scholarly journals The Aromatase Knockout Mouse Presents with a Sexually Dimorphic Disruption to Cholesterol Homeostasis

Endocrinology ◽  
2003 ◽  
Vol 144 (9) ◽  
pp. 3895-3903 ◽  
Author(s):  
Kylie N. Hewitt ◽  
Wah Chin Boon ◽  
Yoko Murata ◽  
Margaret E. E. Jones ◽  
Evan R. Simpson
Keyword(s):  
Elevated Serum ◽  
Dietary Cholesterol ◽  
Cholesterol Homeostasis ◽  
High Cholesterol Diet ◽  
Atp Binding ◽  
Sexually Dimorphic ◽  
Hepatic Cholesterol ◽  
Wild Type ◽  
High Cholesterol ◽  
Atp Binding Cassette

Abstract The aromatase knockout (ArKO) mouse cannot synthesize endogenous estrogens due to disruption of the Cyp19 gene. We have shown previously, that ArKO mice present with age-progressive obesity and hepatic steatosis, and by 1 yr of age both male and female ArKO mice develop hypercholesterolemia. In this present study 10- to 12-wk-old ArKO mice were challenged for 90 d with high cholesterol diets. Our results show a sexually dimorphic response to estrogen deficiency in terms of cholesterol homeostasis in the liver. ArKO females presented with elevated serum cholesterol; conversely, ArKO males had elevated hepatic cholesterol levels. In response to dietary cholesterol, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase transcript levels were significantly reduced in females, whereas males showed more modest changes. Neither low density lipoprotein nor sterol regulatory element-binding protein expression levels were significantly altered by diet or genotype. The expression of Cyp7a, which encodes cholesterol 7α-hydroxylase, was significantly reduced in ArKO females compared with wild-type females and was increased by cholesterol feeding. Cyp7a expression was significantly elevated in the wild-type males on the high cholesterol diet, although no difference was seen between genotypes on the control diet. The ATP-binding cassette G5 and ATP-binding cassette G8 transporters do not appear to be regulated by estrogen. The expression of acyl-coenzyme A:cholesterol acyltransferase 2 showed a sexually dimorphic response, where estrogen appeared to have a stimulatory effect in females, but not males. This study reveals a sexually dimorphic difference in mouse hepatic cholesterol homeostasis and roles for estrogen in the regulation of cholesterol uptake, biosynthesis, and catabolism in the female, but not in the male.

scholarly journals Phosphatidylcholine transfer protein regulates size and hepatic uptake of high-density lipoproteins

2005 ◽  
Vol 289 (6) ◽  
pp. G1067-G1074 ◽  
Author(s):  
Michele K. Wu ◽  
David E. Cohen
Keyword(s):  
Plasma Cholesterol ◽  
High Cholesterol Diet ◽  
Atp Binding ◽  
Cholesterol Diet ◽  
Wild Type ◽  
High Cholesterol ◽  
High Fat ◽  
Transfer Protein ◽  
Phosphatidylcholine Transfer Protein ◽  
Atp Binding Cassette

Phosphatidylcholine transfer protein (PC-TP) is a steroidogenic acute regulatory-related transfer domain protein that is enriched in liver cytosol and binds phosphatidylcholines with high specificity. In tissue culture systems, PC-TP promotes ATP-binding cassette protein A1-mediated efflux of cholesterol and phosphatidylcholine molecules as nascent pre-β-high-density lipoprotein (HDL) particles. Here, we explored a role for PC-TP in HDL metabolism in vivo utilizing 8-wk-old male Pctp−/− and wild-type littermate C57BL/6J mice that were fed for 7 days with either chow or a high-fat/high-cholesterol diet. In chow-fed mice, neither plasma cholesterol concentrations nor the concentrations and compositions of plasma phospholipids were influenced by PC-TP expression. However, in Pctp−/− mice, there was an accumulation of small α-migrating HDL particles. This occurred without changes in hepatic expression of ATP-binding cassette protein A1 or in proteins that regulate the intravascular metabolism and clearance of HDL particles. In Pctp−/− mice fed the high-fat/high-cholesterol diet, HDL particle sizes were normalized, whereas plasma cholesterol and phospholipid concentrations were increased compared with wild-type mice. In the absence of upregulation of hepatic ATP-binding cassette protein A1, reduced HDL uptake from plasma into livers of Pctp−/− mice contributed to higher plasma lipid concentrations. These data indicate that PC-TP is not essential for the enrichment of HDL with phosphatidylcholines but that it does modulate particle size and rates of hepatic clearance.

