Removal of the bile acid pool upregulates cholesterol 7α-hydroxylase by deactivating FXR in rabbits

Xu, Guowang; Pan, Luxing; Erickson, Sandra K.; Forman, Barry M.; Shneider, Benjamin L.; Ananthanarayanan, Meenakshisundaram; Li, Xiaogui; Shefer, Sarah; Balasubramanian, Niranjan; Ma, Lin; Asaoka, Hiroshi; Lear, Steven R.; Nguyen, Lien; Dussault, Isabelle; Suchy, Frederick J.; Tint, G. Stephen; Salen, Gerald

doi:10.1016/s0022-2275(20)30185-1

Cited by 19 publications

(5 citation statements)

References 24 publications

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“…The balance between FXR and LXR pathways controlling Cyp7a1 gene expression remains controversial. The LXR pathway may be prevalent over the FXR pathway in mice and rats [13,46], whereas the opposite was documented in atherosclerosis-prone species such as rabbits or humans [48,49]. Upon CS overload, Cyp7a1 expression decreases in the liver of rabbits and hamsters as well as in primary human hepatocytes [18,36,43].…”

Section: Discussionmentioning

confidence: 99%

“…Cyp7a1 expression is regulated by BA and oxysterols via nuclear receptors FXR and LXR in mice and humans [29,[42][43][44][45]. The LXR pathway was proposed to be more prevalent than the FXR pathway in mice and rats [11,13,46,47], whereas the opposite was claimed in atherosclerosis-prone species such as rabbits and humans [8,48,49]. This is namely due to the absence of a functional LXRE in human CYP7A1 gene promoter [50,51].…”

Section: Cholesterol Feeding Reduces Fxr Signaling Through Enhanced Hydrophilic Bile Acid Synthesismentioning

confidence: 99%

“…Since 1960, animal models are widely used for studying the pathophysiology of hypercholesterolemia and atherosclerosis as well as for the preclinical assessment of drugs in this context [5]. Compared to other laboratory animal models whereas the opposite was claimed in atherosclerosis-prone species such as rabbits and humans [8,48,49]. This is namely due to the absence of a functional LXRE in human CYP7A1 gene promoter [50,51].…”

Section: Introductionmentioning

confidence: 99%

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Muricholic Acids Promote Resistance to Hypercholesterolemia in Cholesterol-Fed Mice

Gaillard

Masson

Garo

et al. 2021

IJMS

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Background and aims: Hypercholesterolemia is a major risk factor for atherosclerosis and cardiovascular diseases. Although resistant to hypercholesterolemia, the mouse is a prominent model in cardiovascular research. To assess the contribution of bile acids to this protective phenotype, we explored the impact of a 2-week-long dietary cholesterol overload on cholesterol and bile acid metabolism in mice. Methods: Bile acid, oxysterol, and cholesterol metabolism and transport were assessed by quantitative real-time PCR, western blotting, GC-MS/MS, or enzymatic assays in the liver, the gut, the kidney, as well as in the feces, the blood, and the urine. Results: Plasma triglycerides and cholesterol levels were unchanged in mice fed a cholesterol-rich diet that contained 100-fold more cholesterol than the standard diet. In the liver, oxysterol-mediated LXR activation stimulated the synthesis of bile acids and in particular increased the levels of hydrophilic muricholic acids, which in turn reduced FXR signaling, as assessed in vivo with Fxr reporter mice. Consequently, biliary and basolateral excretions of bile acids and cholesterol were increased, whereas portal uptake was reduced. Furthermore, we observed a reduction in intestinal and renal bile acid absorption. Conclusions: These coordinated events are mediated by increased muricholic acid levels which inhibit FXR signaling in favor of LXR and SREBP2 signaling to promote efficient fecal and urinary elimination of cholesterol and neo-synthesized bile acids. Therefore, our data suggest that enhancement of the hydrophilic bile acid pool following a cholesterol overload may contribute to the resistance to hypercholesterolemia in mice. This work paves the way for new therapeutic opportunities using hydrophilic bile acid supplementation to mitigate hypercholesterolemia.

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Section: Discussionmentioning

confidence: 99%

Section: Cholesterol Feeding Reduces Fxr Signaling Through Enhanced Hydrophilic Bile Acid Synthesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Muricholic Acids Promote Resistance to Hypercholesterolemia in Cholesterol-Fed Mice

Gaillard

Masson

Garo

et al. 2021

IJMS

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“…From numerous animal and human studies, we now know that, through nuclear receptors, BAs play a role in regulating the qualitative and quantitative bile acid pool, gut microbiome, and glucose and lipid metabolism [6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

A Current Understanding of Bile Acids in Chronic Liver Disease

Farooqui

Elhence

Shalimar

2022

Journal of Clinical and Experimental Hepatology

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…Cholesterol-derived amphipathic bile acids are released from the bile duct, and more than 90% of released bile acids are then reabsorbed in the ileum by the apical sodium-dependent bile acid transporter (ASBT, also known as SLC10A2) . For this reason, ASBT is considered a pharmaceutical target for the treatment of hypercholesterolaemia, cholestatic liver disease, and type 2 diabetes. , Small synthetic ASBT inhibitors have shown considerably lower plasma cholesterol levels in animal models. , Moreover, ASBT inhibitors have been shown to increase the conversion of hepatic cholesterol into bile acids in the liver when they inhibit the recycling of bile acid in the enterohepatic circulation …”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Therapeutic Evaluation of Poly(acrylic acid)–tetraDOCA Conjugate as a Bile Acid Transporter Inhibitor

Park¹,

Al-Hilal

Jeong

et al. 2015

Bioconjugate Chem.

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Regulation of cholesterol and bile acid homeostasis has been attracting attention as a pharmaceutical target for the treatment of diseases, such as hypercholesterolaemia and type 2 diabetes. In recent years, small bile acid analogues have been developed for the purpose of apical sodium-dependent bile acid transporter (ASBT) inhibition. Here, we designed a novel hydrophilic ASBT inhibitor using oligomeric bile acid with a high affinity with ASBT. Polyacrylic acid-tetraDOCA conjugates (PATD) have the ability to bind to ASBT in order to induce hypocholesterolemic effects. Both the viability and the functionality of PATD were evaluated in vitro, showing that PATDs were effective in inhibiting the increases of cholesterol in the blood and oil in the liver induced by high fat diet (HFD). The results indicated that the newly developed biomaterials with oligomeric bile acids and a hydrophilic polymer are potent therapeutic agents for hyperlipidemia.

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Removal of the bile acid pool upregulates cholesterol 7α-hydroxylase by deactivating FXR in rabbits

Cited by 19 publications

References 24 publications

Muricholic Acids Promote Resistance to Hypercholesterolemia in Cholesterol-Fed Mice

Muricholic Acids Promote Resistance to Hypercholesterolemia in Cholesterol-Fed Mice

A Current Understanding of Bile Acids in Chronic Liver Disease

Design, Synthesis, and Therapeutic Evaluation of Poly(acrylic acid)–tetraDOCA Conjugate as a Bile Acid Transporter Inhibitor

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