Distinct gene expression profiles characterize cellular responses to palmitate and oleate

Das, Swapan K.; Mondal, Ashis; Elbein, Steven C.

doi:10.1194/jlr.m004275

Cited by 30 publications

(30 citation statements)

References 38 publications

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“…OA has been shown to prevent PA‐induced ER stress6 through down‐regulation of Pik3ip1 34. Our data indicate that the baseline amount of OA in ATGL KO mice may have a protective function against PA‐derived ER stress.…”

Section: Discussionmentioning

confidence: 61%

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Absence of adipose triglyceride lipase protects from hepatic endoplasmic reticulum stress in mice

Fuchs¹,

Claudel²,

Kumari³

et al. 2012

Hepatology

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Nonalcoholic fatty liver disease (NAFLD) is characterized by triglyceride (TG) accumulation and endoplasmic reticulum (ER) stress. Because fatty acids (FAs) may trigger ER stress, we hypothesized that the absence of adipose triglyceride lipase (ATGL/PNPLA2)-the main enzyme for intracellular lipolysis, releasing FAs, and closest homolog to adiponutrin (PNPLA3) recently implicated in the pathogenesis of NAFLD-protects against hepatic ER stress. Wild-type (WT) and ATGL knockout (KO) mice were challenged with tunicamycin (TM) to induce ER stress. Serum biochemistry, hepatic TG and FA profiles, liver histology, and gene expression for markers of hepatic lipid metabolism, ER stress, and inflammation were explored. Moreover, cell-culture experiments were performed in Hepa1.6 cells after the knockdown of ATGL before FA and TM treatment. TM increased hepatic TG accumulation in ATGL KO, but not in WT, mice. Lipogenesis and b-oxidation were repressed at the gene-expression level (sterol regulatory element-binding transcription factor 1c, fatty acid synthase, acetyl coenzyme A carboxylase 2, and carnitine palmitoyltransferase 1 alpha) in both WT and ATGL KO mice. Genes for very-low-density lipoprotein (VLDL) synthesis (microsomal triglyceride transfer protein and apolipoprotein B) were down-regulated by TM in WT and even more in ATGL KO mice, which displayed strongly reduced serum VLDL cholesterol levels. Notably, ER stress markers glucose-regulated protein, C/EBP homolog protein, spliced X-box-binding protein, endoplasmic-reticulum-localized DnaJ homolog 4, and inflammatory markers Tnfa and iNos were induced exclusively in TM-treated WT, but not ATGL KO, mice. Total hepatic FA profiling revealed a higher palmitic acid/oleic acid (PA/OA) ratio in WT mice, compared to ATGL KO mice, at baseline. Phosphoinositide-3-kinase inhibitor-known to be involved in FA-derived ER stress and blocked by OA-was increased in TM-treated WT mice only. In line with this, in vitro OA protected hepatocytes from TM-induced ER stress. Conclusions: Lack of ATGL may protect from hepatic ER stress through alterations in FA composition. ATGL could constitute a new therapeutic strategy to target ER stress in NAFLD. (HEPATOLOGY 2012;56:270-280)

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Section: Discussionmentioning

confidence: 61%

“…6D). Pik3ip1 expression is induced by PA in vitro 34 and plays an essential role in PA‐induced ER stress. Taken together, these data suggest that saturated FAs, as with PA, are able to induce hepatic ER stress through activation of the Pi3K inhibitor in WT mice.…”

Section: Resultsmentioning

confidence: 99%

Absence of adipose triglyceride lipase protects from hepatic endoplasmic reticulum stress in mice

Fuchs¹,

Claudel²,

Kumari³

et al. 2012

Hepatology

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“…Effects of Modulating DES1 Expression on Insulin SignalingMany protective effects of oleate in palmitate-induced toxicity have been reported previously (11,12,25,38,39). Coll et al (11) demonstrated oleate protects palmitate-induced insulin resistance and inflammation.…”

Section: Restoration Of Insulin Signaling By Oleate Can Be Overcome Bmentioning

confidence: 96%

Differential Regulation of Dihydroceramide Desaturase by Palmitate versus Monounsaturated Fatty Acids

