Rice protein exerts a hypocholesterolemic effect through regulating cholesterol metabolism-related gene expression and enzyme activity in adult rats fed a cholesterol-enriched diet
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Abstract:
The major aim of this study is to elucidate the hypocholesterolemic mechanism exerted by rice protein (RP) in adult rats under cholesterol-enriched dietary condition. Compared with casein, the cholesterol levels in plasma and the liver were significantly reduced by RP, accompanying significant inhibition of cholesterol absorption. RP increased the activity and mRNA level of cholesterol 7α-hydroxylase, whereas acyl-CoA:cholesterol acyltransferase activity and gene expression were significantly depressed with consumption of RP. Neither the activity nor gene expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase of RP differed from that of casein. The gene expression of the peroxisome proliferator-activated receptor α and liver X receptor α were significantly activated by consumption of RP. RP did not modify the mRNA level of sterol regulatory element-binding protein-2 with respect to casein. These results suggest RP can induce a cholesterol-lowering effect through modifying cholesterol metabolism-related gene expression and enzyme activity in adult rats.Keywords:
Sterol O-acyltransferase
Coenzyme A
Liver X receptor
Liver X receptor
Fatty acid synthesis
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Cholesterol carries multiple biological functions in the body, and imbalanced cholesterol metabolism leads to atherosclerosis and cardiovascular diseases. The present thesis aims to extend the knowledge of cholesterol metabolic regulation mediated by nuclear receptor LXRs and bile acids, two major players in the homeostasis of body cholesterol. In the first paper, we aim to understand how liver X receptor (LXR) regulates cholesterol metabolism in the intestine, in particular to compare the effects of the two isoforms, LXRα and LXRβ on dietary cholesterol absorption and serum lipoprotein profiles. We find that selective activation of LXRβ enhances dietary cholesterol absorption in mice, which is accompanied by increased apoB lipoprotein cholesterol in the circulation. We also find that LXRα and LXRβ compensate for each other in the transcriptional regulation of intestinal Abcg5, Abca1 and Npc1l1. Furthermore, the hepatic enzymes Cyp7a1 and Cyp8b1 are differently modulated upon systemic LXR isoform activation. Given the contribution of the hydrophobic bile acid profile in the intestine, these changes together with the net differences in biliary cholesterol output may partially explain the isoform mediated changes in cholesterol absorption. Our findings reinforce the non-redundant function of LXRα and LXRβ, and suggest that selective activation of LXRβ as anti-atherogenic therapy may lead to undesired metabolic adverse effects. Bile acid synthesis represents the crucial elimination pathway for excess cholesterol. The negative feedback regulation by end-product hydrophobic bile acids has been well established, involving the activation of nuclear receptor FXR, and a subsequent upregulation of SHP and Fgf15 for the suppression of bile acid synthesis in mice (Fgf19 as human counterpart). However, the role of hydrophilic bile acids in such context has largely been ignored. By using a cholic acid (CA) deficient mouse model and different bile acid-modulating regimes, we define MCAs as FXR antagonistic bile acids, which counteract the FXR activation by hydrophobic bile acids. By modulating the enterohepatic circulation of bile acids, the positive feedback mechanism regulates bile acid homeostasis without employing the hormonal effect of Fgf15, although such an effect is likely to exist. This finding is of fundamental importance for the understating of bile acid metabolism in both humans and mice, as the Fgf15/19 negative feedback mechanism is believed to operate in both species. Paper III explores the therapeutic potential of CA depletion on systemic cholesterol overloading by using second generation antisense oligonucleotides (ASOs). Several ASOs targeting Cyp8b1, the enzyme responsible for CA production, have been used in the study. In mice, we observe a significant reduction of the CA fraction in the biliary bile acid profile under ASO treatment. This reduction is accompanied by resistance to liver cholesterol accumulation and an athero-protective lipoprotein profile upon cholesterol overloading. The data suggest the feasibility of using second generation ASOs as therapeutic target for cholesterol homeostasis, although a careful systematic study is needed to address the clinical aspect in human subjects. ISBN: 978-91-7549-290-2
Liver X receptor
Farnesoid X receptor
Reverse cholesterol transport
CYP8B1
CYP27A1
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Liver X receptor
Lipogenesis
Fatty acid synthesis
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Cholesterol homoeostasis is the result of the fine tuning between intake and disposal of this molecule. High levels of cholesterol in the blood are detrimental as they may lead to excessive accumulation in vessel walls, a condition predisposing to the development of atherosclerotic lesions. Cholesterol is removed from the vessel wall and transported to the liver through a process called reverse cholesterol transport. Nuclear receptors are among the most important transcription factors regulating genes involved in different steps of reverse cholesterol transport. Here, we discuss the role of the nuclear receptors LXR (liver X receptor) and HNF-4α (hepatocyte nuclear factor-4α) in different steps of reverse cholesterol transport. LXR controls the transcription of crucial genes in cholesterol efflux from macrophages and its transport to the liver, such as ABCA1 (ATP binding cassette A1), CYP27A1 (sterol 27-hydroxylase), CLA-1 (scavenger receptor type B1) and apolipoprotein E. Some oxysterols present in oxidized low-density lipoproteins and proinflammatory cytokines modulate the activity of LXR by antagonizing the effect of activators of this receptor, thus contributing to cholesterol accumulation in macrophages. Bile acid synthesis, which represents the final step of reverse cholesterol transport, is transcriptionally regulated by several nuclear receptors at the level of the liver-specific cytochrome P450 cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme of this metabolic pathway. Bile acids returning to the liver through the enterohepatic circulation down-regulate CYP7A1 transcription via the bile acid sensors farnesoid X receptor and HNF-4α. Based on this evidence, these nuclear receptors are candidate targets of new drugs for the treatment and prevention of atherosclerotic disease.
