Oxysterols from human bile induce apoptosis of canine gallbladder epithelial cells in monolayer culture

Seo, Dong Wan; Choi, Hosoon; Lee, Sum P.; Kuver, Rahul

doi:10.1152/ajpgi.00013.2004

Cited by 22 publications

(17 citation statements)

References 59 publications

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“…Oxysterols such as 7-ketocholesterol accumulate in the core of fibrotic plaques (72,73), leading to the suggestion that oxysterols may be involved in atherogenesis (73) and chronic inflammation (74). Atherosclerosis and Alzheimer's disease share many convergent elements (75), including hypercholesterolemia, oxidative stress, and inflammation.…”

Section: Figmentioning

confidence: 99%

Oxidation of Cholesterol by Amyloid Precursor Protein and β-Amyloid Peptide

Nelson

Alkon

2005

Journal of Biological Chemistry

178

129

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Alzheimer's disease (AD) is characterized by accumulation of the neurotoxic peptide ␤-amyloid, which is produced by proteolysis of amyloid precursor protein (APP). APP is a large membrane-bound copper-binding protein that is essential in maintaining synaptic function and may play a role in synaptogenesis. ␤-Amyloid has been shown to contribute to the oxidative stress that accompanies AD. Later stages of AD are characterized by neuronal apoptosis. However, the biochemical function of APP and the mechanism of the toxicity of ␤-amyloid are still unclear. In this study, we show that both ␤-amyloid and APP can oxidize cholesterol to form 7␤-hydroxycholesterol, a proapoptotic oxysterol that was neurotoxic at nanomolar concentrations. 7␤-Hydroxycholesterol inhibited secretion of soluble APP from cultured rat hippocampal H19 -7/IGF-IR neuronal cells and inhibited tumor necrosis factor-␣-converting enzyme ␣-secretase activity but had no effect on ␤-site APPcleaving enzyme 1 activity. 7␤-Hydroxycholesterol was also a potent inhibitor of ␣-protein kinase C, with a K i of ϳ0.2 nM. The rate of reaction between cholesterol and ␤-amyloid was comparable to the rates of cholesterolmetabolizing enzymes (k cat ‫؍‬ 0.211 min ؊1 ). The rate of production of 7␤-hydroxycholesterol by APP was ϳ200 times lower than by ␤-amyloid. Oxidation of cholesterol was accompanied by stoichiometric production of hydrogen peroxide and required divalent copper. The results suggest that a function of APP may be to produce low levels of 7-hydroxycholesterol. Higher levels produced by ␤-amyloid could contribute to the oxidative stress and cell loss observed in Alzheimer's disease.

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Section: Figmentioning

confidence: 99%

Oxidation of Cholesterol by Amyloid Precursor Protein and β-Amyloid Peptide

Nelson

Alkon

2005

Journal of Biological Chemistry

178

129

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“…Human cholangiocarcinoma cell line (10,94) Potential induction of carcinogenesis Ch-one Dog gallbladder epithelial cells in culture (95) Cholesta-4,6-dien-3-one 5b-Cholestan-3-one Lack of mutagenic effects assessed by an in vitro bacterial mutation assay and an in vitro chromosome aberration assay…”

Section: -Oh-chmentioning

confidence: 99%

Cellular toxicity of oxycholesterols

et al. 2006

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Oxycholesterols (OS) are formed from cholesterol or its immediate precursors by enzymatic or free radical action in vivo, or they may be derived from food. OS exhibit a wide spectrum of biological activities. In OS cytotoxicity, several mechanisms seem to be involved: e.g. inhibition of HMG-CoA reductase activity, antiproliferative action, apoptosis induction, replacement of cholesterol by OS in membranes followed by changes in cellular membrane structure and functionality, and immune system functions alteration. Furthermore, OS may be mutagenic and carcinogenic and may serve as intracellular signaling or regulatory molecules. Here we review OS cellular activities with special attention to the cytotoxic action in vivo and in vitro using experimental models.

