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

2017 ◽  
Vol 95 (1) ◽  
pp. 142-147 ◽  
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.

Experimental Hypercholesterolemia and Auditory Function in the Chinchilla

1982 ◽  
Vol 90 (6) ◽  
pp. 814-818 ◽  
Author(s):  
Tetsuo Morizono ◽  
Michael A. Sikora
Keyword(s):  
Differential Susceptibility ◽  
Control Group ◽  
High Cholesterol Diet ◽  
Auditory Function ◽  
Cholesterol Levels ◽  
Auditory Dysfunction ◽  
Experimental Hypercholesterolemia ◽  
Susceptibility To Noise ◽  
The Relationship ◽  
Harmful Effects

Possible harmful effects of a high-cholesterol diet on auditory function were suggested by our previous work in rabbits, in which evoked potentials were measured from a chronic electrode inserted into the inferior colliculus. However, serum cholesterol levels in those rabbits tended to be extraordinarily high, ie, more than 1,500 mg/dL. Chinchillas were used in the present work as an animal model to study the relationship between hypercholesterolemia and auditory dysfunction. One percent cholesterol in standard Chinchow was fed to chinchillas for three months. The experimental groups showed a high mean cholesterol level of 437 ± 394 mg/dL (N = 9). Isopotential curve of the cochlear microphonics, threshold of action potentials (AP), and endocochlear DC potential did not differ from those in the control group. When moderately intense sound (12 kHz, 95 dB SPL) was given for ten minutes, however, the reduction in AP threshold was significantly greater (P=.036) in the cholesterol group. It is postulated that hypercholesterolemia may be one of the factors involved in differential susceptibility to noise.

Abstract 130: Hypercholesterolemia Suppresses Carotid Artery Endothelial NOS3 Expression via Epigenetic Mechanisms

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Alex Sotolongo ◽  
Yi-Zhou Jiang ◽  
John Karanian ◽  
William Pritchard ◽  
Peter Davies
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Endothelial Cells ◽  
Dna Methyltransferase ◽  
Control Group ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
High Fat

Objective: One of the first clinically detectable changes in the vasculature during atherogenesis is the accumulation of cholesterol within the vessel wall. Hypercholesterolemia is characterized by dysfunctional endothelial-dependent vessel relaxation and impaired NOS3 function. Since DNA methylation at gene promoter regions strongly suppresses gene expression, we postulated that high-fat/high-cholesterol diet suppresses endothelial NOS3 through promoter DNA methylation. Methods: Domestic male pigs were fed control diet (CD) or isocaloric high fat and high cholesterol diet (HC; 12% fat and 1.5% cholesterol) for 2, 4, 8 or 12 weeks prior to tissue collection. Furthermore, to determine the effects of risk factor withdrawal, an additional group of swine received HC for 12 weeks and then CD for 8 weeks; a control group received HC continuously for 20 weeks. Endothelial cells were harvested from common carotid aorta. In parallel in vitro studies, cultured human aortic endothelial cells (HAEC) were treated with human LDL, GW3956 (LXR agonist) and RG108 (DNA methyltransferase [DNMT] inhibitor). In cells from both sources, DNA methylation at the NOS3 promoter was measured using methylation specific pyro sequencing, and endothelial gene expression was measured using RT PCR. Results: HC diet increased plasma cholesterol level from 75 mg/dl on CD to a plateau of about 540 mg/dl within 2 weeks. Endothelial NOS3 expression was significantly reduced (71±9 % of CD) after 4 weeks of HC, a level sustained at subsequent time points. Withdrawal of HC for 8 weeks did not recover NOS3 expression. After 12-week HC, the NOS3 promoter was hypermethylated. Withdrawal of HC did not reverse NOS3 promoter methylation. In vitro treatment of HAEC with human LDL (200 mg/dl total cholesterol) or GW3956 (5μM) suppressed NOS3 mRNA to 50% and 30% respectively, suggesting that LXR/RXR is involved in suppression of NOS3. Nitric oxide production was consistently suppressed by GW3959. Both could be reversed through inhibition of DNMTs by RG108. Conclusions: DNA methylation and LXR/RXR pathway can mediate the HC-suppression of endothelial NOS3. The study identifies novel pharmaceutical targets in treating endothelial dysfunction. Crosstalk between these pathways is under investigation.

