Autism - Oleic Acid
Oleic Acid induces Autophagy

Adrenoleukodystrophy

ALD is a disorder of peroxisomal fatty acid beta oxidation which results in the accumulation of very long chain fatty acids(LIPIDS) in tissues throughout the body. The most severely affected tissues are the myelin in the central nervous system, the adrenal cortex and the Leydig cells in the testes. Clinically, ALD is a heterogenous disorder, presenting with several distinct phenotypes, and no clear pattern of genotype-phenotype correlation.
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As an X-linked disorder, ALD presents most commonly in males(same as Autism), however approximately 50% of heterozygote females show some symptoms later in life. Approximately two-thirds of ALD patients will present with the childhood cerebral form of the disease, which is the most severe form. It is characterized by normal development in early childhood, followed by rapid degeneration to a vegetative state.

CAUSATION
downregulation of autophagy due to lysosomal dysfunction

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590273/

Autophagy. 2013 Mar 1; 9(3): 442–444.

Dysfunctional lysosomal autophagy leads to peroxisomal oxidative
burnout and damage during endotoxin-induced stress

Radovan Vasko 1 , 2 ,* and Michael S. Goligorsky 1

Abstract

Mammalian peroxisomes are ubiquitous organelles that possess a comprehensive ensemble of more than 50 enzymes. Cells regulate the number of organelles through dynamic interplay between biogenesis and degradation. Under basal conditions, approximately 30% of the peroxisomal pool is turned over daily. Recycling of peroxisomes is necessary for preservation of their functional competence, and correctly functioning autophagic/lysosomal pathways play a central role.

In this study, we investigated

(1) how lipopolysaccharide (LPS) influences peroxisomal dynamics and functions; and

(2) how a superimposed lysosomal dysfunction affects pexophagy and modifies peroxisomal responses to LPS.

We demonstrated that a transiently increased autophagic degradation of peroxisomes, pexophagy, followed by increased proliferation of peroxisomes is a default response to endotoxic stress. Impairment of autophagy due to lysosomal dysfunction, however, abolishes the above peroxisomal dynamics and results in accumulation of functionally compromised peroxisomes.

These exhibit an imbalance between preserved hydrogen peroxide (H2O2)-generating acyl-CoA oxidase (ACOX) and dysfunctional/inactivated catalase (CAT), which leads to intra-peroxisomal redox disequilibrium. This metabolic-oxidative mismatch causes further worsening of peroxisomal functions, peroxisomal burnout, with the consequence of enhanced oxidative stress and aggravated organ injury.

REVERSAL OF CAUSATION
upregulation of autophagy via oleic acid

http://www.ncbi.nlm.nih.gov/pubmed/25586377

2015 Apr 15;34(8):1025-41. doi: 10.15252/embj.201489363. Epub 2015 Jan 13.

Unsaturated fatty acids induce non-canonical autophagy

Abstract

To obtain mechanistic insights into the cross talk between lipolysis and autophagy, two key metabolic responses to starvation, we screened the autophagy-inducing potential of a panel of fatty acids in human cancer cells. Both saturated and unsaturated fatty acids such as palmitate and oleate, respectively, triggered autophagy, but the underlying molecular mechanisms differed. Oleate, but not palmitate, stimulated an autophagic response that required an intact Golgi apparatus.

Conversely, autophagy triggered by palmitate, but not oleate, required AMPK, PKR and JNK1 and involved the activation of the BECN1/PIK3C3 lipid kinase complex. Accordingly, the downregulation of BECN1 and PIK3C3 abolished palmitate-induced, but not oleate-induced, autophagy in human cancer cells. Moreover, Becn1(+/-) mice as well as yeast cells and nematodes lacking the ortholog of human BECN1 mounted an autophagic response to oleate, but not palmitate.

Thus, unsaturated fatty acids induce a non-canonical, phylogenetically conserved, autophagic response that in mammalian cells relies on the Golgi apparatus.

http://www.ncbi.nlm.nih.gov/pubmed/24857031

2014 Sep;25(9):903-13. doi: 10.1016/j.jnutbio.2014.04.001. Epub 2014 Apr 24.

Synergistic effect of natural compounds on the fatty acid-induced autophagy of activated hepatic stellate cells.

Abstract

Autophagy, a lysosomal pathway to maintain cellular homeostasis, is mediated via the mammalian target of rapamycin (mTOR)-dependent pathways. Hepatic stellate cells (HSCs), previously termed fat- or vitamin A-storing cells, can transdifferentiate into myofibroblast-like cells and are the most relevant cell type for overproduction of extracellular matrix (ECM) and development of liver fibrosis during injury. However, the role of autophagy in fat metabolism of HSCs remains unclear.

This study investigates the regulatory effect of natural compounds on fatty acid-induced autophagy pathways of nonchemical-induced HSC (NHSC) and thioacetamide-induced HSC.

