Peroxisomal disorders affecting phytanic acid α-oxidation: a review

2007 ◽  
Vol 35 (5) ◽  
pp. 881-886 ◽  
Author(s):  
A.S. Wierzbicki
Keyword(s):  
Fatty Acids ◽  
Phytanic Acid ◽  
Acid Metabolism ◽  
Differential Regulation ◽  
Peroxisomal Disorders ◽  
Refsum's Disease ◽  
Cytochrome P450 Family ◽  
Active Investigation ◽  
Synthesis And Degradation

Peroxisomes are involved in the synthesis and degradation of complex fatty acids. They contain enzymes involved in the α-, β- and ω-oxidation pathways for fatty acids. Investigation of these pathways and the diseases associated with mutations in enzymes involved in the degradation of phytanic acid have led to the clarification of the pathophysiology of Refsum's disease, rhizomelic chondrodysplasia and AMACR (α-methylacyl-CoA racemase) deficiency. This has highlighted the role of an Fe(II)- and 2-oxoglutarate-dependent oxygenases [PhyH (phytanoyl-CoA 2-hydroxylase), also known as PAHX], thiamin-dependent lyases (phytanoyl-CoA lyase) and CYP (cytochrome P450) family 4A in fatty acid metabolism. The differential regulation and biology of these pathways is suggesting novel ways to treat the neuro-ophthalmological sequelae of Refsum's disease. More recently, the discovery that AMACR and other peroxisomal β-oxidation pathway enzymes are highly expressed in prostate and renal cell cancers has prompted active investigation into the role of these oxidation pathways and the peroxisome in the progression of obesity- and insulin resistance-related cancers.

Role of the AMP-activated protein kinase in regulating fatty acid metabolism during exerciseThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 34 (3) ◽  
pp. 315-322 ◽  
Author(s):  
Gregory R. Steinberg
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Moderate Intensity ◽  
Amp Activated Protein Kinase

During moderate-intensity exercise, fatty acids are the predominant substrate for working skeletal muscle. The release of fatty acids from adipose tissue stores, combined with the ability of skeletal muscle to actively fine tune the gradient between fatty acid and carbohydrate metabolism, depending on substrate availability and energetic demands, requires a coordinated system of metabolic control. Over the past decade, since the discovery that AMP-activated protein kinase (AMPK) was increased in accordance with exercise intensity, there has been significant interest in the proposed role of this ancient stress-sensing kinase as a critical integrative switch controlling metabolic responses during exercise. In this review, studies examining the role of AMPK as a regulator of fatty acid metabolism in both adipose tissue and skeletal muscle during exercise will be discussed. Exercise induces activation of AMPK in adipocytes and regulates triglyceride hydrolysis and esterfication through phosphorylation of hormone sensitive lipase (HSL) and glycerol-3-phosphate acyl-transferase, respectively. In skeletal muscle, exercise-induced activation of AMPK is associated with increases in fatty acid uptake, phosphorylation of HSL, and increased fatty acid oxidation, which is thought to occur via the acetyl-CoA carboxylase-malony-CoA-CPT-1 signalling axis. Despite the importance of AMPK in regulating fatty acid metabolism under resting conditions, recent evidence from transgenic models of AMPK deficiency suggest that alternative signalling pathways may also be important for the control of fatty acid metabolism during exercise.

scholarly journals Refsum's Disease—Use of the Intestinal Lipase Inhibitor, Orlistat, as a Novel Therapeutic Approach to a Complex Disorder

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Nimalie J. Perera ◽  
Barry Lewis ◽  
Huy Tran ◽  
Michael Fietz ◽  
David R. Sullivan
Keyword(s):  
Fatty Acids ◽  
Phytanic Acid ◽  
Retinal Dystrophy ◽  
Neurological Deficits ◽  
Oxidative Enzymes ◽  
Lipase Inhibitor ◽  
Branched Chain Fatty Acids ◽  
Refsum's Disease ◽  
Branched Chain ◽  
Chain Fatty Acids

