increased Acat activity, esterified cholesterol concentrations in livers of Pctp−/− mice were increased, whereas unesterified cholesterol concentrations were reduced. Hepatic phospholipid concentrations were also decreased in the absence of PC-TP and consequently, unesterified cholesterol-to-phospholipid ratios in liver remained unchanged. The lithogenic diet downregulated 3-hydroxy-3-methylglutaryl-CoA reductase in wild-type and Pctp−/− mice, whereas Acat was increased only in wild-type mice. In response to the lithogenic diet, a greater reduction in cholesterol 7α-hydroxylase activity in Pctp−/− mice could be attributed to increased size and hydrophobicity of the bile salt pool. Despite higher hepatic phospholipid concentrations, the unesterified cholesterol-to-phospholipid ratio increased. The lack of Acat upregulation suggests that, in the setting of the dietary challenge, the capacity for esterification to defend against hepatic accumulation of unesterified cholesterol was exceeded in the absence of PC-TP expression. We speculate that regulation of cholesterol homeostasis is a physiological function of PC-TP in liver, which can be overcome with a cholesterol-rich lithogenic diet.

Niemann-Pick C2 Protein Expression Regulates Lithogenic Diet-Induced Gallstone Formation and Dietary Cholesterol Metabolism in Mice

Lipids ◽  
2011 ◽  
Vol 47 (1) ◽  
pp. 13-25 ◽  
Author(s):  
Elisa Balboa ◽  
Gabriela Morales ◽  
Paula Aylwin ◽  
Gonzalo Carrasco ◽  
Ludwig Amigo ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cholesterol Metabolism ◽  
Dietary Cholesterol ◽  
Gallstone Formation ◽  
Lithogenic Diet ◽  
Niemann Pick

Influence of Deoxycholic Acid Feeding on the Elimination of Cholesterol in Normolipaemic Subjects

1974 ◽  
Vol 47 (5) ◽  
pp. 425-433
Author(s):  
K. Einarsson ◽  
K. Hellström ◽  
M. Kallner
Keyword(s):  
Bile Acid ◽  
Total Synthesis ◽  
Bile Acids ◽  
Cholic Acid ◽  
Chenodeoxycholic Acid ◽  
Deoxycholic Acid ◽  
Cholesterol Metabolism ◽  
Pool Size ◽  
Faecal Excretion ◽  
The Mean

1. The turnover of [24−14C]cholic acid and [3H]chenodeoxycholic acid and the faecal excretion of neutral steroids were studied in six normolipaemic subjects before and during the ingestion of 1.3–2.6 mmol (0.5–1.0 g) of deoxycholic acid/day. Before the second study the subjects had been fed deoxycholic acid for 2 weeks. 2. The administration of deoxycholic acid did not appear to influence cholesterol metabolism as judged by the absence of change in the serum concentrations and the overall transformation into primary bile acids and neutral faecal steroids. 3. During the deoxycholic acid feeding period the mean total synthesis of bile acids was reduced by about 30%, corresponding to approximately 0.25 mmol (100 mg)/day. In one subject the pool size and in another the synthesis of cholic acid remained unchanged; otherwise the cholic acid pool size and its rate of formation decreased in all subjects. No consistent effects were observed with regard to the turnover of chenodeoxycholic acid. 4. Assuming that the bile acid turnover is equivalent to bile acid excretion then the total amount of cholesterol eliminated as bile acids and neutral faecal steroids averaged between 1.6 and 1.8 mmol/day before and during the administration of deoxycholic acid.

Effects of bile acids on fecal excretion of end products of cholesterol metabolism

1960 ◽  
Vol 199 (4) ◽  
pp. 736-740 ◽  
Author(s):  
William T. Beher ◽  
Gizella D. Baker ◽  
William L. Anthony
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Cholic Acid ◽  
Cholesterol Metabolism ◽  
Fecal Excretion ◽  
Liver Cholesterol ◽  
Hyodeoxycholic Acid ◽  
End Products ◽  
Tissue Cholesterol ◽  
Steroid Excretion