scholarly journals The Effects of High Hydrostatic Pressure Extract of Mulberry Fruit on Hepatic Cholesterol Metabolism in Rats (P06-013-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Jaerin Lee ◽  
Soojin Lee ◽  
Mak-Soon Lee ◽  
Yoonjin Lee ◽  
Jiyeon Kim ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Cholesterol Metabolism ◽  
High Cholesterol Diet ◽  
Atp Binding ◽  
Mrna Levels ◽  
Cholesterol Diet ◽  
Hepatic Cholesterol ◽  
High Cholesterol ◽  
Mulberry Fruit ◽  
Atp Binding Cassette

Abstract Objectives The objective of this study is to investigate the effects of high hydrostatic pressure (HHP) extract of mulberry fruit on the regulation of hepatic cholesterol metabolism in high-cholesterol diet fed rats. Methods Male Sprague-Dawley rats(6-week-old) were randomly divided into 5 groups, and fed with a normal diet (NOR), High cholesterol diet (HC), HC supplemented with 0.4% mulberry (ML) or 0.8% mulberry (MH) and HC treated with statin (ST) for 4 weeks. Results The HHP extract of mulberry fruit did not affect body weight gain and food intake and reduced the serum and liver lipids in the mulberry supplemented groups (ML, MH). In this study, we found that the HHP extract of mulberry fruit changed the level of genes involved in hepatic cholesterol metabolism. In the MH group, the mRNA levels of apolipoprotein A-1 (apoA-1), ATP-binding cassette transporter A1 (ABCA1) and lecithin-cholesterol acyltransferase (LCAT), which are involved in hepatic HDL biogenesis, were significantly increased by 1.80-, 1.77- and 2.65-fold, respectively, compared with the HC group. The MH group also significantly upregulated mRNA levels of cholesterol efflux related gene such as the liver X receptor α (LXRα), ATP-binding cassette protein G5 (ABCG5) and ATP-binding cassette protein G8 (ABCG8) compared to the HC group in the liver tissue. ABCG5 and ABCG8 expression levels of the MH group were also higher than those of the ST group. The mRNA level of cholesterol 7a-hydroxylase (CYP7A1), which is bile acid synthetic rate-limiting enzyme was higher in the MH group than that of the HC group. Furthermore, the immunohistochemical staining intensity became evident for CYP7A1 in liver of the MH group. Conclusions These results suggest at least partial involvement of HDL cholesterol synthesis, cholesterol efflux and bile acid synthesis in HHP extract of mulberry fruit mediated beneficial effects on hepatic cholesterol metabolism. Funding Sources None.

Quercetin Dihydrate and Gallate Supplements Lower Plasma and Hepatic Lipids and Change Activities of Hepatic Antioxidant Enzymes in High Cholesterol-Fed Rats

2002 ◽  
Vol 72 (3) ◽  
pp. 161-169 ◽  
Author(s):  
Song-Hae Bok ◽  
Sun-Young Park ◽  
Yong Bok Park ◽  
Mi-Kyung Lee ◽  
Seon-Min Jeon ◽  
...  
Keyword(s):  
Reductase Activity ◽  
Dietary Cholesterol ◽  
The Other ◽  
Lipid Lowering ◽  
Control Group ◽  
High Cholesterol Diet ◽  
Hepatic Cholesterol ◽  
High Cholesterol ◽  
Lower Plasma ◽  
Quercetin Dihydrate

This study was designed to test the lipid-lowering and antioxidant activity of two bioflavonoids, quercetin dihydrate and gallate. Four groups of rats were given a semisynthetic diet containing 10 g cholesterol/kg for six weeks. The control group received only a high-cholesterol diet, whereas the other three groups received a diet including 1 g lovastatin, 1 g quercetin dihydrate, or 1 g gallate/kg. The quercetin dihydrate and gallate supplements both significantly lowered the plasma lipid and hepatic cholesterol levels compared to those of the control. The hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity was significantly lowered by the quercetin dihydrate when compared to the other groups, while the hepatic acyl CoA:cholesterol acyltransferase (ACAT) activity was only significantly higher in the control group. The overall potential for antioxidant protection was significantly enhanced by the quercetin dihydrate and gallate supplements through lowering the plasma and hepatic thiobarbituric acid reactive substances (TBARS) levels and increasing the hepatic superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in high-cholesterol-fed rats. These results suggest that the supplementation of quercetin dihydrate and gallate promotes an increase in fecal sterols, which in turn leads to a decreased absorption of dietary cholesterol as well as lower plasma and hepatic cholesterol.