Refsum's Disease is an inherited metabolic disorder in which a metabolite of branched chain fatty acids accumulates due to lack of appropriate oxidative enzymes. Patients have elevated plasma phytanic acid levels and high concentrations of phytanic acid in a variety of tissues leading to progressive tissue damage. Besides retinal degeneration or retinal dystrophy associated with adult onset retinitis pigmentosa, additional symptoms include chronic polyneuropathy, cerebellar ataxia, sensorineural hearing loss, anosmia, ichthyosis, as well as skeletal, cardiac, hepatic, and renal abnormalities. Current management includes avoidance of dietary sources of branched chain fatty acids and regular plasmapheresis to prevent accumulation of these compounds to ameliorate progressive neurological deficits. Two brothers with Refsum's disease who experienced progressive symptoms despite optimal diet and plasmapheresis were commenced on a novel therapy. We report the effect of the intestinal lipase inhibitor, Orlistat, which led to significant reduction (P-value<0.001on 2-sample unpairedt-test) of mean preplasmapheresis phytanic acid levels with retardation of the progression of most of their dermatological and neurological symptoms.

Role of Phytanoyl-CoA 2-Hydroxylase in Phytanic Acid Metabolism

2004 ◽  
pp. 303-304 ◽  
Author(s):  
Matthew D. Lloyd ◽  
Mridul Mukherji ◽  
Nadia J. Kershaw ◽  
Winnie Chien ◽  
Anthony S. Wierzbicki ◽  
...  
Keyword(s):  
Phytanic Acid ◽  
Acid Metabolism

Inflammation, obesity, and fatty acid metabolism: influence ofn-3 polyunsaturated fatty acids on factors contributing to metabolic syndrome

2007 ◽  
Vol 32 (6) ◽  
pp. 1008-1024 ◽  
Author(s):  
Lindsay E. Robinson ◽  
Andrea C. Buchholz ◽  
Vera C. Mazurak
Keyword(s):  
Metabolic Syndrome ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Polyunsaturated Fatty Acids ◽  
Abdominal Obesity ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Preliminary Evidence ◽  
Postprandial Period

Metabolic syndrome (MetS) comprises an array of metabolic risk factors including abdominal obesity, dyslipidemia, hypertension, and glucose intolerance. Individuals with MetS are at elevated risk for diabetes and cardiovascular disease. Central to the etiology of MetS is an interrelated triad comprising inflammation, abdominal obesity, and aberrations in fatty acid metabolism, coupled with the more recently recognized changes in metabolism during the postprandial period. We review herein preliminary evidence regarding the role of dietary n-3 polyunsaturated fatty acids in modulating each of the components of the triad of adiposity, inflammation, and fatty acid metabolism, with particular attention to the role of the postprandial period as a contributor to the pathophysiology of MetS.

scholarly journals Reprogramming of fatty acid metabolism in cancer

2019 ◽  
Vol 122 (1) ◽  
pp. 4-22 ◽  
Author(s):  
Nikos Koundouros ◽  
George Poulogiannis
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
De Novo ◽  
Great Promise ◽  
Molecular Heterogeneity

AbstractA common feature of cancer cells is their ability to rewire their metabolism to sustain the production of ATP and macromolecules needed for cell growth, division and survival. In particular, the importance of altered fatty acid metabolism in cancer has received renewed interest as, aside their principal role as structural components of the membrane matrix, they are important secondary messengers, and can also serve as fuel sources for energy production. In this review, we will examine the mechanisms through which cancer cells rewire their fatty acid metabolism with a focus on four main areas of research. (1) The role of de novo synthesis and exogenous uptake in the cellular pool of fatty acids. (2) The mechanisms through which molecular heterogeneity and oncogenic signal transduction pathways, such as PI3K–AKT–mTOR signalling, regulate fatty acid metabolism. (3) The role of fatty acids as essential mediators of cancer progression and metastasis, through remodelling of the tumour microenvironment. (4) Therapeutic strategies and considerations for successfully targeting fatty acid metabolism in cancer. Further research focusing on the complex interplay between oncogenic signalling and dysregulated fatty acid metabolism holds great promise to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.