The influence of bile acids on liver cholesterol mobilization and on the excretion of fecal end products of cholesterol-4-C14 metabolism was studied in mice. Tissue cholesterol was elevated by feeding a fat-free diet containing cholesterol or cholesterol-4-C14. The mice were then divided into three groups: cholic acid treated, control and hyodeoxycholic acid treated. Fecal collections were made at intervals for 20 days, and steroids extracted and fractionated. The quantity of the sterol fractions and the C14 activity of the sterol and bile acid fractions were determined. Regression of hepatic cholesterol was followed at the same time intervals. Cholic acid inhibited liver cholesterol mobilization, while hyodeoxycholic acid effected a rapid regression of liver cholesterol to subnormal levels. Cholic acid depressed total steroid excretion, the depression occurring in the bile acid fraction; while excretion of fecal sterols remained relatively unaltered. Hyodeoxycholic acid greatly increased total steroid excretion. The increase was in the sterol fraction (95%), while bile acid excretion was depressed. These data indicate that bile acids are important factors in determining the rate and route of cholesterol metabolism.

Fenugreek seeds reduce atherogenic diet-induced cholesterol gallstone formation in experimental mice

2009 ◽  
Vol 87 (11) ◽  
pp. 933-943 ◽  
Author(s):  
R.L.R. Reddy ◽  
K. Srinivasan
Keyword(s):  
Cholesterol Metabolism ◽  
Cholesterol Gallstone ◽  
Saturation Index ◽  
Gallstone Formation ◽  
Atherogenic Diet ◽  
High Cholesterol ◽  
Cholesterol Gallstones ◽  
Lithogenic Diet ◽  
Fenugreek Seed ◽  
Cholesterol Saturation Index

Dietary hypocholesterolemic adjuncts may have a beneficial role in the prevention and treatment of cholesterol gallstones (CGS). In this investigation, fenugreek (Trigonella foenum-graecum) seed was evaluated for this potential on the experimental induction of CGS in laboratory mice. CGS was induced by maintaining mice on a lithogenic diet (0.5% cholesterol) for 10 weeks. Fenugreek seed powder was included at 5%, 10%, and 15% of this lithogenic diet. Dietary fenugreek significantly lowered the incidence of CGS in these mice; the incidence was 63%, 40%, and 10% in the 5%, 10%, and 15% fenugreek groups, respectively, compared with 100% in the lithogenic control. The antilithogenic influence of fenugreek is attributable to its hypocholesterolemic effect. Serum cholesterol level was decreased by 26%–31% by dietary fenugreek, while hepatic cholesterol was lowered by 47%–64% in these high cholesterol-fed animals. Biliary cholesterol was 8.73–11.2 mmol/L as a result of dietary fenugreek, compared with 33.6 mmol/L in high-cholesterol feeding without fenugreek. Cholesterol saturation index in bile was reduced to 0.77–0.99 in fenugreek treatments compared with 2.57 in the high-cholesterol group. Thus, fenugreek seed offers health-beneficial antilithogenic potential by virtue of its favourable influence on cholesterol metabolism.

scholarly journals Endurance exercise training reduces gallstone development in mice

2008 ◽  
Vol 104 (3) ◽  
pp. 761-765 ◽  
Author(s):  
Kenneth R. Wilund ◽  
Laura A. Feeney ◽  
Emily J. Tomayko ◽  
Hae R. Chung ◽  
Kijin Kim
Keyword(s):  
Exercise Training ◽  
Bile Acids ◽  
Endurance Exercise ◽  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Gallstone Formation ◽  
Low Density ◽  
Endurance Exercise Training ◽  
Bile Cholesterol

Gallstones form when the ratio of bile cholesterol to bile acids and phospholipids is elevated, causing cholesterol to precipitate. Physical inactivity is hypothesized to increase gallstone development, but experimental evidence supporting this is lacking, and potential mechanisms for the antilithogenic effects of exercise have not been described. The purpose of this study was to examine the effect of endurance exercise training on gallstone formation and the expression of genes involved in bile cholesterol metabolism in gallstone-sensitive (C57L/J) mice. At 10 wk, 50 male mice began a lithogenic diet and were randomly assigned to an exercise-training (EX) or sedentary (SED) group ( n = 25 per group). Mice in the EX group ran on a treadmill at ∼15 m/min for 45 min/day for 12 wk. At the time animals were euthanized, gallstones were collected, pooled by group, and weighed. The weight of the gallstones was 2.5-fold greater in the SED mice compared with EX mice (143 vs. 57 mg, respectively). In the EX mice, hepatic expression of the low-density lipoprotein receptor (LDLr), scavenger receptor class B type 1 (SRB1), and sterol 27 hydroxylase (Cyp27) was increased by ∼2-fold ( P < 0.05 for each). The LDLr and SRB1 increase cholesterol clearance by low-density lipoprotein and high-density lipoprotein particles, respectively, while Cyp27 promotes the catabolism of cholesterol to bile acids. Taken together, these data indicate that exercise promotes changes in hepatic gene expression that increase cholesterol uptake by the liver but simultaneously increase the catabolism of cholesterol to bile acids, effectively reducing cholesterol saturation in the bile. This suggests a mechanism by which exercise improves cholesterol clearance from the circulation while simultaneously inhibiting gallstone formation.

