Identification of Novel Pathways That Control Farnesoid X Receptor-mediated Hypocholesterolemia

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2009 Dec 10

PMID 19996107

Citations 48

Authors

Yanqiao Zhang

Liya Yin

Jody Anderson

Huiyan Ma

Frank J Gonzalez

Timothy M Willson

Peter A Edwards

Affiliations

Soon will be listed here.

Abstract

Farnesoid X receptor (FXR) plays important regulatory roles in bile acid, lipoprotein, and glucose homeostasis. Here, we have utilized Fxr(-/-) mice and mice deficient in scavenger receptor class B type I (SR-BI), together with an FXR-specific agonist and adenovirus expressing hepatocyte nuclear factor 4alpha or constitutively active FXR, to identify the mechanisms by which activation of FXR results in hypocholesterolemia. We identify a novel pathway linking FXR to changes in hepatic p-JNK, hepatocyte nuclear factor 4alpha, and finally SR-BI. Importantly, we demonstrate that the FXR-dependent increase in SR-BI results in both hypocholesterolemia and an increase in reverse cholesterol transport, a process involving the transport of cholesterol from peripheral macrophages to the liver for excretion into the feces. In addition, we demonstrate that FXR activation also induces an SR-BI-independent increase in reverse cholesterol transport and reduces intestinal cholesterol absorption. Together, these data indicate that FXR is a promising therapeutic target for treatment of hypercholesterolemia and coronary heart disease.

Citing Articles

Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development.

Li T, Chiang J Pharmacol Rev. 2024; 76(6):1221-1253.

PMID: 38977324 PMC: 11549937. DOI: 10.1124/pharmrev.124.000978.

Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets.

Fleishman J, Kumar S Signal Transduct Target Ther. 2024; 9(1):97.

PMID: 38664391 PMC: 11045871. DOI: 10.1038/s41392-024-01811-6.

Bile salt signaling and bile salt-based therapies in cardiometabolic disease.

Groenen C, Nguyen T, Paulusma C, van de Graaf S Clin Sci (Lond). 2024; 138(1):1-21.

PMID: 38180064 PMC: 10767275. DOI: 10.1042/CS20230934.

Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation.

Wulfridge P, Davidovich A, Salvador A, Manno G, Tryggvadottir R, Idrizi A PLoS Genet. 2023; 19(10):e1010997.

PMID: 37871105 PMC: 10621921. DOI: 10.1371/journal.pgen.1010997.

Resveratrol intervention attenuates chylomicron secretion via repressing intestinal FXR-induced expression of scavenger receptor SR-B1.

Pang J, Raka F, Heirali A, Shao W, Liu D, Gu J Nat Commun. 2023; 14(1):2656.

PMID: 37160898 PMC: 10169763. DOI: 10.1038/s41467-023-38259-1.

References

Arai T, Wang N, Bezouevski M, Welch C, Tall A . Decreased atherosclerosis in heterozygous low density lipoprotein receptor-deficient mice expressing the scavenger receptor BI transgene. J Biol Chem. 1999; 274(4):2366-71. DOI: 10.1074/jbc.274.4.2366. View

Calpe-Berdiel L, Rotllan N, Fievet C, Roig R, Blanco-Vaca F, Escola-Gil J . Liver X receptor-mediated activation of reverse cholesterol transport from macrophages to feces in vivo requires ABCG5/G8. J Lipid Res. 2008; 49(9):1904-11. DOI: 10.1194/jlr.M700470-JLR200. View

Kim I, Ahn S, Inagaki T, Choi M, Ito S, Guo G . Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res. 2007; 48(12):2664-72. DOI: 10.1194/jlr.M700330-JLR200. View

Ma K, Saha P, Chan L, Moore D . Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest. 2006; 116(4):1102-9. PMC: 1409738. DOI: 10.1172/JCI25604. View

Zhang Y, Lee F, Barrera G, Lee H, Vales C, Gonzalez F . Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A. 2006; 103(4):1006-11. PMC: 1347977. DOI: 10.1073/pnas.0506982103. View