Oleic acid (OA) and palmitic acid (PA) have shown a significant effect on cell proliferation with oil red O staining and Western blot confirming that OA and PA induce fat storage ability and autophagy protein expression in NHSC.

http://www.ncbi.nlm.nih.gov/pubmed/24120424

2014 Jan 3;224(1):114-20. doi: 10.1016/j.toxlet.2013.09.018. Epub 2013 Oct 10.

Role of p53 in the cellular response following oleic acid accumulation in Chang liver cells.

Park EJ¹, Lee AY, Chang SH, Yu KN, Kim JH, Cho MH.

Abstract

Abnormal accumulation of fatty acids triggers the harmful cellular response called lipotoxicity. In this study, we investigated the cellular response following accumulation of oleic acid (OA), a monounsaturated fatty acid, in human Chang liver cells. OA droplets were distributed freely in the cytoplasm and/or degraded within lysosomes. OA exposure increased ATP production and concomitantly dilated mitochondria.

At 24h after OA exposure, cell viability decreased slightly and was coupled with a reduction in mitochondrial Ca(2+) concentration, the alteration in cell viability was also associated with the generation of reactive oxygen species and changes in the cell cycle. Moreover, OA treatment increased the expression of autophagy- and apoptotic cell death-related proteins in a dose-dependent manner.

http://www.ncbi.nlm.nih.gov/pubmed/23133576

PLoS One. 2012;7(10):e48235. doi: 10.1371/journal.pone.0048235. Epub 2012 Oct 25.

2-Hydroxyoleic acid induces ER stress and autophagy in various human glioma cell lines.

Marcilla-Etxenike A1, Martín ML, Noguera-Salvà MA, García-Verdugo JM, Soriano-Navarro M, Dey I, Escribá PV, Busquets X.

Abstract

BACKGROUND:

2-Hydroxyoleic acid is a synthetic fatty acid with potent anti-cancer activity which does not induce undesired side effects. However, the molecular and cellular mechanisms by which this compound selectively kills human glioma cancer cells without killing normal cells is not fully understood. The present study was designed to determine the molecular bases underlying the potency against 1321N1, SF-767 and U118 human glioma cell lines growth without affecting non cancer MRC-5 cells.

METHODOLOGY/PRINCIPAL FINDINGS:

The cellular levels of endoplasmic reticulum (ER) stress, unfolded protein response (UPR) and autophagy markers were determined by quantitative RT-PCR and immunoblotting on 1321N1, SF-767 and U118 human glioma cells and non-tumor MRC-5 cells incubated in the presence or absence of 2OHOA or the ER stress/autophagy inducer, palmitate. The cellular response to these agents was evaluated by fluorescence microscopy, electron microscopy and flow cytometry. We have observed that 2OHOA treatments induced augments in the expression of important ER stress/UPR markers, such as phosphorylated eIF2α, IRE1α, CHOP, ATF4 and the spliced form of XBP1 in human glioma cells. Concomitantly, 2OHOA led to the arrest of 1321N1 cells in the G(2)/M phase of the cell cycle, with down-regulation of cyclin B1 and Cdk1/Cdc2 proteins in the three glioma cell lines studied.

Finally, 2OHOA induced autophagy in 1321N1, SF-767 and U118 cells, with the appearance of autophagic vesicles and the up-regulation of LC3BI, LC3BII and ATG7 in 1321N1 cells, increases of LC3BI, LC3BII and ATG5 in SF-767 cells and up-regulation of LC3BI and LC3BII in U118 cells. Importantly, 2OHOA failed to induce such changes in non-tumor MRC-5 cells.

CONCLUSION/SIGNIFICANCE:

The present results demonstrate that 2OHOA induces ER stress/UPR and autophagy in human glioma (1321N1, SF-767 and U118 cell lines) but not normal (MRC-5) cells, unraveling the molecular bases underlying the efficacy and lack of toxicity of this compound.

Induced autophagy prevents lipid over-accumulation
which is the key feature of Adrenoleukodystrophy

http://www.ncbi.nlm.nih.gov/pubmed/19339967

Nature. 2009 Apr 30;458(7242):1131-5. doi: 10.1038/nature07976. Epub 2009 Apr 1.

Autophagy regulates lipid metabolism.

Singh R1, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ.

Abstract

The intracellular storage and utilization of lipids are critical to maintain cellular energy homeostasis. During nutrient deprivation, cellular lipids stored as triglycerides in lipid droplets are hydrolysed into fatty acids for energy. A second cellular response to starvation is the induction of autophagy, which delivers intracellular proteins and organelles sequestered in double-membrane vesicles (autophagosomes) to lysosomes for degradation and use as an energy source.
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Lipolysis and autophagy share similarities in regulation and function but are not known to be interrelated. Here we show a previously unknown function for autophagy in regulating intracellular lipid stores (macrolipophagy). Lipid droplets and autophagic components associated during nutrient deprivation, and inhibition of autophagy in cultured hepatocytes and mouse liver increased triglyceride storage in lipid droplets.
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This study identifies a critical function for autophagy in lipid metabolism that could have important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome.

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