Ultrastructural analysis of HNE‐treated <i>Saccharomyces cerevisiae</i> cells reveals fragmentation of the vacuole and an accumulation of lipids in the cytosol

Deposition and mobilization of fat in an organism are tightly controlled by multiple levels of endocrine and neuroendocrine regulation. Because these hormonal mechanisms ultimately act by affecting biochemical reactions of fat synthesis or utilization, obesity could be also modulated by altering directly the underlying lipid biochemistry. We have previously shown that genetically modified mice with an elevated level of the lipid peroxidation product 4-HNE become obese. We now demonstrate that the process is phylogenetically conserved and thus likely to be universal. In the nematode C. elegans, disruption of either conjugation or oxidation of 4-HNE leads to fat accumulation, whereas augmentation of 4-HNE conjugation results in a lean phenotype. Moreover, direct treatment of C. elegans with synthetic 4-HNE causes increased lipid storage, directly demonstrating a causative role of 4-HNE. The postulated mechanism, which involves modulation of acetyl-CoA carboxylase activity, could contribute to the triggering and maintenance of the obese phenotype on a purely metabolic level.

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“…(ii) Fat deposition was reported for yeast directly treated with 4‑HNE [31], an experimental design that points to 4‑HNE as the causative agent. …”

Section: Discussionmentioning

confidence: 99%

Fat accumulation in Caenorhabditis elegans triggeredby the electrophilic lipid peroxidation product 4-Hydroxynonenal (4-HNE)

Singh

Niemczyk²,

Zimniak³

et al. 2008

Aging

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“…Cells (2 Â 10 8 ) were fixed in 3% glutaraldehyde for 1 h at room temperature and processed as described by Wonisch et al (4). Finally, cells were resuspended in 500 AL of 100% Spurr resin and transferred to capsules where resin polymerized for 20 h at 60jC.…”

Section: Methodsmentioning

confidence: 99%

Levels of SCS7/FA2H-Mediated Fatty Acid 2-Hydroxylation Determine the Sensitivity of Cells to Antitumor PM02734

et al. 2008

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PM02734 is a novel synthetic antitumor drug that is currently in phase I clinical trials. To gain some insight into its mode of action, we used the yeast Saccharomyces cerevisiae as a model system. Treatment of S. cerevisiae with PM02734 rapidly induced necrosis-like cell death, as also found for mammalian cells treated with its close analogue kahalalide F. We have screened the complete set of 4,848 viable S. cerevisiae haploid deletion mutants to identify genes involved in sensitivity or resistance to PM02734. Forty-five percent of the 40 most sensitive strains identified had a role in intracellular vesicle trafficking, indicating that the drug severely affects this process. A mutant strain lacking the sphingolipid fatty acyl 2-hydroxylase Scs7 was found to be the most resistant to PM02734, whereas overexpression of Scs7 rendered the cells hypersensitive to PM02734. To validate these findings in human cells, we did small interfering RNA experiments and also overexpressed the Scs7 human homologue FA2H in human cancer cell lines. As in yeast, FA2H silencing turned the cells resistant to the drug, whereas FA2H overexpression led to an increased sensitivity. Moreover, exogenous addition of the 2-hydroxylated fatty acid 2-hydroxy palmitic acid to different human cell lines increased their sensitivity to the cytotoxic compound. Taken together, these results suggest that the cell membrane and, in particular, 2-hydroxy fatty acidcontaining ceramides are important for PM02734 activity. These findings may have important implications in the development of PM02734 because tumor cells with high FA2H expression are expected to be particularly sensitive to this drug. [Cancer Res 2008;68(23):9779-87]

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“…However, the correlation in humans between high-fat diet, HNE level in blood and obesity/metabolic syndrome is suggestive, but it does not prove causality. Nevertheless, studies of experimental models have shown that exposure to HNE can induce excessive fat accumulation (Wonisch et al, 2001; Singh et al, 2009). …”

Section: Hne and Ms-related Diseasesmentioning

confidence: 99%

Roles of the lipid peroxidation product 4-hydroxynonenal in obesity, the metabolic syndrome, and associated vascular and neurodegenerative disorders

Mattson

2009

Experimental Gerontology

261

205

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A rising tide of obesity and type 2 diabetes has resulted from the development of technologies that have made inexpensive high calorie foods readily available and exercise unnecessary for many people. Obesity and the metabolic syndrome (insulin resistance, visceral adiposity and dyslipidemia) wreak havoc on cells throughout the body thereby promoting cardiovascular and kidney disease, and degenerative diseases of the brain and body. Obesity and insulin resistance promote disease by increasing oxidative damage to proteins, lipids and DNA as the result of a combination of increased free radical production and an impaired ability of cells to detoxify the radicals and repair damaged molecules. By covalently modifying membrane-associated proteins, the membrane lipid peroxidation product 4-hydroxynonenal (HNE) may play particularly sinister roles in the metabolic syndrome and associated disease processes. HNE can damage pancreatic β cells and can impair the ability of muscle and liver cells to respond to insulin. HNE may promote atherosclerosis by modifying lipoproteins and can cause cardiac cell damage by impairing metabolic enzymes. An adverse role for HNE in the brain in obesity and the metabolic syndrome is suggested by studies showing that HNE levels are increased in brain cells with aging and Alzheimer's disease. HNE can cause the dysfunction and degeneration of neurons by modifying membrane-associated glucose and glutamate transporters, ion-motive ATPases, enzymes involved in amyloid metabolism, and cytoskeletal proteins. Exercise and dietary energy restriction reduce HNE production and may also increase cellular systems for HNE detoxification including glutathione and oxidoreductases. The recent development of low molecular weight molecules that scavenge HNE suggests that HNE can be targeted in the design of drugs for the treatment of obesity, the metabolic syndrome, and associated disorders.

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Ultrastructural analysis of HNE‐treated Saccharomyces cerevisiae cells reveals fragmentation of the vacuole and an accumulation of lipids in the cytosol

Cited by 9 publications

References 18 publications

Fat accumulation in Caenorhabditis elegans triggeredby the electrophilic lipid peroxidation product 4-Hydroxynonenal (4-HNE)

Fat accumulation in Caenorhabditis elegans triggeredby the electrophilic lipid peroxidation product 4-Hydroxynonenal (4-HNE)

Levels of SCS7/FA2H-Mediated Fatty Acid 2-Hydroxylation Determine the Sensitivity of Cells to Antitumor PM02734

Roles of the lipid peroxidation product 4-hydroxynonenal in obesity, the metabolic syndrome, and associated vascular and neurodegenerative disorders

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