Modulating liver cholesterol metabolism by 3-Iodothyronamine

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. It is hypothesized to develop due to the dysfunction of two major proteins, amyloid-β (Aβ) and microtubule-associated protein, tau. Evidence supports the involvement of cholesterol changes in both the generation and deposition of Aβ. This study was performed to better understand the role of liver cholesterol and bile acid metabolism in the pathophysiology of AD. We used male and female wild-type control (C57BL/6J) mice to compare to two well-characterized amyloidosis models of AD, APP/PS1, and AppNL-G-F. Both conjugated and unconjugated primary and secondary bile acids were quantified using UPLC-MS/MS from livers of control and AD mice. We also measured cholesterol and its metabolites and identified changes in levels of proteins associated with bile acid synthesis and signaling. We observed sex differences in liver cholesterol levels accompanied by differences in levels of synthesis intermediates and conjugated and unconjugated liver primary bile acids in both APP/PS1 and AppNL-G-F mice when compared to controls. Our data revealed fundamental deficiencies in cholesterol metabolism and bile acid synthesis in the livers of two different AD mouse lines. These findings strengthen the involvement of liver metabolism in the pathophysiology of AD.

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Deleting myeloid IL-10 receptor signalling attenuates atherosclerosis in LDLR-/- mice by altering intestinal cholesterol fluxes

Thrombosis and Haemostasis ◽

10.1160/th16-01-0043 ◽

2016 ◽

Vol 116 (09) ◽

pp. 565-577 ◽

Cited By ~ 6

Author(s):

Gemma Brufau ◽

Marion J. J. Gijbels ◽

Ine M. J. Wolfs ◽

Saskia van der Velden ◽

Chantal C. H. Pöttgens ◽

...

Keyword(s):

Inflammatory Responses ◽

Cholesterol Metabolism ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Cholesterol Homeostasis ◽

Liver Cholesterol ◽

Specific Cell ◽

Low Density ◽

Atherosclerosis Development ◽

Deficient Mice

SummaryInflammatory responses and cholesterol homeostasis are interconnected in atherogenesis. Interleukin (IL)-10 is an important anti-inflammatory cytokine, known to suppress atherosclerosis development. However, the specific cell types responsible for the atheroprotective effects of IL-10 remain to be defined and knowledge on the actions of IL-10 in cholesterol homeostasis is scarce. Here we investigated the functional involvement of myeloid IL-10-mediated atheroprotection. To do so, bone marrow from IL-10 receptor 1 (IL-10R1) wild-type and myeloid IL-10R1-deficient mice was transplanted to lethally irradiated female LDLR-/- mice. Hereafter, mice were given a high cholesterol diet for 10 weeks after which atherosclerosis development and cholesterol metabolism were investigated. In vitro, myeloid IL-10R1 deficiency resulted in a pro-inflammatory macrophage phenotype. However, in vivo significantly reduced lesion size and severity was observed. This phenotype was associated with lower myeloid cell accumulation and more apoptosis in the lesions. Additionally, a profound reduction in plasma and liver cholesterol was observed upon myeloid IL-10R1 deficiency, which was reflected in plaque lipid content. This decreased hypercholesterolaemia was associated with lowered very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels, likely as a response to decreased intestinal cholesterol absorption. In addition, IL-10R1 deficient mice demonstrated substantially higher faecal sterol loss caused by increased non-biliary cholesterol efflux. The induction of this process was linked to impaired ACAT2-mediated esterification of liver and plasma cholesterol. Overall, myeloid cells do not contribute to IL-10-mediated atheroprotection. In addition, this study demonstrates a novel connection between IL-10-mediated inflammation and cholesterol homeostasis in atherosclerosis. These findings make us reconsider IL-10 as a beneficial influence on atherosclerosis.Supplementary Material to this article is available online at www.thrombosis-online.com.

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Impaired cholesterol metabolism in the mice model of cystic fibrosis. A vicious circle?

10.1101/2019.12.13.875336 ◽

2019 ◽

Author(s):

Felice Amato ◽

Alice Castaldo ◽

Giuseppe Castaldo ◽

Gustavo Cernera ◽

Gaetano Corso ◽

...