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 Cysteine Is Exported from theEscherichia coliCytoplasm by CydDC, an ATP-binding Cassette-type Transporter Required for Cytochrome Assembly

2002 ◽  
Vol 277 (51) ◽  
pp. 49841-49849 ◽  
Author(s):  
Marc S. Pittman ◽  
Hazel Corker ◽  
Guanghui Wu ◽  
Marie B. Binet ◽  
Arthur J. G. Moir ◽  
...  
Keyword(s):  
Redox Homeostasis ◽  
Membrane Vesicles ◽  
Major Facilitator Superfamily ◽  
Atp Binding ◽  
Major Protein ◽  
Wild Type ◽  
Independent Manner ◽  
Periplasmic Transport ◽  
Major Facilitator ◽  
Atp Binding Cassette

Assembly ofEscherichia colicytochromebdand periplasmic cytochromes requires the ATP-binding cassette transporter CydDC, whose substrate is unknown. Two-dimensional SDS-PAGE comparison of periplasm from wild-type andcydDmutant strains revealed that the latter was deficient in several periplasmic transport binding proteins, but no single major protein was missing in thecydDperiplasm. Instead, CydDC exports from cytoplasm to periplasm the amino acid cysteine, demonstrated using everted membrane vesicles that transported radiolabeled cysteine inward in an ATP-dependent, uncoupler-independent manner. New pleiotropiccydDphenotypes are reported, including sensitivity to benzylpenicillin and dithiothreitol, and loss of motility, consistent with periplasmic defects in disulfide bond formation. Exogenous cysteine reversed these phenotypes and affected levels of periplasmicc-type cytochromes incydDand wild-type strains but did not restore cytochromed. Consistent with CydDC being a cysteine exporter,cydDmutant growth was hypersensitive to high cysteine concentrations and accumulated higher cytoplasmic cysteine levels, as did a mutant defective inorf299, encoding a transporter of the major facilitator superfamily. AcydD orf299double mutant was extremely cysteine-sensitive and had higher cytoplasmic cysteine levels, whereas CydDC overexpression conferred resistance to high extracellular cysteine concentrations. We propose that CydDC exports cysteine, crucial for redox homeostasis in the periplasm.

scholarly journals Formulation and Characterization of Quercetin-loaded Oil in Water Nanoemulsion and Evaluation of Hypocholesterolemic Activity in Rats

Nutrients ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 244 ◽  
Author(s):  
Hye-Yeon Son ◽  
Mak-Soon Lee ◽  
Eugene Chang ◽  
Seog-Young Kim ◽  
Bori Kang ◽  
...  
Keyword(s):  
Bile Acid ◽  
Water Solubility ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Chemical Degradation ◽  
High Cholesterol Diet ◽  
Atp Binding ◽  
Food Ingredient ◽  
Effects Of Ph ◽  
Atp Binding Cassette

Due to poor water solubility and high susceptibility to chemical degradation, the applications of quercetin have been limited. This study investigated the effects of pH on the formation of quercetin-loaded nanoemulsion (NQ) and compared the hypocholesterolemic activity between quercetin and NQ to utilize the quercetin as functional food ingredient. NQ particle size exhibited a range of 207–289 nm with polydispersity index range (<0.47). The encapsulation efficiency increased stepwise from 56 to 92% as the pH increased from 4.0 to 9.0. Good stability of NQ was achieved in the pH range of 6.5–9.0 during 3-month storage at 21 and 37 °C. NQ displayed higher efficacy in reducing serum and hepatic cholesterol levels and increasing the release of bile acid into feces in rats fed high-cholesterol diet, compared to quercetin alone. NQ upregulated hepatic gene expression involved in bile acid synthesis and cholesterol efflux, such as cholesterol 7 alpha-hydroxylase (CYP7A1), liver X receptor alpha (LXRα), ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette sub-family G member 1 (ABCG1). These results suggest at least partial involvement of hepatic bile acid synthesis and fecal cholesterol excretion in nanoemulsion quercetin-mediated beneficial effect on lipid abnormalities.

scholarly journals Liver X Receptor β (LXRβ) Interacts Directly with ATP-binding Cassette A1 (ABCA1) to Promote High Density Lipoprotein Formation during Acute Cholesterol Accumulation

2011 ◽  
Vol 286 (22) ◽  
pp. 20117-20124 ◽  
Author(s):  
Masako Hozoji-Inada ◽  
Youichi Munehira ◽  
Kohjiro Nagao ◽  
Noriyuki Kioka ◽  
Kazumitsu Ueda
Keyword(s):  
Translational Regulation ◽  
Cholesterol Efflux ◽  
Density Lipoprotein ◽  
Transcriptional Response ◽  
Liver X Receptor ◽  
Cholesterol Homeostasis ◽  
Atp Binding ◽  
Transcriptional Level ◽  
Cholesterol Accumulation ◽  
Atp Binding Cassette