Ross

Geng

et al. 2011

Journal of Biological Chemistry

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Much data implicate saturated fatty acids in deleterious processes associated with obesity, diabetes, and the metabolic syndrome. Many of these changes may be due to aberrant generation of bioactive lipids when saturated fatty acid availability to tissues is increased. On the other hand, studies are emerging that implicate the monounsaturated fatty acid oleate in protection from saturated fat mediated toxicity; however, the mechanisms are not well understood. Our data demonstrate a novel role for palmitate in increasing mRNA encoding DES1, which is the enzyme responsible for generating ceramide from its precursor dihydroceramide and thus controls synthesis of the bioactive lipid ceramide. Moreover, co-treatment with oleate prevented the increase in ceramide, and this occurred through attenuation of the increase in message and activity of DES1. Knockdown of DES1 also protected from palmitate-induced insulin resistance, and overexpression of this enzyme ameliorated the protective effect of oleate. Together, these findings provide insight into the mechanisms of oleate-mediated protection against metabolic disease and provide novel evidence for fatty acid-mediated regulation of a key enzyme of ceramide biosynthesis.The rise in obesity in recent years has initiated a pandemic of metabolic disease including heart disease and diabetes (1, 2). Perturbations in lipid metabolism and/or endocrine function that occur in obesity likely mediate the development of a disorders, including insulin resistance, nonalcoholic fatty liver disease, pancreatic cell death, hypertension, and the "metabolic syndrome" (3, 4). Although the mechanistic links between obesity and these pathophysiological processes remain incompletely understood, one proposed mechanism is that the elevation in plasma lipids associated with obesity overloads tissues with precursors for synthesis of bioactive lipids, including diacylglycerols (DAG) 2 and ceramides (5, 6).Epidemiological data link diets high in saturated fatty acids with increased incidence of metabolic disease (6, 7). Supporting a mechanistic connection between saturated fatty acids and metabolic syndrome, many studies demonstrate that the saturated fatty acid palmitate promotes insulin resistance in heart, adipose, and skeletal muscle (8 -10). On the other hand, data are emerging which support that unsaturated fatty acids such as oleate have protective effects against palmitate toxicity, though the mechanisms are not fully understood (11,12).Several studies demonstrate that ceramide plays a key role in insulin resistance in human skeletal muscle cells (13-15). Biosynthesis of sphingolipids including ceramide begins with condensation of serine with acyl-CoA such as palmitoyl-CoA. Exposing muscle cells to palmitate increased ceramide synthesis and inhibited insulin stimulation of Akt/protein kinase B, a serine/threonine kinase that is a central mediator of insulinstimulated anabolic metabolism (13); moreover, inhibiting ceramide synthesis negated the antagonistic effect of saturated free fatty acid...

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“…Other in vitro studies showed that palmitate may induce endoplasmatic reticulum (ER) and oxidative stress in hepatocytes [15] and trigger the inflammasome via the activation of macrophages through TLR2/1 dimerization [16]. On the contrary, the contribution of unsaturated fatty acids (e.g., oleate, linoleate) to insulin resistance is still debated; they seem unable to affect the cell, but can impact TG storage [17]. Finally, FFAs are the source of diacyl glycerol (DAG), triglycerides and other metabolites, such as ceramides, which are synthesized in the ER of hepatocytes from long-chain SFA, as a substrate [18].…”

Section: Circulating Lipidsmentioning

confidence: 99%

Pathophysiology of Non Alcoholic Fatty Liver Disease

Petta

Gastaldelli

Rebelos

et al. 2016

IJMS

143

105

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The physiopathology of fatty liver and metabolic syndrome are influenced by diet, life style and inflammation, which have a major impact on the severity of the clinicopathologic outcome of non-alcoholic fatty liver disease. A short comprehensive review is provided on current knowledge of the pathophysiological interplay among major circulating effectors/mediators of fatty liver, such as circulating lipids, mediators released by adipose, muscle and liver tissues and pancreatic and gut hormones in relation to diet, exercise and inflammation.

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Distinct gene expression profiles characterize cellular responses to palmitate and oleate

Cited by 30 publications

References 38 publications

Absence of adipose triglyceride lipase protects from hepatic endoplasmic reticulum stress in mice

Absence of adipose triglyceride lipase protects from hepatic endoplasmic reticulum stress in mice

Differential Regulation of Dihydroceramide Desaturase by Palmitate versus Monounsaturated Fatty Acids

Pathophysiology of Non Alcoholic Fatty Liver Disease

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