FXR-mediated down-regulation of CYP7A1 dominates LXRα in long-term cholesterol-fed NZW rabbits

Xu, Guowang; Li, Hai; Pan, Luxing; Shang, Qing; Honda, Akira; Ananthanarayanan, Meenakshisundaram; Erickson, Sandra K.; Shneider, Benjamin L.; Shefer, Sarah; Bollineni, Jaya; Forman, Barry M.; Matsuzaki, Yasushi; Suchy, Frederick J.; Tint, G. Stephen; Salen, Gerald

doi:10.1194/jlr.m300182-jlr200

Cited by 36 publications

(27 citation statements)

References 42 publications

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“…35,36 Under normal conditions, high concentrations of cholesterol in tissue stimulate oxysterol production, and the oxysterols, as well as cholesterol, downregulate cholesterol biosynthesis 37 by inhibiting HMGCR, the rate-limiting enzyme in the cholesterol biosynthetic pathway. In McA-RH7777 hepatomas, however, HMGCR was markedly upregulated despite the increased concentrations of both oxysterols and cholesterol.…”

Section: Discussionmentioning

confidence: 99%

Hypercholesterolemia in rats with hepatomas: Increased oxysterols accelerate efflux but do not inhibit biosynthesis of cholesterol

et al. 2006

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Hypercholesterolemia is an important paraneoplastic syndrome in patients with hepatoma, but the nature of this defect has not yet been identified. We investigated the molecular mechanisms of hypercholesterolemia in a hepatoma-bearing rat model. Buffalo rats were implanted in both flanks with Morris hepatoma 7777 (McA-RH7777) cells. After 4 weeks, tumor weight was 5.5 ؎ 1.7 g, and serum cholesterol level increased from 60 ؎ 2 to 90 ؎ 2 mg/dL. Protein and mRNA expression of the ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) was markedly higher in tumors than in livers. These increases were associated with activation of liver X receptor ␣ (LXR␣) as a result of the increased tissue oxysterol concentrations. The accumulation of oxysterols in the hepatomas appeared to be caused mainly by the upregulation of cholesterol biosynthesis, despite the increased tissue sterol concentrations. Overexpression of the sterol regulatory element-binding protein (SREBP) processing system relative to sterol concentration contributed to the resistance to sterols in this tumor. In addition, bile acid biosynthesis was inhibited despite the reduced expression of the small heterodimer partner (SHP) and activated LXR␣, which also appeared to contribute to the accumulation of oxysterols followed by the acceleration of cholesterol efflux. In conclusion, hypercholesterolemia in McA-RH7777 hepatoma-bearing rats was caused by increased cholesterol efflux from tumors as a result of activation of LXR␣. Overexpression of the SREBP processing system contributed to the activation of LXR␣ by maintaining high oxysterol levels in tissue. (HEPATOLOGY 2006;44:602-611.) H ypercholesterolemia is one of the well-known paraneoplastic manifestations that may occur in patients with hepatomas. 1,2 It presents in 10%-25% of patients with hepatomas 2,3 and is an unfavorable prognostic factor for these patients. 4 Hypercholesterolemia associated with hepatoma has also been reported in rats implanted with some types of Morris hepatomas. 5-7 Although the exact mechanism remains to be identified, hypercholesterolemia in rats has been reported to be a result of the increased release of cholesterol from the tumor into the blood. 6,8 Many years ago, Siperstein et al. reported that cholesterol feedback control, which is characteristic of normal liver function, was consistently lost in all hepatomas regardless of animal species, degree of tumor differentiation, or method of induction of the hepatoma. 9 However, further studies demonstrated that dietary cholesterol slightly but significantly inhibited the activity of HMGCoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway, in rat hepatomas. 10 In addition, the injection of mevalonolactone, a precursor of cholesterol, into rats bearing hepatomas suppressed cholesterol biosynthesis in the tumors. 11 Therefore, defective cholesterol feedback regulation in hepatomas was considered to result from the secondary effects of altered cholesterol metabolism rather than from an inherent defe...

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Section: Discussionmentioning

confidence: 99%

Hypercholesterolemia in rats with hepatomas: Increased oxysterols accelerate efflux but do not inhibit biosynthesis of cholesterol

et al. 2006

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“…We know that CYP7A1 in the liver and FXR in the ileum and liver is up-and downregulated in these models ( 8,9 ). Thus, these models are appropriate for studying the relationship between the expression of ileal FGF15/19 and the protein levels of the gut-hepatic signal in the portal blood, as well as the expression of CYP7A1 in the liver.…”

Section: Animal Experimentsmentioning

confidence: 99%

FGF15/19 protein levels in the portal blood do not reflect changes in the ileal FGF15/19 or hepatic CYP7A1 mRNA levels