scholarly journals Mechanisms of cholesterol-lowering effects of dietary insoluble fibres: relationships with intestinal and hepatic cholesterol parameters

2005 ◽  
Vol 94 (3) ◽  
pp. 331-337 ◽  
Author(s):  
Ariëtte M. van Bennekum ◽  
David V. Nguyen ◽  
Georg Schulthess ◽  
Helmut Hauser ◽  
Michael C. Phillips
Keyword(s):  
Bile Acid ◽  
Food Intake ◽  
Serum Cholesterol ◽  
Cholesterol Absorption ◽  
Cholesterol Homeostasis ◽  
Hepatic Cholesterol ◽  
Intestinal Cholesterol Absorption ◽  
Cholesterol Lowering ◽  
Dietary Fibres ◽  
Bile Acid Binding

Fibres with a range of abilities to perturb cholesterol homeostasis were used to investigate how the serum cholesterol-lowering effects of insoluble dietary fibres are related to parameters of intestinal cholesterol absorption and hepatic cholesterol homeostasis in mice. Cholestyramine, chitosan and cellulose were used as examples of fibres with high, intermediate and low bile acid-binding capacities, respectively. The serum cholesterol levels in a control group of mice fed a high fat/high cholesterol (HFHC) diet for 3 weeks increased about 2-fold to 4·3 mm and inclusion of any of these fibres at 7·5 % of the diet prevented this increase from occurring. In addition, the amount of cholesterol accumulated in hepatic stores due to the HFHC diet was reduced by treatment with these fibres. The three kinds of fibres showed similar hypocholesterolaemic activity; however, cholesterol depletion of liver tissue was greatest with cholestyramine. The mechanisms underlying the cholesterol-lowering effect of cholestyramine were (1) decreased cholesterol (food) intake, (2) decreased cholesterol absorption efficiency, and (3) increased faecal bile acid and cholesterol excretion. The latter effects can be attributed to the high bile acid-binding capacity of cholestyramine. In contrast, incorporation of chitosan or cellulose in the diet reduced cholesterol (food) intake, but did not affect either intestinal cholesterol absorption or faecal sterol output. The present study provides strong evidence that above all satiation and satiety effects underlie the cholesterol-lowering properties of insoluble dietary fibres with moderate or low bile acid-binding capabilities.

Relation of Serum Cholesterol to in vitro 7α-Dehydroxylation of Primary Bile Acids by Fecal Bacteria in Infants and Children

PEDIATRICS ◽  
1974 ◽  
Vol 54 (2) ◽  
pp. 222-228
Author(s):  
Paul Samuel ◽  
Arnold Schussheim ◽  
Sidney Lieberman ◽  
Eugene C. Don
Keyword(s):  
Bile Acids ◽  
Serum Cholesterol ◽  
Bacterial Flora ◽  
Progressive Increase ◽  
Infants And Children ◽  
Cholesterol Levels ◽  
Degrading Bacteria ◽  
Fresh Feces ◽  
Low Levels

Fresh feces from 104 infants and children (aged 3 days to 16 years) were homogenized and incubated with labeled cholic or chenodeoxycholic acid. After 2 and/or 24 hours' incubation, the percentage of converted (mostly 7α-dehydroxylated) primary bile acids was measured, and the degree of conversion was correlated with serum cholesterol levels. It was found that stool homogenates of patients with low levels of serum cholesterol (&lt; 160 mg/100 ml) converted labeled primary bile acids poorly or not at all, whereas in patients with higher serum cholesterol levels (&gt; l60 mg/100 ml) the conversion process was markedly increased. Thus, highly significant correlations were found between serum cholesterol levels and the capability of the fecal bacterial flora to convert both primary bile acids "in vitro." The possibility is proposed that in man the relatively rapid progressive increase of serum cholesterol level following birth may be related to the colonization of the intestinal tract by 7α-dehydroxylating and/or bile acid degrading bacteria. It is suggested that the prevalence of these bacteria is subject to environmental effects, and it may be one of the important factors regulating cholesterol levels in man.