Cells have evolved multiple mechanisms for maintaining cholesterol homeostasis, and, among these, ATP-binding cassette protein A1 (ABCA1)-mediated cholesterol efflux is highly regulated at the transcriptional level through the activity of the nuclear receptor liver X receptor (LXR). Here, we show that in addition to its well defined role in transcription, LXRβ directly binds to the C-terminal region (2247LTSFL2251) of ABCA1 to mediate its post-translational regulation. In the absence of cholesterol accumulation in the macrophage-like cell line THP-1, the ABCA1-LXRβ complex stably localizes to the plasma membrane, but apolipoprotein A-I (apoA-I) binding or cholesterol efflux does not occur. Exogenously added LXR ligands, which mimic cholesterol accumulation, cause LXRβ to dissociate from ABCA1, thus freeing ABCA1 for apoA-I binding and subsequent cholesterol efflux. Photoaffinity labeling experiments with 8-azido-[α-32P]ATP showed that the interaction of LXRβ with ABCA1 inhibits ATP binding by ABCA1. This is the first study to show that a protein-protein interaction with the endogenous protein suppresses the function of ABC proteins by inhibiting ATP binding. LXRβ can cause a post-translational response by binding directly to ABCA1, as well as a transcriptional response, to maintain cholesterol homeostasis.

scholarly journals Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Li Zhang ◽  
Prashant Rajbhandari ◽  
Christina Priest ◽  
Jaspreet Sandhu ◽  
Xiaohui Wu ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Plasma Cholesterol ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
High Cholesterol Diet ◽  
High Cholesterol ◽  
Cholesterol Levels ◽  
Expression Of Genes ◽  
Lysine Residues ◽  
Genetic Deletion

Cholesterol homeostasis is maintained through concerted action of the SREBPs and LXRs. Here, we report that RNF145, a previously uncharacterized ER membrane ubiquitin ligase, participates in crosstalk between these critical signaling pathways. RNF145 expression is induced in response to LXR activation and high-cholesterol diet feeding. Transduction of RNF145 into mouse liver inhibits the expression of genes involved in cholesterol biosynthesis and reduces plasma cholesterol levels. Conversely, acute suppression of RNF145 via shRNA-mediated knockdown, or chronic inactivation of RNF145 by genetic deletion, potentiates the expression of cholesterol biosynthetic genes and increases cholesterol levels both in liver and plasma. Mechanistic studies show that RNF145 triggers ubiquitination of SCAP on lysine residues within a cytoplasmic loop essential for COPII binding, potentially inhibiting its transport to Golgi and subsequent processing of SREBP-2. These findings define an additional mechanism linking hepatic sterol levels to the reciprocal actions of the SREBP-2 and LXR pathways.

Effects of dietary flaxseed on vascular contractile function and atherosclerosis during prolonged hypercholesterolemia in rabbits

2006 ◽  
Vol 291 (6) ◽  
pp. H2987-H2996 ◽  
Author(s):  
C. M. C. Dupasquier ◽  
A.-M. Weber ◽  
B. P. Ander ◽  
P. P. Rampersad ◽  
S. Steigerwald ◽  
...  
Keyword(s):  
Vascular Function ◽  
Contractile Function ◽  
Plasma Cholesterol ◽  
Dietary Cholesterol ◽  
Relaxation Response ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
Beneficial Effects ◽  
Atherosclerotic Lesions

Dietary flaxseed has significant anti-atherogenic effects. However, the limits of this action and its effects on vascular contractile function are not known. We evaluated the effects of flaxseed supplementation on atherosclerosis and vascular function under prolonged hypercholesterolemic conditions in New Zealand White rabbits assigned to one of four groups for 6, 8, or 16 wk of feeding: regular diet (RG), 10% flaxseed-supplemented diet (FX), 0.5% cholesterol-supplemented diet (CH), and 0.5% cholesterol- and 10% flaxseed-supplemented diet (CF). Cholesterol feeding resulted in elevated plasma cholesterol levels and the development of atherosclerosis. The CF group had significantly less atherosclerotic lesions in the aorta and carotid arteries after 6 and 8 wk than the CH animals. However, the anti-atherogenic effect of flaxseed supplementation was completely attenuated by 16 wk. Maximal tension induced in aortic rings either by KCl or norepinephrine was not impaired by dietary cholesterol until 16 wk. This functional impairment was not prevented by including flaxseed in the high-cholesterol diet. Aortic rings from the cholesterol-fed rabbits exhibited an impaired relaxation response to acetylcholine at all time points examined. Including flaxseed in the high-cholesterol diet completely normalized the relaxation response at 6 and 8 wk and partially restored it at 16 wk. No significant changes in the relaxation response induced by sodium nitroprusside were observed in any of the groups. In summary, dietary flaxseed is a valuable strategy to limit cholesterol-induced atherogenesis as well as abnormalities in endothelial-dependent vasorelaxation. However, these beneficial effects were attenuated during prolonged hypercholesterolemic conditions.

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