Increased Plasma, Biliary, and Hepatic Cholesterol Precursors in Pigs with Ileal Autotransplantation-Induced Malabsorption of Cholesterol and Bile Acids

In α-naphthylisothiocyanate-treated mice, plasma phospholipid (PL) levels were elevated 10- and 13-fold at 48 and 168 h, respectively, whereas free cholesterol (FC) levels increased between 48 h (17-fold) and 168 h (39-fold). Nearly all of these lipids were localized to lipoprotein X-like particles in the low-density lipoprotein density range. The PL fatty acyl composition was indicative of biliary origin. Liver cholesterol and PL content were near normal at all time points. Hepatic hydroxymethylglutaryl CoA reductase activity was increased sixfold at 48 h, and cholesterol 7α-hydroxylase activity was decreased by ∼70% between 24 and 72 h. These findings suggest a metabolic basis for the appearance of abnormal plasma lipoproteins during cholestasis. Initially, PL and bile acids appear in plasma where they serve to promote the efflux of cholesterol from hepatic cell membranes. Hepatic cholesterol synthesis is then likely stimulated in the response to the depletion of hepatic cell membranes of cholesterol. We speculate that the enhanced synthesis of cholesterol and impaired conversion to bile acids, particularly during the early phase of drug response, contribute to the accumulation of FC in the plasma.

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Effects of dietary polychlorinated biphenyls on cholesterol catabolism in rats

British Journal Of Nutrition ◽

10.1079/bjn19900018 ◽

1990 ◽

Vol 64 (1) ◽

pp. 161-169 ◽

Cited By ~ 9

Author(s):

Satoshi Nagaoka ◽

Hitoshi Miyazaki ◽

Yoritaka Aoyama ◽

Akira Yoshida

Keyword(s):

Polychlorinated Biphenyls ◽

Bile Acids ◽

Cholesterol Synthesis ◽

Control Group ◽

Hepatic Cholesterol ◽

Biliary Cholesterol ◽

Faecal Excretion ◽

Hepatic Cholesterol Synthesis ◽

Total Bile Acids

Dietary polychlorinated biphenyls (PCBs) caused hypercholesterolaemia in rats. The concentration and output of biliary cholesterol was significantly lower than that of the control group. Biliary output of total bile acids was significantly decreased in rats given the PCB-supplemented diet. Faecal excretion of total steroids (sum of neutral steroids and acidic steroids) was not significantly changed in rats given the PCB-supplemented diet. The present results indicate that dietary PCBs cause hypercholesterolaemia without modifying the faecal total steroids excretion. These results suggest that PCBs produce hyper-cholesterolaemia accompanied by changes in biliary or faecal excretion of bile acids and neutral steroids in addition to an increase in hepatic cholesterol synthesis.

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Variations of hepatic cholesterol precursors during altered flows of endogenous and exogenous squalene in the rat

Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism ◽

10.1016/0005-2760(89)90141-0 ◽

1989 ◽

Vol 1001 (2) ◽

pp. 150-156 ◽

Cited By ~ 25

Author(s):

Timo E. Strandberg ◽

Reijo S. Tilvis ◽

Tatu A. Miettinen

Keyword(s):

Hepatic Cholesterol ◽

Cholesterol Precursors

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

British Journal Of Nutrition ◽

10.1079/bjn19960082 ◽

1996 ◽

Vol 76 (5) ◽

pp. 765-772 ◽

Cited By ~ 11

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.