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“…These new findings generated intriguing questions as to the origin of oxysterols and their pathological significance, leading us [8] and others [19] to hypothesize that they mediate important biological effects, including cytotoxicity [8] and carcinogenesis. The hypothesis that chronic, low grade or asymptomatic bacterial infection, such as present in biliary stones and primary sclerosing cholangitis, can be pathogenetically linked to cancer formation is reinforced by observations in carriers of Salmonella typhi.…”

Section: Resultsmentioning

confidence: 99%

“…The occurrence of oxidized forms of cholesterol (oxysterols) in living tissues has now been known for more than six decades [1] and these compounds have been associated with atherogenicity for forty years [2]. It is now well established that oxysterols are closely associated with the genesis of atherosclerosis [3][4][5] and most probably with various forms of cancer [6][7][8]. Cancer of the biliary system has recently shown an alarming upsurge in incidence and mortality in both the UK and US [9,10] in addition to continuing increases in countries with already high incidence, such as Japan [11].…”

mentioning

confidence: 99%

The production of oxysterols in bile by activated human leukocytes

Haigh

Wong

Lee

2006

Biochemical and Biophysical Research Communications

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Oxysterols are naturally occurring intermediates in the conversion of cholesterol to bile acids, the major route for elimination of cholesterol. Additionally, they are important signaling agents, particularly in control of cholesterol synthesis; however, some species also are cytotoxic and carcinogenic. Oxysterols in plasma, contained in oxidized low-density lipoprotein, are strongly correlated with atherosclerosis. Oxysterols are found in infected human bile and the oxysterol content in gallstones correlates with bacterial DNA in the stones. Here we demonstrate that human leukocytes, activated by the presence of bacterial lipopolysaccharide, are able to oxidize cholesterol to a variety of oxysterols, including species known to be carcinogenic. The occurrence of oxidized forms of cholesterol (oxysterols) in living tissues has now been known for more than six decades [1] and these compounds have been associated with atherogenicity for forty years [2]. It is now well established that oxysterols are closely associated with the genesis of atherosclerosis [3][4][5] and most probably with various forms of cancer [6][7][8]. Cancer of the biliary system has recently shown an alarming upsurge in incidence and mortality in both the UK and US [9,10] in addition to continuing increases in countries with already high incidence, such as Japan [11]. Little is known of the etiology of cholangiocarcinoma and gallbladder cancer. However, we have shown that bacterial infection is involved in the pathogenesis of mixed cholesterol stones and brown pigment stones [12] and that the content of oxysterols is negatively correlated with the cholesterol content of gallstones [13]. We have demonstrated the presence of bacteria in gallstones [12] and of oxysterols in human gallstones and bile [13]. We also have shown that hepatic bile from patients with biliary infection contains significantly higher levels of oxysterols than does such bile from patients lacking infection of the biliary system [18]. We hypothesize that the oxidation of cholesterol in bile occurs as a result of the action of activated leukocytes on invading bacteria. Here we demonstrate that the incubation of activated human peripheral leukocytes with normal human bile, or with model bile, can result in the production of a wide range of oxysterols. Keywords Materials and methods Model bileModel bile was made by dissolving 108 mg of sodium taurocholate (Calbiochem, La Jolla, CA) in 10 ml of methanol and adding 38 mg of phosphatidylcholine (Type XVIE, Sigma, St. Louis, MO). Ten milligrams of three-times recrystallized cholesterol was added with suffcient chloroform to dissolve all components with gentle warming. The solvent was removed on a rotary evaporator at 40 °C, the flask filled with argon, sealed, and stored at -70 °C until used. At that time, 10 ml of DMEM (Gibco, Grand Island, NY) was added with warming to make a clear solution. LeukocytesOne hundred milliliters of blood, drawn from volunteers, was mixed with 100 ml Hanks" BSS (Mediatech, Fisher Scientific, Los...

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Oxysterols from human bile induce apoptosis of canine gallbladder epithelial cells in monolayer culture

Cited by 22 publications

References 59 publications

Oxidation of Cholesterol by Amyloid Precursor Protein and β-Amyloid Peptide

Oxidation of Cholesterol by Amyloid Precursor Protein and β-Amyloid Peptide

Cellular toxicity of oxycholesterols

The production of oxysterols in bile by activated human leukocytes

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