27-Hydroxycholesterol Is an Endogenous Ligand for Liver X Receptor in Cholesterol-loaded Cells

Fu, Xuan; Menke, John; Chen, Yuli; Zhou, Gaochao; MacNaul, Karen L.; Wright, Samuel D.; Sparrow, Carl P.; Lund, Erik

doi:10.1074/jbc.m105805200

Cited by 490 publications

(365 citation statements)

References 62 publications

(42 reference statements)

Supporting

Mentioning

347

Contrasting

Unclassified

Order By: Relevance

“…It should be noted that although we quantified total SREBP1 instead of SREBP1c, the 1c transcript predominates over the 1a transcript in McA-RH7777 cells. 32 The LXR␣ is activated by several oxysterols including 24S-hydroxycholesterol, 24S,25-epoxycholesterol, 25-hydroxycholesterol, and 27-hydroxycholesterol, 33,34 and their concentrations were all significantly elevated in the tumors. Therefore, the accumulation of tissue oxysterols appears to be an important factor in the acceleration of cholesterol efflux from McA-RH7777 hepatomas.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

View full text Add to dashboard Cite

show abstract

“…von Bahr et al showed that the CYP27A1 itself was important for the efflux of both cholesterol and cholestanol from xanthomas (21). Recently, it was reported that 27-hydroxycholesterol was a ligand for the nuclear receptor liver X receptor (LXR) (22,23) and 27-hydroxycholesterol generated in macrophages was identified as an important endogenous ligand for up-regulating cholesterol efflux via the ATP-binding cassette (ABC) transporter pathway (22). ABC transporters have been shown to be responsive to the nuclear receptor LXR (24).…”

Section: Y O F T H E Ac H I L L E S T E N D O N O F C a S E 2 Ma S mentioning

confidence: 99%

Identification of a Novel Missense Mutation in the Sterol 27-Hydroxylase Gene in Two Japanese Patients with Cerebrotendinous Xanthomatosis

et al. 2010

View full text Add to dashboard Cite

show abstract

“…In contrast, LXR is widely expressed. In vivo, LXRs are activated by physiologic concentrations of 22(R)-, 24(S)-, and 27-sterol metabolites in addition to 24(S), 25-hydroxycholesterol ligands (Janowski et al 1996;Lehmann et al 1997;Fu et al 2001). Constitutively nuclear LXR/RXR partners bind LXR response elements of two AGGTCA repeats separated by four nucleotides (DR-4).…”

Section: Lxrsmentioning

confidence: 99%

Nuclear receptors, mitochondria and lipid metabolism

2008

View full text Add to dashboard Cite

Lipid metabolism is a continuum from emulsification and uptake of lipids in the intestine to cellular uptake and transport to compartments such as mitochondria. Whether fats are shuttled into lipid droplets in adipose tissue or oxidized in mitochondria and peroxisomes depends on metabolic substrate availability, energy balance and endocrine signaling of the organism. Several members of the nuclear hormone receptor superfamily are lipid-sensing factors that affect all aspects of lipid metabolism. The physiologic actions of glandular hormones (e.g. thyroid, mineralocorticoid and glucocorticoid), vitamins (e.g. vitamins A and D) and reproductive hormones (e.g. progesterone, estrogen and testosterone) and their cognate receptors are well established. The peroxisome proliferator activated receptors (PPARs) and Liver X receptors (LXRs), acting in concert with PPARγ Coactivator 1α (PGC-1α), have been shown to regulate insulin sensitivity and lipid handling. These receptors are the focus of intense pharmacologic studies to expand the armamentarium of small molecule ligands to treat diabetes and the metabolic syndrome (hypertension, insulin resistance, hyperglycemia, dyslipidemia, and obesity). Recently, additional partners of PGC-1α have moved to the forefront of metabolic research, the Estrogen-related Receptors (ERRs). Although no endogenous ligands for these receptors have been identified, phenotypic analyses of knockout mouse models demonstrate an important role for these molecules in substrate sensing and handling as well as mitochondrial function.

show abstract

27-Hydroxycholesterol Is an Endogenous Ligand for Liver X Receptor in Cholesterol-loaded Cells

Cited by 490 publications

References 62 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

Identification of a Novel Missense Mutation in the Sterol 27-Hydroxylase Gene in Two Japanese Patients with Cerebrotendinous Xanthomatosis

Nuclear receptors, mitochondria and lipid metabolism

Contact Info

Product

Resources

About