Short term regulation of acyl CoA: Cholesterol acyl transferase (ACAT) activity in the regenerating and perinatal liver

1985 ◽  
Vol 5 (3) ◽  
pp. 237-242 ◽  
Author(s):  
G. Bruscalupi ◽  
S. Leoni ◽  
M. T. Mangiantini ◽  
F. Piemonte ◽  
S. Spagnuolo ◽  
...  
Keyword(s):  
Differential Sensitivity ◽  
Liver Development ◽  
Acyl Transferase ◽  
Regenerating Liver ◽  
Hepatic Cholesterol ◽  
Short Term ◽  
Cholesterol Acyl Transferase ◽  
Acat Activity ◽  
Stimulation Of

Acyl coenzyme A:cholesterol acyltransferase (ACAT), the enzyme catalyzing the hepatic cholesterol esterification could be involved in the modified availability of cholesterol detectable in proliferating systems. While no significant variations are detectable in the regenerating liver, the modified ACAT activity during liver development and its differential sensitivity to the in vitro stimulation of modulatory systems suggest an involvement of the enzyme in this proliferating process.

scholarly journals Circadian Rhythm Disruption Influenced Hepatic Lipid Metabolism, Gut Microbiota and Promoted Cholesterol Gallstone Formation in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Chuanqi He ◽  
Weiyi Shen ◽  
Chaobo Chen ◽  
Qihan Wang ◽  
Qifan Lu ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Lipid Metabolism ◽  
Bile Acid ◽  
Gut Microbiota ◽  
Cholesterol Metabolism ◽  
Gallstone Formation ◽  
Hepatic Lipid Metabolism ◽  
Hepatic Lipid ◽  
Lithogenic Diet ◽  
Circadian Expression

BackgroundHepatic lipid metabolism regulates biliary composition and influences the formation of cholesterol gallstones. The genes Hmgcr and Cyp7a1, which encode key liver enzymes, are regulated by circadian rhythm-related transcription factors. We aimed to investigate the effect of circadian rhythm disruption on hepatic cholesterol and bile acid metabolism and the incidence of cholesterol stone formation.MethodsAdult male C57BL/6J mice were fed either a lithogenic diet (LD) only during the sleep phase (time-restricted lithogenic diet feeding, TRF) or an LD ad libitum (non-time-restricted lithogenic diet feeding, nTRF) for 4 weeks. Food consumption, body mass gain, and the incidence of gallstones were assessed. Circulating metabolic parameters, lipid accumulation in the liver, the circadian expression of hepatic clock and metabolic genes, and the gut microbiota were analyzed.ResultsTRF caused a dysregulation of the circadian rhythm in the mice, characterized by significant differences in the circadian expression patterns of clock-related genes. In TRF mice, the circadian rhythms in the expression of genes involved in bile acid and cholesterol metabolism were disrupted, as was the circadian rhythm of the gut microbiota. These changes were associated with high biliary cholesterol content, which promoted gallstone formation in the TRF mice.ConclusionDisordered circadian rhythm is associated with abnormal hepatic bile acid and cholesterol metabolism in mice, which promotes gallstone formation.

scholarly journals Disruption of the Murine Protein Kinase Cβ Gene Promotes Gallstone Formation and Alters Biliary Lipid and Hepatic Cholesterol Metabolism

2011 ◽  
Vol 286 (26) ◽  
pp. 22795-22805 ◽  
Author(s):  
Wei Huang ◽  
Rishipal R. Bansode ◽  
Yan Xie ◽  
Leslie Rowland ◽  
Madhu Mehta ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cholesterol Metabolism ◽  
Gallstone Formation ◽  
Biliary Lipid ◽  
Hepatic Cholesterol
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