Shang

Guo

Honda

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org transcription ( 1-3 ). Hydrophobic bile acids, chenodeoxycholic acid (CDCA), lithocholic acid, and deoxycholic acid (DCA) are potent ligands that activate FXR. It was proposed that activated FXR enhances SHP expression in the liver, which in turn inhibits LRH-1-mediated transcriptional activation of the CYP7A1 gene ( 4,5 ). This hypothesis, involving a cascade reaction in the liver, provides an explanation at the molecular level for the indirect repression of CYP7A1 by bile acid-activated FXR. Our results from in vivo studies in rabbits ( 6-8 ) and rats ( 9 ) agree with the hypothesis that activation of hepatic FXR by the increased circulating enterohepatic bile acid pool plays a crucial role in the downregulation of CYP7A1 expression. Pandak et al. ( 10 ) reported that intravenous perfusion of taurocholate via the internal jugular vein failed to downregulate CYP7A1 expression in rats with bile fi stula and proposed that there should be an "intestinal factor" which is necessary for the downregulation of CYP7A1. When the bile duct was ligated in rats ( 11 ) or mice ( 12 ), where bile acids accumulated in the liver and did not reach the intestine, CYP7A1 expression unexpectedly increased indicating a role for the intestine in regulation of CYP7A1. Furthermore, it was suggested that bile acids infused through peripheral ( 10, 13, 14 ) and portal venous systems ( 15 ) did not exert "feedback regulation" to downregulate CYP7A1/ bile acid synthesis in rats.Recently, an alternative hypothesis was proposed that CYP7A1 gene expression was controlled by the gut-hepatic signal fi broblast growth factor (FGF)15 expressed in the intestine via the ileal FXR-FGF15-FGF4 receptor pathway ( 12 ). FGF15 in mice ( 12 ), or its ortholog FGF19 Abstract It has been proposed that bile acid suppression of CYP7A1 gene expression is mediated through a gut-liver signaling pathway fi broblast growth factor (FGF)15/19-fi broblast growth factor receptor 4 which is initiated by activation of farnesoid X receptor in the ileum but not in the liver. This study evaluated whether FGF15/19 protein levels in the portal blood refl ected changes in FGF15/19 mRNA in the ileum. Studies were conducted in Sprague Dawley rats and New Zealand white rabbits fed regular chow (controls), supplemented with cholesterol (Ch) or cholic acid (CA). After feeding CA, ileal FGF15 mRNA increased 8.5-fold in rats and FGF19 rose 16-fold in rabbits associated with 62 and 75% reduction of CYP7A1 mRNA, respectively. Neither FGF15 nor FGF19 protein levels changed in the portal blood to correspond with the marked increase of FGF15/19 mRNA levels in the ileum or inhibited CYP7A1 expression in the liver. Further, in Ch-fed rats, CYP7A1 mRNA increased 1.9-fold ( P < 0.001) although FGF15 mRNA levels in the ileum and portal blood FGF15 protein levels were not decreased. In Ch-fed rabbits, although FGF19 mRNA levels in the ileum and liver did not increase signifi cantly, CYP7A1 mRNA declined 49% ( P < 0.05). We were unable to ...

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“…It has been reported that rodents have a very hydrophilic bile acid pool, which is less potent in activation of FXR; thus, the LXRα could function as an important regulator of CYP7A1 in mice (Chiang et al, 2001). In contrast, CYP7A1 expression was down-regulated by a high-cholesterol diet in African green monkeys (Rudel et al, 1994) and in rabbits (Xu et al, 2003), since the inhibitory effect of FXR may override the stimulatory effect of LXRα. There are another Figure 7.…”

Section: Discussionmentioning

confidence: 71%

Inhibition of acyl-coenzyme A:cholesterol acyltransferase stimulates cholesterol efflux from macrophages and stimulates farnesoid X receptor in hepatocytes

Jang

Park

et al. 2008

Exp Mol Med

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We investigated the mechanism of spontaneous cholesterol efflux induced by acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibition, and how an alteration of cholesterol metabolism in macrophages impacts on that in HepG2 cells. Oleic acid anilide (OAA), a known ACAT inhibitor reduced lipid storage substantially by promotion of cholesterol catabolism and repression of cholesteryl ester accumulation without further increase of cytotoxicity in acetylated low-density lipoprotein-loaded THP-1 macrophages. Analysis of expressed mRNA and protein revealed that cholesterol 7α-hydroxylase (CYP7A1), oxysterol 7α-hydroxylase (CYP7B1), and cholesterol 27-hydroxylase (CYP27) were highly induced by ACAT inhibition. The presence of a functional cytochrome P450 pathway was confirmed by quantification of the biliary cholesterol mass in cell monolayers and extracelluar medium. Notably, massively secreted biliary cholesterol from macrophages suppressed the expression of CYP7 proteins in a farnesoid X receptor (FXR)-dependent manner in HepG2 cells. The findings reported here provide new insight into mechanisms of spontaneous cholesterol efflux, and suggest that ACAT inhibition may stimulate cholesterol-catabolic (cytochrome P450) pathway in lesion-macrophages, in contrast, suppress it in hepatocyte via FXR induced by biliary cholesterol (BC).

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FXR-mediated down-regulation of CYP7A1 dominates LXRα in long-term cholesterol-fed NZW rabbits

Cited by 36 publications

References 42 publications

Hypercholesterolemia in rats with hepatomas: Increased oxysterols accelerate efflux but do not inhibit biosynthesis of cholesterol

Hypercholesterolemia in rats with hepatomas: Increased oxysterols accelerate efflux but do not inhibit biosynthesis of cholesterol

FGF15/19 protein levels in the portal blood do not reflect changes in the ileal FGF15/19 or hepatic CYP7A1 mRNA levels

Inhibition of acyl-coenzyme A:cholesterol acyltransferase stimulates cholesterol efflux from macrophages and stimulates farnesoid X receptor in hepatocytes

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