Keyword(s):

Cystic Fibrosis ◽

Cholesterol Metabolism ◽

Cholesterol Biosynthesis ◽

Cholesterol Absorption ◽

Vicious Circle ◽

Liver Cholesterol ◽

Mice Model ◽

Hepatic Expression ◽

Expression Of Genes ◽

Low Cholesterol

AbstractPatients with cystic fibrosis (CF) have low cholesterol absorption and, despite enhanced endogenous biosynthesis, low serum cholesterol. Herein, we investigated cholesterol metabolism in a murine CF model in comparison to wild type (WT) testing serum and liver surrogate biomarkers together with the hepatic expression of genes involved in cholesterol metabolism. CF mice display lower sterols absorption and increased endogenous biosynthesis. Subsequently, we evaluated the effects of a cholesterol-supplemented diet on cholesterol metabolism in CF and WT mice. The supplementation in WT mice determines biochemical changes similar to humans. Instead, CF mice with supplementation did not show significant changes, except for serum phytosterols (−50%), liver cholesterol (+35%) and TNFα mRNA expression, that resulted 5-fold higher than in CF without supplementation. However, liver cholesterol in CF mice with supplementation resulted significantly lower compared to WT supplemented mice. This study shows that in CF mice there is a vicious circle in which the altered bile salts synthesis/secretion contribute to reduce cholesterol digestion/absorption. The consequence is the enhanced liver cholesterol biosynthesis that accumulates in the cell triggering inflammation.

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Pinto Beans (Phaseolus vulgaris L.) Lower Non-HDL Cholesterol in Hamsters Fed a Diet Rich in Saturated Fat and Act on Genes Involved in Cholesterol Homeostasis

Journal of Nutrition ◽

10.1093/jn/nxz044 ◽

2019 ◽

Vol 149 (6) ◽

pp. 996-1003 ◽

Cited By ~ 2

Author(s):

An Tien Nguyen ◽

Sami Althwab ◽

Haowen Qiu ◽

Richard Zbasnik ◽

Carlos Urrea ◽

...

Keyword(s):

Fatty Acids ◽

Molecular Mechanisms ◽

Cholesterol Metabolism ◽

Saturated Fatty Acids ◽

Saturated Fat ◽

Density Lipoprotein ◽

Cholesterol Homeostasis ◽

Liver Cholesterol ◽

Intestinal Cholesterol Absorption ◽

Pinto Beans

ABSTRACT Background Pinto beans contain multiple active agents such as polyphenols, flavonoids, and saponins, and have been shown to lower cholesterol, but the mechanisms involved in this effect have not been explored. Objective This study was to investigate the changes in cholesterol metabolism in response to whole pinto beans (wPB) and their hulls (hPB) supplemented into a diet rich in saturated fat and the molecular mechanisms potentially responsible for these effects in hamsters. Methods Forty-four 9-wk-old male Golden Syrian hamsters were randomly assigned to 4 diet groups (n = 11), including a 5% (wt:wt) fat diet [normal-fat diet (NF)], a 15% (wt:wt) fat diet [diet rich in saturated fat (HSF), saturated fatty acids accounted for 70% of total fatty acids], or HSF supplemented with 5% (wt:wt) wPB or 0.5% (wt:wt) hPB for 4 wk. Plasma, liver, intestinal, and fecal samples were collected to evaluate multiple cholesterol markers and gene targets. Results The plasma non-high-density lipoprotein (non-HDL) concentration was significantly reduced in the wPB- and hPB-supplemented groups by 31.9 ± 3.5% and 53.6 ± 3.2%, respectively, compared with the HSF group (P < 0.01), to concentrations comparable with the NF group. The wPB-supplemented hamsters had significantly lower liver cholesterol (45.1%, P < 0.001) and higher fecal cholesterol concentrations (94.8%, P = 0.001) than those fed the HSF. The expressions of hepatic 3-hydroxy-3-methylglutaryl CoA reductase (Hmgcr) and small intestinal acyl-coenzyme A: cholesterol acyltransferase 2 (Acat2) were significantly decreased in animals administered wPB (by 89.1% and 63.8%, respectively) and hPB (by 72.9% and 47.7%, respectively) compared with their HSF-fed counterparts (P < 0.05). The wPB normalized the expression of Acat2 to the level of the NF group. Conclusion Pinto beans remediated high cholesterol induced by HSF in male hamsters by decreasing hepatic cholesterol synthesis and intestinal cholesterol absorption, effects which were partially exerted by the hulls.