Abstract 65: Flavin Monoxygenase 3 (FMO3) is a Novel Regulator of Hepatic Cholesterol Metabolism and Transintestinal Cholesterol Efflux (TICE).

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Manya Warrier ◽  
Stepahie Marshall ◽  
Allison McDaniel ◽  
Martha Wilson ◽  
Amanda Brown ◽  
...  
Keyword(s):  
Cholesteryl Ester ◽  
Plasma Levels ◽  
Cholesterol Efflux ◽  
Cholesterol Metabolism ◽  
Transcriptional Profiling ◽  
Dietary Cholesterol ◽  
High Cholesterol Diet ◽  
Hepatic Cholesterol ◽  
Hepatic Expression ◽  
Cholesterol Levels

Recent studies have revealed a novel route for cholesterol disposal through intestine known as transintestinal cholesterol efflux (TICE) that significantly contributes to fecal neutral sterol loss. This pathway is an integral part of reverse cholesterol transport (RCT), yet major mechanisms regulating TICE are not well understood. Using an unbiased transcriptional profiling approach in mouse models of augmented TICE, we found that hepatic expression of the enzyme Flavin monoxygenase 3 (FMO3) was dramatically repressed. At the same time we identified this enzyme through transcriptional profiling, it was reported that plasma levels of its product trimethylamineoxide (TMAO) are highly predictive of atheroslcerosis in humans, and TMAO is proatherogenic in mice. To further understand FMO3’s role as a regulator of cholesterol metabolism we used antisense oligonucleotides (ASO) to knockdown FMO3 expression in mouse liver in C57BL/6 mice fed either low (0.02%) or high (0.2%) levels of dietary cholesterol. As expected, FMO3 knockdown (>90% knockdown in the liver) increased the TMA/TMAO ratio in plasma more than 3-fold. Interestingly, knockdown of FMO biliary cholesterol levels were reduced by 60%, whereas fecal cholesterol loss was quite normal in FMO3 ASO treated mice fed a high cholesterol diet, which phenocopies a previously described mouse model where TICE predominates (NPC1L1-liver transgenic mice). ASO-mediated knockdown of FMO3 also unexpectedly reduced hepatic cholesteryl ester (CE) storage by 70% in mice fed 0.2% cholesterol. In parallel, knockdown of FMO3 reduces plasma VLDL cholesterol levels and the secretion rate of VLDL cholesteryl ester, but not triacylglycerol in cholesterol fed mice. FMO3 knockdown also reduced the hepatic expression of several liver X receptor (LXR) target genes, while increasing expression of genes involved in cholesterol synthesis. Collectively, these studies have identified FMO3 as a novel regulator of hepatic cholesterol metabolism and TICE. Given that plasma levels of FMO3’s product (TMAO) are strongly associated with atherosclerosis development in humans, and production of TMAO promotes atherosclerosis in mice, these studies have important implications for future cardiovascular drug discovery.

scholarly journals Intestine-Specific Overexpression of LDLR Enhances Cholesterol Excretion and Induces Metabolic Changes in Male Mice

Endocrinology ◽  
2018 ◽  
Vol 160 (4) ◽  
pp. 744-758 ◽  
Author(s):  
Luca Meoli ◽  
Danny Ben-Zvi ◽  
Courtney Panciotti ◽  
Stephanie Kvas ◽  
Palmenia Pizarro ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cholesterol Metabolism ◽  
Treatment Options ◽  
Density Lipoprotein ◽  
Cholesterol Absorption ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Metabolic Effects ◽  
Cholesterol Levels ◽  
Cholesterol Excretion

Abstract Roux-en-Y gastric bypass (RYGB) surgery is one of the most effective treatment options for severe obesity and related comorbidities, including hyperlipidemia, a well-established risk factor of cardiovascular diseases. Elucidating the molecular mechanisms underlying the beneficial effects of RYGB may facilitate development of equally effective, but less invasive, treatments. Recent studies have revealed that RYGB increases low-density lipoprotein receptor (LDLR) expression in the intestine of rodents. Therefore, in this study we first examined the effects of RYGB on intestinal cholesterol metabolism in human patients, and we show that they also exhibit profound changes and increased LDLR expression. We then hypothesized that the upregulation of intestinal LDLR may be sufficient to decrease circulating cholesterol levels. To this end, we generated and studied mice that overexpress human LDLR specifically in the intestine. This perturbation significantly affected intestinal metabolism, augmented fecal cholesterol excretion, and induced a reciprocal suppression of the machinery related to luminal cholesterol absorption and bile acid synthesis. Circulating cholesterol levels were significantly decreased and, remarkably, several other metabolic effects were similar to those observed in RYGB-treated rodents and patients, including improved glucose metabolism. These data highlight the importance of intestinal cholesterol metabolism for the beneficial metabolic effects of RYGB and for the treatment of hyperlipidemia.

