Association of cholesterol oxidation and abnormalities in fatty acid metabolism in cystic fibrosis

Iuliano, Luigi; Monticolo, Roberto; Straface, Giuseppe; Zullo, Sabina; Galli, Francesco; Boaz, Mona; Quattrucci, Serena

doi:10.3945/ajcn.2009.27757

Cited by 43 publications

(38 citation statements)

References 38 publications

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“…Free radical mediated oxidation of cholesterol in the 5,6 position forms 7β-hydroxycholesterol (7β-OHC) and 7-ketocholesterol (7-KC). An elevation of these cholesterol oxidation products (COPs) has been reported in several diseases and pathological models that involve oxidative stress [35][36][37][38].…”

Section: Introductionmentioning

confidence: 99%

Brain Cholesterol Synthesis and Metabolism is Progressively Disturbed in the R6/1 Mouse Model of Huntington’s Disease: A Targeted GC-MS/MS Sterol Analysis

Kreilaus

Spiro

Hannan

et al. 2015

JHD

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. (2015). Brain cholesterol synthesis and metabolism is progressively disturbed in the R6/1 mouse model of Huntington's disease: a targeted GC-MS/MS sterol analysis. Journal of Huntington's Disease, 4 (4), 305-318.Brain cholesterol synthesis and metabolism is progressively disturbed in the R6/1 mouse model of Huntington' s disease: a targeted GC-MS/MS sterol analysis AbstractBackground:Cholesterol has essential functions in neurological processes that require tight regulation of synthesis and metabolism. Perturbed cholesterol homeostasis has been demonstrated in Huntington's disease, however the exact role of these changes in disease pathogenesis is not fully understood. Objective:This study aimed to comprehensively examine changes in cholesterol biosynthetic precursors, metabolites and oxidation products in the striatum and cortex of the R6/1 transgenic mouse model of Huntington's disease. We also aimed to characterise the progression of the physical phenotype in these mice. Methods:GC-MS/MS was used to quantify a broad range of sterols in the striatum and cortex of R6/1 and wild type mice at 6, 12, 20, 24 and 28 weeks of age. Motor dysfunction was assessed over 28 weeks using the RotaRod and the hind-paw clasping tests. Results:24(S)-Hydroxycholesterol and 27-hydroxycholesterol were the major cholesterol metabolites that significantly changed in R6/1 mice. These changes were specifically localised to the striatum and were detected at the end stages of the disease. Cholesterol synthetic precursors (lathosterol and lanosterol) were significantly reduced in the cortex and striatum by 6 weeks of age, prior to the onset of motor dysfunction, as well as the cognitive and affective abnormalities previously reported. Elevated levels of desmosterol, a substrate of delta(24)-sterol reductase (DHCR24), were also detected in R6/1 mice at the end time-point. Female R6/1 mice exhibited a milder weight loss and hind paw clasping phenotype compared to male R6/1 mice, however, no difference in the brain sterol profile was detected between sexes. Conclusion:Several steps in cholesterol biosynthetic and metabolic pathways are differentially altered in the R6/1 mouse brain as the disease progresses and this is most severe in the striatum. This provides further insights into early molecular mediators of HD onset and disease progression and identifies candidate molecular targets for novel therapeutic approaches.

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Section: Introductionmentioning

confidence: 99%

Brain Cholesterol Synthesis and Metabolism is Progressively Disturbed in the R6/1 Mouse Model of Huntington’s Disease: A Targeted GC-MS/MS Sterol Analysis

Kreilaus

Spiro

Hannan

et al. 2015

JHD

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“…Some authors also mention significantly low levels of vitamin E associated with significantly high levels of oxysterols in patients with pancreatic insufficiency or diabetes. These two groups of patients presented more markers of impaired FA profiles (77).…”

Section: Fatty Acidsmentioning

confidence: 84%

“…In fact, high plasma levels of 8-isoPGF2a (produced by the nonenzymatic oxidation of AA) have been reported over the course of respiratory exacerbation periods in CF (160). Markers of protein damage evolve along with the importance of neutrophilia and respiratory dysfunction (77).…”