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Dietary animal proteins and cholesterol metabolism in rabbits

British Journal Of Nutrition ◽

10.1079/bjn19900047 ◽

1990 ◽

Vol 64 (2) ◽

pp. 473-485 ◽

Cited By ~ 30

Author(s):

Maria R. Lovati ◽

Clive E. West ◽

Cesare R. Sirtori ◽

Anton C. Beynen

Keyword(s):

Bile Acid ◽

Whey Protein ◽

Serum Cholesterol ◽

Cholesterol Metabolism ◽

Soya Bean ◽

Liver Cholesterol ◽

Fish Protein ◽

High Background ◽

Neutral Steroid ◽

Bean Protein

The effect in rabbits of giving isonitrogenous purified diets containing casein, ovalbumin, fish protein, milk-whey protein and soya-bean protein were compared. The diets were balanced for cholesterol and for the amount and type of fat. When incorporated into low-cholesterol diets (0.8 g cholesterol/kg), casein, ovalbumin and soya-bean protein produced similar levels of serum cholesterol. With a high background of dietary cholesterol (1.5 g/kg), serum cholesterol concentrations increased with soya-bean protein, whey protein, casein and fish protein, in that order. Thus, the hypercholesterolaemic effect of casein in carefully balanced diets was only seen against a high-cholesterol background. The development of hypercholesterolaemia produced by giving fish protein was different from that produced by casein. First, less cholesterol accumulated in the very-low-density-lipoprotein fractions and more in the lipoproteins of higher density with fish protein than with casein. Second, fish protein, unlike casein, did not increase liver cholesterol. Third, transfer of rabbits from a diet containing soya-bean protein to one containing casein resulted in an immediate marked depression in neutral steroid and bile acid excretion in faeces. However, when rabbits were fed on the diet with fish protein after the diet with soya-bean protein, there was no significant depression in neutral steroid output and the depression in bile acid output was delayed. The present study suggests that different animal proteins cause hypercholesterolaemia by different mechanisms.

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Effect of cupric ions on serum and liver cholesterol metabolism

Lipids ◽

10.1007/bf02536442 ◽

1987 ◽

Vol 22 (12) ◽

pp. 1016-1019 ◽

Cited By ~ 8

Author(s):

Mitsuo Tanaka ◽

Toshihiro Iio ◽

Toshikazu Tabata

Keyword(s):

Cholesterol Metabolism ◽

Liver Cholesterol

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THE EFFECT OF DIETARY OILS AND FATTY ACIDS ON CHOLESTEROL METABOLISM IN THE RAT

Canadian Journal of Biochemistry and Physiology ◽

10.1139/y58-049 ◽

1958 ◽

Vol 36 (1) ◽

pp. 433-438 ◽

Cited By ~ 9

Author(s):

J. D. Wood ◽

B. B. Migicovsky

Keyword(s):

Fatty Acids ◽

Total Cholesterol ◽

Lauric Acid ◽

Opposite Effect ◽

Cholesterol Metabolism ◽

Coconut Oil ◽

Liver Cholesterol ◽

Dietary Oils ◽

Liver Homogenates

Rats were fed diets containing 20% oils and 9% fatty acids and the effect of these compounds on cholesterol metabolism was studied. Unsaturated oils and fatty acids increased total cholesterol in the liver and stimulated the incorporation of C14-acetate into cholesterol both in vivo and in liver homogenates. Saturated material such as coconut oil and lauric acid had the opposite effect with respect to amount of liver cholesterol and to in vivo incorporation. The saturated material had no significant effect on synthesis in homogenates. The effect of oils in the diet was rapid, the stimulating effect of rapeseed oils being observed after the rats had been placed on the diet for as short a period as 3 days.

