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

Hirayama, Takeshi; Honda, Akira; Matsuzaki, Yasushi; Miyazaki, Teruo; Ikegami, Tadashi; Doy, Mikio; Xu, Guowang; Lea, Michael A.; Salen, Gerald

doi:10.1002/hep.21291

Cited by 18 publications

(10 citation statements)

References 45 publications

(36 reference statements)

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“…An important feature of malignant transformation is the loss of cholesterol feedback inhibition mechanism that regulates cholesterol synthesis through the activity of rate-limiting enzyme of cholesterol biosynthesis, HMG CoA reductase [59]. Elevation of cholesterol increases the fluidity of tumour membrane, which relaxes the contact inhibition of tumour cells and hence invades to any part of the body, where it induces secondary tumours [60]. Triglycerides are the major source of metabolic energy and they are the principal storage form of energy.…”

Section: Discussionmentioning

confidence: 99%

Studies on the neuroprotective role of Piper longum in C6 glioma induced rats

2009

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Many naturally occurring substances of plant origin ingested in human diet, exhibit anticarcinogenic and antimutagenic effects. One of the active phytochemical which shows the active anticarcinogenic role is Piper longum Linn. (Pl). Pl is widely used in ayurvedic industry due to its property in healing some of the bodily ailments. Despite being known for the antioxidant, antimicrobial and anticarcinogenic effects, its relation to brain and its tumour development is still scarce. Hence, the experimental glioma model was developed in rats using C6 glioma cells and the effect of Pl was evaluated in the brain tissue of experimental group of rats. From the study, the glioma induced animals showed an increased level of lipid peroxides (LPO), tissue marker enzymes lactate dehydrogenase (LDH), creatine kinase (CK), 5'nucleotidase (5'ND) and acetylcholine esterase (AChE). But Pl treatment (20 mg/kg body weight) significantly attenuated these alterations thereby showing potent anticancer effect in glioma induced rats. In addition, the anticarcinogenic effect of Pl was confirmed by microscopic analysis and the restoration of increased lipids and protein bound carbohydrates (PBCs) in the brain tissue of glioma induced rats. Hence our results implicate a major role for Pl in preventing the cancer development in the experimental glioma model.

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Section: Discussionmentioning

confidence: 99%

Studies on the neuroprotective role of Piper longum in C6 glioma induced rats

2009

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“…However, the hepatic content or blood concentration of 7-KC in hepatoma patients has not been reported. In hepatoma-bearing rats with hyperlipidemia, the mRNA and protein levels of cholesterol efflux pumps ABCA1 and ABCG1 in tumor tissues were significantly higher than their respective levels in host or control livers [15]. In patients with familial combined hyperlipidemia, the cholesterol lowering agent atorvastatin efficiently decreased plasma 7-KC levels to those of normolipidemic controls [16].…”

Section: Introductionmentioning

confidence: 99%

7-Ketocholesterol induces P-glycoprotein through PI3K/mTOR signaling in hepatoma cells

Wang

Chou

Mazumder³

et al. 2013

Biochemical Pharmacology

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7-Ketocholesterol (7-KC) is found at an elevated level in patients with cancer and chronic liver disease. The up-regulation of an efflux pump, P-glycoprotein (P-gp) leads to drug resistance. To elucidate the effect of 7-KC on P-gp, P-gp function and expression were investigated in hepatoma cell lines Huh-7 and HepG2 and in primary hepatocyte-derived HuS-E/2 cells. At a subtoxic concentration, 48-h exposure to 7-KC reduced the intracellular accumulation and cytotoxicity of P-gp substrate doxorubicin in hepatoma cells, but not in HuS-E/2 cells. In Huh-7 cells, 7-KC elevated efflux function through the activation of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. 7-KC activated the downstream protein synthesis initiation factor 4E-BP1 and induced P-gp expression post-transcriptionally. The stimulation of efflux was reversible and could not be prevented by N-acetyl cysteine. Total cellular ATP content remained the same, whereas the lactate production was increased and fluorescence lifetime of protein-bound NADH was shortened. These changes suggested a metabolic shift to glycolysis, but glycolytic inhibitors did not eliminate 7-KC-mediated P-gp induction. These results demonstrate that 7-KC induces P-gp through PI3K/mTOR signaling and decreased the cell-killing efficacy of doxorubicin in hepatoma cells.