Section: Pathophysiology Of Respiratory Dysfunctionsmentioning

confidence: 99%

“…Their incorporation into patient management protocols in the form of routine supplementation has therefore been widespread. However, certain studies aimed at evaluating the effects of this type of supplementation in CF patients have revealed generally low levels of antioxidants (CoQ 10, a-tocopherol, vitamin A, GSH) (8,62,77,90,119,159), more or less casting doubt on their efficacy. This was the motivation for various intervention studies aimed at supplementing patients over a determined period and evaluating the impact on their antioxidant profile.…”

Section: Antioxidantsmentioning

confidence: 99%

“…However, various studies show the limited impact of this routine therapy on patients' clinical conditions. In fact, a negligible improvement in anthropometric measures, an increase in saturated FAs and monounsaturated FAs, an increase in DHA/AA ratio, and onset of diabetes-type hepatic and metabolic complications have been reported (34,49,77,108). Some authors also mention significantly low levels of vitamin E associated with significantly high levels of oxysterols in patients with pancreatic insufficiency or diabetes.…”

Section: Fatty Acidsmentioning

confidence: 99%

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Cystic Fibrosis-Related Oxidative Stress and Intestinal Lipid Disorders

Kleme

Lévy²

2015

Antioxidants & Redox Signaling

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Significance: Cystic fibrosis (CF) is the most common lethal genetic disorder in the Caucasian people. It is due to the mutation of cystic fibrosis transmembrane conductance regulator (CFTR) gene located on the long arm of the chromosome 7, which encodes for CFTR protein. The latter, an adenosine triphosphate binding cassette, is a transmembrane chloride channel that is also involved in glutathione transport. As glutathione/glutathione disulfide constitutes the most important pool of cellular redox systems, CFTR defects could thus disrupt the intracellular redox balance. Resulting multisystemic diseases are essentially characterized by a chronic respiratory failure, a pancreatic insufficiency, an essential fatty acid deficiency (EFAD), and inadequate levels of antioxidant vitamins. Recent Advances: The pathophysiology of CF is complex; however, several mechanisms are proposed, including oxidative stress (OxS) whose implication is recognized and has been clearly demonstrated in CF airways. Critical Issues: Little is known about OxS intrinsic triggers and its own involvement in intestinal lipid disorders. Despite the regular administration of pancreatic supplements, high-fat high-calorie diets, and antioxidant fat-soluble vitamins, there is a persistence of steatorrhea, EFAD, and harmful OxS. Intriguingly, several trials with elevated doses of antioxidant vitamins have not yielded significant improvements. Future Directions: The main sources and self-maintenance of OxS in CF should be clarified to improve treatment of patients. Therefore, this review will discuss the potential sources and study the mechanisms of OxS in the intestine, known to develop various complications, and its involvement in intestinal lipid disorders in CF patients. Antioxid. Redox Signal. 22, 614-631.

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Serum metabolomics indicate altered cellular energy metabolism in children with cystic fibrosis

et al. 2013

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Association of cholesterol oxidation and abnormalities in fatty acid metabolism in cystic fibrosis

Abstract: Cystic fibrosis is characterized by relevant cholesterol oxidation that is associated with an abnormal fatty acid profile. The interplay between oxysterols and fatty acids potentially provides insight into the biological mechanisms that underlie this complex disease.

Cited by 43 publications

References 38 publications

Brain Cholesterol Synthesis and Metabolism is Progressively Disturbed in the R6/1 Mouse Model of Huntington’s Disease: A Targeted GC-MS/MS Sterol Analysis

Brain Cholesterol Synthesis and Metabolism is Progressively Disturbed in the R6/1 Mouse Model of Huntington’s Disease: A Targeted GC-MS/MS Sterol Analysis

Cystic Fibrosis-Related Oxidative Stress and Intestinal Lipid Disorders

Serum metabolomics indicate altered cellular energy metabolism in children with cystic fibrosis

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