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THE EFFECT OF DIETARY OILS AND FATTY ACIDS ON CHOLESTEROL METABOLISM IN THE RAT

Canadian Journal of Biochemistry and Physiology ◽

10.1139/o58-049 ◽

1958 ◽

Vol 36 (4) ◽

pp. 433-438 ◽

Cited By ~ 20

Author(s):

J. D. Wood ◽

B. B. Migicovsky

Keyword(s):

Fatty Acids ◽

Total Cholesterol ◽

Lauric Acid ◽

Opposite Effect ◽

Cholesterol Metabolism ◽

Coconut Oil ◽

Liver Cholesterol ◽

Dietary Oils ◽

Liver Homogenates

Rats were fed diets containing 20% oils and 9% fatty acids and the effect of these compounds on cholesterol metabolism was studied. Unsaturated oils and fatty acids increased total cholesterol in the liver and stimulated the incorporation of C14-acetate into cholesterol both in vivo and in liver homogenates. Saturated material such as coconut oil and lauric acid had the opposite effect with respect to amount of liver cholesterol and to in vivo incorporation. The saturated material had no significant effect on synthesis in homogenates. The effect of oils in the diet was rapid, the stimulating effect of rapeseed oils being observed after the rats had been placed on the diet for as short a period as 3 days.

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Effect of ginseng saponins on cholesterol metabolism. I. The level and the synthesis of serum and liver cholesterol in rats treated with ginsenosides.

Chemical and Pharmaceutical Bulletin ◽

10.1248/cpb.23.1009 ◽

1975 ◽

Vol 23 (5) ◽

pp. 1009-1016 ◽

Cited By ~ 21

Author(s):

KOTAKA SAKAKIBARA ◽

YASUO SHIBATA ◽

TOKUHIKO HIGASHI ◽

SYUICHI SANADA ◽

JUNZO SHOJI

Keyword(s):

Cholesterol Metabolism ◽

Liver Cholesterol

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Effect of dietary methionine on plasma and liver cholesterol concentrations in rats and expression of hepatic genes involved in cholesterol metabolism

British Journal Of Nutrition ◽

10.1079/bjn20061729 ◽

2006 ◽

Vol 95 (5) ◽

pp. 879-888 ◽

Cited By ~ 40

Author(s):

F. Hirche ◽

A. Schröder ◽

B. Knoth ◽

G. I. Stangl ◽

K. Eder

Keyword(s):

Cholesterol Synthesis ◽

Cholesterol Metabolism ◽

Plasma Cholesterol ◽

Rat Hepatocytes ◽

Liver Cholesterol ◽

Isolated Rat Hepatocytes ◽

Hepatic Expression ◽

Hepatic Cholesterol Synthesis ◽

Methionine Concentration ◽

Ldl Uptake

Methionine has been shown to increase plasma cholesterol in animals. In the present study, mechanisms were investigated by which methionine could alter cholesterol metabolism. In the first experiment, forty growing rats were fed four casein-based diets differing in methionine content (2·6, 3·5, 4·5 or 6·0 g/kg) for 14 d. In the second experiment, isolated rat hepatocytes were incubated in media supplemented with 50, 100 or 200 μmol/l methionine. Dietary methionine tended to increase plasma homocysteine concentrations in the rats (P=0·058). A weak positive correlation between circulating homocysteine and plasma cholesterol was observed (R20·27, P<0·01). Rats fed 3·5 g/kg or more of methionine had higher concentrations of cholesterol in their plasma, in lipoprotein fractions of density (ρ kg/l) 1·006 < ρ<, 1·063 and ρ>. 1·063, and in liver than rats fed 2·6 g/kg methionine. Rats fed 6 g/kg methionine had a higher hepatic expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase and cholesterol-7α-hydroxylase than rats fed less methionine. The phosphatidylcholine:phosphatidylethanolamine ratio in rat liver increased with rising dietary methionine concentration; the relative mRNA concentrations of phosphatidylethanolamine N-methyltransferase and cystathionine β-synthase remained unaffected. Hepatocytes incubated in media supplemented with 100 or 200 μmol/l methionine had a higher cholesterol synthesis than hepatocytes incubated in a medium supplemented with 50μmol/l methionine; the LDL uptake in hepatocytes was independent of the methionine concentration of the medium. In conclusion, the present study suggests that dietary methionine induces hypercholesterolaemia at least in part via an enhanced hepatic cholesterol synthesis.

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