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“…Rat serum was prepared in our previous study ( 9 ) and had been stored at Ϫ 20°C until it was used in the present experiments.…”

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confidence: 99%

Highly sensitive quantification of serum malonate, a possible marker for de novo lipogenesis, by LC-ESI-MS/MS

Honda

Yamashita

Ikegami

et al. 2009

Journal of Lipid Research

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This article is available online at http://www.jlr.org Acetyl-CoA carboxylase (ACC) is the rate-controlling enzyme in the fatty acid biosynthetic pathway, and catalyzes the formation of malonyl-CoA from acetyl-CoA plus bicarbonate. Malonyl-CoA is not only substrate for fatty acid synthase (FAS) but is also a potent inhibitor of carnitine palmitoyl transferase 1 ( 1 ), the rate-limiting enzyme of fatty acid ␤ -oxidation. Therefore, malonyl-CoA is a key molecule that controls fatty acid metabolism in the body. In addition, recent studies have shown that the level of hypothalamic malonyl-CoA is dynamically regulated by fasting and feeding and that it alters subsequent feeding behavior ( 2 ).To determine ACC activity in tissues, an invasive tissue biopsy is necessary. However, whole body synthesis of fatty acid may be evaluated by the quantifi cation of serum malonyl-CoA metabolites. This concept originates from our previous studies, which showed that serum concentrations of the immediate products of the rate-controlling enzymes in cholesterol and bile acid biosynthetic pathways refl ected the activities of the rate-controlling enzymes and whole body cholesterol and bile acid biosynthesis ( 3 ). Furthermore, patients with malonyl-CoA decarboxylase (MCD) defi ciency, who must have increased tissue malonyl-CoA concentrations, are characterized by markedly elevated urinary malonic acid (MA), called "malonic aciduria" ( 4 ). This phenomenon suggests that malonyl-CoA is easily hydrolyzed into MA by an unidentifi ed tissue thioesterase(s). Therefore, we thought that serum MA concentrations might well refl ect total body FAS.Abstract We describe a new sensitive and specifi c method for the quantifi cation of serum malonate (malonic acid, MA), which could be a new biomarker for de novo lipogenesis (fatty acid synthesis). This method is based upon a stable isotope-dilution technique using LC-MS/MS. MA from 50 l of serum was derivatized into di-(1-methyl-3-piperidinyl)malonate (DMP-MA) and quantifi ed by LC-MS/MS using the positive electrospray ionization mode. The detection limit of the DMP-MA was approximately 4.8 fmol (500 fg) (signal-to-noise ratio = 10), which was more than 100 times more sensitive compared with that of MA by LC-MS/MS using the negative electrospray ionization mode. The relative standard deviations between sample preparations and measurements made using the present method were 4.4% and 3.2%, respectively, by one-way ANOVA. Recovery experiments were performed using 50 l aliquots of normal human serum spiked with 9.6 pmol (1 ng) to 28.8 pmol (3 ng) of MA and were validated by orthogonal regression analysis. The results showed that the estimated amount within a 95% confi dence limit was 14.1 ± 1.1 pmol, which was in complete agreement with the observed X 0 = 15.0 ± 0.6 pmol, with a mean recovery of 96.0%. This method provides reliable and reproducible results for the quantifi cation of MA in human serum. Abbreviations: ACC, acetyl-CoA carboxylase; DMP-MA, Di-(1-methyl-3-piperidinyl)malonate; FAS, fatty aci...

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

Cited by 18 publications

References 45 publications

Studies on the neuroprotective role of Piper longum in C6 glioma induced rats

Studies on the neuroprotective role of Piper longum in C6 glioma induced rats

7-Ketocholesterol induces P-glycoprotein through PI3K/mTOR signaling in hepatoma cells

Highly sensitive quantification of serum malonate, a possible marker for de novo lipogenesis, by LC-ESI-MS/MS

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