Inoue Y, Yu A, Yim S, Ma X, Krausz K, Inoue J . Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4alpha. J Lipid Res. 2005; 47(1):215-27. PMC: 1413576. DOI: 10.1194/jlr.M500430-JLR200. View

Flatt B, Martin R, Wang T, Mahaney P, Murphy B, Gu X . Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR). J Med Chem. 2009; 52(4):904-7. DOI: 10.1021/jm8014124. View

Shih D, Bussen M, Sehayek E, Ananthanarayanan M, Shneider B, Suchy F . Hepatocyte nuclear factor-1alpha is an essential regulator of bile acid and plasma cholesterol metabolism. Nat Genet. 2001; 27(4):375-82. DOI: 10.1038/86871. View

Naik S, Wang X, da Silva J, Jaye M, Macphee C, Reilly M . Pharmacological activation of liver X receptors promotes reverse cholesterol transport in vivo. Circulation. 2005; 113(1):90-7. DOI: 10.1161/CIRCULATIONAHA.105.560177. View

10.

Wang D, Tazuma S, Cohen D, Carey M . Feeding natural hydrophilic bile acids inhibits intestinal cholesterol absorption: studies in the gallstone-susceptible mouse. Am J Physiol Gastrointest Liver Physiol. 2003; 285(3):G494-502. DOI: 10.1152/ajpgi.00156.2003. View

11.

Zhang Y, Edwards P . FXR signaling in metabolic disease. FEBS Lett. 2007; 582(1):10-8. DOI: 10.1016/j.febslet.2007.11.015. View

12.

Jung D, Inagaki T, Gerard R, Dawson P, Kliewer S, Mangelsdorf D . FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorption. J Lipid Res. 2007; 48(12):2693-700. DOI: 10.1194/jlr.M700351-JLR200. View

13.

Gupta S, Stravitz R, Dent P, Hylemon P . Down-regulation of cholesterol 7alpha-hydroxylase (CYP7A1) gene expression by bile acids in primary rat hepatocytes is mediated by the c-Jun N-terminal kinase pathway. J Biol Chem. 2001; 276(19):15816-22. DOI: 10.1074/jbc.M010878200. View

14.

BLIGH E, Dyer W . A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959; 37(8):911-7. DOI: 10.1139/o59-099. View

15.

Kozarsky K, Donahee M, Glick J, Krieger M, Rader D . Gene transfer and hepatic overexpression of the HDL receptor SR-BI reduces atherosclerosis in the cholesterol-fed LDL receptor-deficient mouse. Arterioscler Thromb Vasc Biol. 2000; 20(3):721-7. DOI: 10.1161/01.atv.20.3.721. View

16.

Navab M, Anantharamaiah G, Reddy S, Hama S, Hough G, Grijalva V . Oral D-4F causes formation of pre-beta high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apolipoprotein E-null mice. Circulation. 2004; 109(25):3215-20. DOI: 10.1161/01.CIR.0000134275.90823.87. View

17.

Cariou B, van Harmelen K, Duran-Sandoval D, van Dijk T, Grefhorst A, Abdelkarim M . The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem. 2006; 281(16):11039-49. DOI: 10.1074/jbc.M510258200. View

18.

Maloney P, Parks D, Haffner C, Fivush A, Chandra G, Plunket K . Identification of a chemical tool for the orphan nuclear receptor FXR. J Med Chem. 2000; 43(16):2971-4. DOI: 10.1021/jm0002127. View

19.

Makishima M, Okamoto A, REPA J, Tu H, Learned R, Luk A . Identification of a nuclear receptor for bile acids. Science. 1999; 284(5418):1362-5. DOI: 10.1126/science.284.5418.1362. View

20.

Zhang Y, Castellani L, Sinal C, Gonzalez F, Edwards P . Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR. Genes Dev. 2004; 18(2):157-69. PMC: 324422. DOI: 10.1101/gad.1138104. View