Effect of three different dihydroxy bile acids on intestinal cholesterol absorption in normal volunteers

1984 ◽  
Vol 87 (1) ◽  
pp. 144-149 ◽  
Author(s):  
Ottmar Leiss ◽  
Klaus von Bergmann ◽  
Ursula Streicher ◽  
Heribert Strotkoetter
Keyword(s):  
Bile Acids ◽  
Cholesterol Absorption ◽  
Intestinal Cholesterol Absorption ◽  
Normal Volunteers

scholarly journals Effects of dietary polychlorinated biphenyls on cholesterol catabolism in rats

1990 ◽  
Vol 64 (1) ◽  
pp. 161-169 ◽  
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.

scholarly journals Effect of esterified 4-desmethylsterols and -stanols or 4,4′-dimethylsterols on cholesterol and bile acid metabolism in hamsters

2002 ◽  
Vol 87 (3) ◽  
pp. 227-237 ◽  
Author(s):  
Elke A. Trautwein ◽  
Claudia Schulz ◽  
Dörte Rieckhoff ◽  
Angelika Kunath-Rau ◽  
Helmut F. Erbersdobler ◽  
...  
Keyword(s):  
Bile Acid ◽  
Acid Metabolism ◽  
Ldl Cholesterol ◽  
Cholesterol Absorption ◽  
Bile Acid Metabolism ◽  
Acid Excretion ◽  
Hepatic Cholesterol ◽  
Intestinal Cholesterol Absorption ◽  
Cholesterol Lowering ◽  
Esterified Sterols

4-Desmethylsterols and -stanols reduce plasma total cholesterol (TC) and LDL cholesterol by inhibition of intestinal cholesterol absorption, while the cholesterol-lowering potential of 4,4′-dimethylsterols is less well defined. The present study aimed to compare the effects of 4-desmethylsterols, -stanols, and 4,4′-dimethylsterols on plasma and hepatic cholesterol, sterol excretion and bile acid metabolism. Male golden Syrian hamsters were fed diets containing 13 g/100 g fat, 0·08 g/100 g cholesterol and 0 (control), 0·24 or 0·48 % (w/w) esterified 4-desmethylsterols (sterols) and esterified hydrogenated 4-desmethylsterols (stanols) from common vegetable oils or esterified 4,4′-dimethylsterols from rice bran oil for 5 weeks. Sterol and stanol esters at the dose of 0·24 % were equally effective and significantly (P<0·05) lowered TC by 15 %, while 0·24 % 4,4-dimethylsterols reduced TC by 10 %. Liver total and esterified cholesterol concentrations were significantly (P<0·05) lowered by 40, 22, 43 and 31 % in hamsters fed 0·48 % sterols, 0·24 % stanols, 0·48 % stanols or 0·48 % dimethylsterols, respectively. Daily faecal bile acid excretion and hepatic cholesterol 7α-hydroxylase activity were not altered, indicating that sterols, stanols and dimethylsterols had no effect on the intestinal re-absorption of bile acids or on hepatic bile acid synthesis. Daily excretion of cholesterol was significantly higher in hamsters fed esterified sterols and stanols, but was only slightly increased in those fed dimethylsterols. The results indicate that esterified sterols and stanols were equally effective in lowering plasma TC and LDL cholesterol, while dimethylsterol esters caused a weaker cholesterol-lowering effect. Sterols and stanols achieve their cholesterol-lowering effect by stimulating faecal cholesterol excretion through inhibiting intestinal cholesterol absorption, but do not affect bile acid excretion. Other mechanisms need to be considered to explain the effect on plasma and hepatic cholesterol of dimethylsterols.

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