scholarly journals The expanded role of fatty acid metabolism in cancer: new aspects and targets

2019 ◽  
Vol 2 (3) ◽  
pp. 183-191 ◽  
Author(s):  
Ming Chen ◽  
Jiaoti Huang
Keyword(s):  
Fatty Acids ◽  
Cell Proliferation ◽  
Lipid Metabolism ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Acid Metabolism ◽  
Metabolic Reprogramming ◽  
Metabolic Plasticity ◽  
Support Cell

Abstract Cancer cells undergo metabolic reprogramming to support cell proliferation, growth, and dissemination. Alterations in lipid metabolism, and specifically the uptake and synthesis of fatty acids (FAs), comprise one well-documented aspect of this reprogramming. Recent studies have revealed an expanded range of roles played by FA in promoting the aggressiveness of cancer while simultaneously identifying new potential targets for cancer therapy. This article provides a brief review of these advances in our understanding of FA metabolism in cancer, highlighting both recent discoveries and the inherent challenges caused by the metabolic plasticity of cancer cells in targeting lipid metabolism for cancer therapy.

Role of n‐3 Fatty Acids on Bile Acid Metabolism and Transport in Dyslipidemia: A Review

Lipids ◽  
2020 ◽  
Author(s):  
Pooja Acharya ◽  
Vinayak Uppin ◽  
Mehrdad Zarei ◽  
Ramaprasad R. Talahalli
Keyword(s):  
Fatty Acids ◽  
Bile Acid ◽  
Acid Metabolism ◽  
Bile Acid Metabolism

Disorders of peroxisomal metabolism in adults

2020 ◽  
pp. 2157-2173
Author(s):  
Anthony S. Wierzbicki
Keyword(s):  
Fatty Acids ◽  
Phytanic Acid ◽  
Night Vision ◽  
Dietary Interventions ◽  
Peroxisomal Disorders ◽  
Abc Protein ◽  
Brain White Matter ◽  
Multiple Phenotypes ◽  
Time Specific ◽  
Enzymatic Pathways

The peroxisome is a specialized organelle which employs molecular oxygen in the oxidation of complex organic molecules including lipids. Enzymatic pathways for the metabolism of fatty acids, including very long-chain fatty acids (VLCFAs), enable this organelle to carry out β‎-oxidation in partnership with mitochondria. A peroxisomal pathway for isoprenoid lipids derived from chlorophyll, such as phytanic acid, utilizes α‎-oxidation, but a default mechanism involving ω‎-oxidation may also metabolize phytanic acid and its derivatives. The biochemical manifestations, molecular pathology, and diverse clinical features of many peroxisomal disorders have now been clarified, offering the promise of prompt diagnosis, better management, and useful means to provide appropriate genetic counselling for affected families. At the same time, specific treatments including rigorous dietary interventions and plasmapheresis to remove undegraded toxic metabolites offer credible hope of improvement and prevention of disease in affected individuals. X-linked adrenoleukodystrophy (X-ALD)—due to mutations in the gene for an ATP-binding cassette (ABC) protein of unknown function and characterized by accumulation of unbranched saturated VLCFAs, particularly hexacosanoate (C26), in the cholesterol esters of brain white matter, adrenal cortex, and certain sphingolipids of the brain. The disease has multiple phenotypes. Most cases develop increasing handicap; management is palliative and supportive in most instances. Adult Refsum’s disease—due in most cases to mutations in the gene for phytanoyl-CoA hydroxylase (PHYH) such that patients are unable to detoxify phytanic acid by α‎-oxidation and have greatly elevated levels of this in their plasma. Usually presents in late childhood with progressive deterioration of night vision, the occurrence of progressive retinitis pigmentosa, and anosmia. Treatment is by restriction of dietary phytanic acid, with or without its elimination by plasmapheresis or apheresis.

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