Liver X receptor
Reverse cholesterol transport
Liver receptor homolog-1
CYP27A1
Farnesoid X receptor
Hepatocyte nuclear factors
CYP8B1
Pregnane X receptor
Small heterodimer partner
Enterohepatic circulation
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The liver X receptors (LXRs) sense oxysterols and regulategenesinvolvedincholesterolmetabolism.SyntheticagonistsofLXRs are potent stimulators of fatty acid synthesis, which ismediated largely by sterol regulatory element-binding pro-tein-1c (SREBP-1c). Paradoxically, an improved hepatic lipidprofilebyLXRwasobservedinmicefedaWesternhighfat(HF)diet. To explore the underlying mechanism, we administeredmicenormalchoworanHFdietandoverexpressedLXR intheliver.TheHFdietwithtail-veininjectionofadenovirusofLXRincreasedtheexpressionofLXR-targetedgenesinvolvedincho-lesterol reverse transport but not those involved in fatty acidsynthesis.Asimilareffectwasalsoobservedwiththeuseof22R-hydroxycholesterol, an LXR ligand, in cultured hepatocytes.Consequently, SREBP-1c maturation was inhibited by the HFdiet,whichresultedfromtheinductionofInsig-2a.Importantly,increasedcholesterollevelsuppressedtheexpressionof2,3-ox-idosqualene cyclase (OSC), which led to an increase in endoge-nousLXRligand(s).Furthermore,siRNA-mediatedknockdownof OSC expression enhanced LXR activity and selectively up-regulated LXR-targeted genes involved in cholesterol reversetransport. Thus, down-regulation of OSC may account for anovel mechanism underlying the LXR-mediated lipid metabo-lism in the liver of mice fed an HF diet.
Liver X receptor
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The synthesis of cholesterol and fatty acids (FA) in the liver is independently regulated by SREBP-2 and SREBP-1c, respectively. Here, we genetically deleted Srebf-2 from hepatocytes and confirmed that SREBP-2 regulates all genes involved in cholesterol biosynthesis, the LDL receptor, and PCSK9; a secreted protein that degrades LDL receptors in the liver. Surprisingly, we found that elimination of Srebf-2 in hepatocytes of mice also markedly reduced SREBP-1c and the expression of all genes involved in FA and triglyceride synthesis that are normally regulated by SREBP-1c. The nuclear receptor LXR is necessary for Srebf-1c transcription. The deletion of Srebf-2 and subsequent lower sterol synthesis in hepatocytes eliminated the production of an endogenous sterol ligand required for LXR activity and SREBP-1c expression. These studies demonstrate that cholesterol and FA synthesis in hepatocytes are coupled and that flux through the cholesterol biosynthetic pathway is required for the maximal SREBP-1c expression and high rates of FA synthesis.
Liver X receptor
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The liver X receptors (LXRalpha and LXRbeta) are members of the nuclear hormone receptor family of ligand‐activated transcription factors. LXRs have been identified as cellular sterol sensors that are activated by cholesterol‐derived oxysterols to increase the expression of genes that contribute to cholesterol catabolism, efflux and elimination. These qualities make the LXRs attractive therapeutic targets for intervention in atherosclerosis. The majority of studies defining the actions of LXRs have been performed in the mouse model, taking advantage of genetically modified mouse strains devoid of LXRs. When an LXRalpha‐null mouse is fed dietary cholesterol, it fails to increase the expression of LXR target genes and consequently accumulates plasma and hepatic cholesterol and shows no increase in plasma and liver triglycerides. Interestingly, the Golden Syrian hamster also shows this dietary cholesterol‐induced phenotype, and fails to exhibit upregulation of hepatic LXR target genes such as CYP7A1 and SREBP‐1c. These observations prompted us to ask if the LXR‐signaling pathway is intact in the hamster, and whether we could use these qualities to further investigate LXR biology using the cholesterol‐fed hamster. We have cloned and characterized hamster LXRalpha, evaluated the promoter motifs of LXR target genes, and compared the effects of dietary cholesterol and synthetic LXR ligands on cholesterol homeostasis and hepatic gene regulation to define this differential response to dietary cholesterol in this valuable animal model. Supported by a grant from the American Heart Association (JJR)
Liver X receptor
Reverse cholesterol transport
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The liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily that are bound and activated by oxysterols. These receptors serve as sterol sensors to regulate the transcription of gene products that control intracellular cholesterol homeostasis through catabolism and transport. In this report, we describe a novel LXR target, the sterol regulatory element-binding protein-1c gene (SREBP-1c), which encodes a membrane-bound transcription factor of the basic helix-loop-helix-leucine zipper family. SREBP-1c expression was markedly increased in mouse tissues in an LXR-dependent manner by dietary cholesterol and synthetic agonists for both LXR and its heterodimer partner, the retinoid X receptor (RXR). Expression of the related gene products, SREBP-1a and SREBP-2, were not increased. Analysis of the mouse SREBP-1c gene promoter revealed an RXR/LXR DNA-binding site that is essential for this regulation. The transcriptional increase in SREBP-1c mRNA by RXR/LXR was accompanied by a similar increase in the level of the nuclear, active form of the SREBP-1c protein and an increase in fatty acid synthesis. Because this active form of SREBP-1c controls the transcription of genes involved in fatty acid biosynthesis, our results reveal a unique regulatory interplay between cholesterol and fatty acid metabolism.
Liver X receptor
Retinoid X receptor
Oxysterol
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Liver X receptor
Fatty acid synthesis
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Liver X receptor
Reverse cholesterol transport
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