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Uteroplacental Insufficiency Impairs Cholesterol Elimination in Adult Female Growth-Restricted Rat Offspring Fed a High-Fat Diet

Reproductive Sciences ◽

10.1177/1933719118811649 ◽

2018 ◽

Vol 26 (9) ◽

pp. 1173-1180 ◽

Cited By ~ 1

Author(s):

Erin K. Zinkhan ◽

Baifeng Yu ◽

Robert McKnight

Keyword(s):

Young Adult ◽

Bile Acids ◽

Adult Female ◽

High Fat Diet ◽

Female Rats ◽

Hepatic Cholesterol ◽

High Fat ◽

Hepatic Bile ◽

Artery Ligation ◽

Hepatic Bile Acids

Uteroplacental insufficiency (UPI) causes intrauterine growth restriction (IUGR) and increases the risk of hypercholesterolemia and cardiovascular disease, which are leading causes of morbidity and mortality worldwide. Little is known about the mechanism through which UPI increases cholesterol. Hepatic Cholesterol 7 alpha-hydroxylase (Cyp7a1) is the rate-limiting and most highly regulated step of cholesterol catabolism to bile acids. Cholesterol 7 alpha-hydroxylase is regulated by transcription factor liver X receptor α (Lxrα) and by microRNA-122. We previously showed that microRNA-122 inhibition of Cyp7a1 translation decreased cholesterol catabolism to bile acids in female IUGR rats at the time of weaning. We hypothesized that UPI would increase cholesterol and microRNA-122 and decrease Cyp7a1 protein and hepatic bile acids in young adult female IUGR rats. To test our hypothesis, we used a rat model of IUGR induced by bilateral uterine artery ligation. Both control and IUGR offspring were exposed to a maternal high-fat diet from before conception through lactation, and all offspring were weaned to a high-fat diet on postnatal day 21. At postnatal day 60, IUGR female rats had increased total and low-density lipoprotein serum cholesterol and hepatic cholesterol, decreased Lxrα and Cyp7a1 protein, and decreased hepatic bile acids. Hepatic microRNA-122 was not changed by UPI. Our findings suggest that UPI decreased cholesterol catabolism to bile acids in young adult female rats through a mechanism independent of microRNA-122.

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Lactoferrin interacts with bile acids and increases fecal cholesterol excretion in rats

Biochemistry and Cell Biology ◽

10.1139/bcb-2016-0052 ◽

2017 ◽

Vol 95 (1) ◽

pp. 142-147 ◽

Cited By ~ 9

Author(s):

Kanae Nakamura ◽

Satoru Morishita ◽

Tomoji Ono ◽

Michiaki Murakoshi ◽

Keikichi Sugiyama ◽

...

Keyword(s):

Bile Acids ◽

Cholesterol Absorption ◽

Control Group ◽

High Cholesterol Diet ◽

Hepatic Cholesterol ◽

Intestinal Cholesterol Absorption ◽

Cationic Protein ◽

Cholesterol Levels ◽

Cholesterol Excretion

Lactoferrin (LF) is a multifunctional cationic protein (pI 8.2–8.9) in mammalian milk. We previously reported that enteric-LF prevented hypercholesterolemia and atherosclerosis in a diet-induced atherosclerosis model using Microminipig, although the underlying mechanisms remain unclear. Because LF is assumed to electrostatically interact with bile acids to inhibit intestinal cholesterol absorption, LF could promote cholesterol excretion. In this study, we assessed the interaction between LF and taurocholate in vitro, and the effect of LF on cholesterol excretion in rats. The binding rate of taurocholate to LF was significantly higher than that to transferrin (pI 5.2–6.3). When rats were administered a high-cholesterol diet (HCD) containing 5% LF, LF was detected using ELISA in the upper small intestine from 7.5 to 60 min after the administration. Rats were fed one of the following diets: control, HCD, or HCD + 5% LF for 21 days. Fecal neutral steroids and hepatic cholesterol levels in the HCD group were significantly higher than those in the control group. The addition of LF to a HCD significantly increased fecal neutral steroids levels (22% increase, p < 0.05) and reduced hepatic cholesterol levels (17% decrease, p < 0.05). These parameters were inversely correlated (R = −0.63, p < 0.05). These results suggest that LF promotes cholesterol excretion via interactions with bile acids.

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