Fatty acid‐mediated endoplasmic reticulum stress in the liver in vivo: Differential response to saturated and unsaturated fatty acids

Liver specific deletion of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) induces steatosis and hypersensitivity to insulin. Saturated fatty acids, which induce endoplasmic reticulum stress and cell death, appear to increase PTEN, whereas unsaturated fatty acids which do not induce endoplasmic reticulum stress or cell death reduce this protein. In the present study, the role of PTEN in saturated fatty acid-induced cytotoxicity was examined in H4IIE and HepG2 liver cells. Palmitate and stearate increased the expression of PTEN, whereas the unsaturated fatty acids, oleate and linoleate, reduced PTEN expression in both cell types. SiRNA-mediated knockdown of PTEN did not increase liver cell triglyceride stores or reduce palmitate- or stearate-mediated ER stress or apoptosis. These results suggest that PTEN does not play a significant role in saturated fatty acid-induced cytotoxicity in these liver cell models and in the absence of insulin.

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Fatty acid-mediated endoplasmic reticulum stress in vivo: Differential response to the infusion of Soybean and Lard Oil in rats

Metabolism ◽

10.1016/j.metabol.2012.12.001 ◽

2013 ◽

Vol 62 (5) ◽

pp. 753-760 ◽

Cited By ~ 32

Author(s):

Angela M. Nivala ◽

Lauren Reese ◽

Melinda Frye ◽

Christopher L. Gentile ◽

Michael J. Pagliassotti

Keyword(s):

Endoplasmic Reticulum ◽

Fatty Acid ◽

Endoplasmic Reticulum Stress ◽

Differential Response

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Abstract 4115: Depletion of unsaturated fatty acids by stearoyl-coA desaturase inhibition results in endoplasmic reticulum stress-mediated tumor cell death

10.1158/1538-7445.am2012-4115 ◽

2012 ◽

Author(s):

Urvashi V. Roongta ◽

Jonathan G. Pabalan ◽

Cindy Wang ◽

Rolf-Peter Ryseck ◽

Joseph Fargnoli ◽

...

Keyword(s):

Fatty Acids ◽

Endoplasmic Reticulum ◽

Cell Death ◽

Endoplasmic Reticulum Stress ◽

Tumor Cell ◽

Unsaturated Fatty Acids ◽

Tumor Cell Death ◽

Stearoyl Coa Desaturase

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Docosahexaenoic and Eicosapentaenoic Acids Prevent Altered-Muc2 Secretion Induced by Palmitic Acid by Alleviating Endoplasmic Reticulum Stress in LS174T Goblet Cells

Nutrients ◽

10.3390/nu11092179 ◽

2019 ◽

Vol 11 (9) ◽

pp. 2179

Author(s):

Quentin Escoula ◽

Sandrine Bellenger ◽

Michel Narce ◽

Jérôme Bellenger

Keyword(s):

Fatty Acids ◽

Endoplasmic Reticulum ◽

Palmitic Acid ◽

Er Stress ◽

Unsaturated Fatty Acids ◽

Saturated Fatty Acids ◽

Goblet Cells ◽

The Impact

Diets high in saturated fatty acids (FA) represent a risk factor for the development of obesity and associated metabolic disorders, partly through their impact on the epithelial cell barrier integrity. We hypothesized that unsaturated FA could alleviate saturated FA-induced endoplasmic reticulum (ER) stress occurring in intestinal secretory goblet cells, and consequently the reduced synthesis and secretion of mucins that form the protective mucus barrier. To investigate this hypothesis, we treated well-differentiated human colonic LS174T goblet cells with palmitic acid (PAL)—the most commonly used inducer of lipotoxicity in in vitro systems—or n-9, n-6, or n-3 unsaturated fatty acids alone or in co-treatment with PAL, and measured the impact of such treatments on ER stress and Muc2 production. Our results showed that only eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids protect goblet cells against ER stress-mediated altered Muc2 secretion induced by PAL, whereas neither linolenic acid nor n-9 and n-6 FA are able to provide such protection. We conclude that EPA and DHA could represent potential therapeutic nutrients against the detrimental lipotoxicity of saturated fatty acids, associated with type 2 diabetes and obesity or inflammatory bowel disease. These in vitro data remain to be explored in vivo in a context of dietary obesity.

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Dietary Coleus Amboinicus Herb Decreases Ruminal Methanogenesis and Biohydrogenation, and Improves Meat Quality and Fatty Acid Composition in Longissimus Thoracis of Lambs

10.21203/rs.3.rs-663920/v1 ◽

2021 ◽

Author(s):

Yulianri Rizki Yanza ◽

Malgorzata Szumacher-Strabel ◽

Dorota Lechniak ◽

Sylwester Ślusarczyk ◽

Pawel Kolodziejski ◽

...

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Meat Quality ◽

Methane Production ◽

Fatty Acid Synthase ◽

Unsaturated Fatty Acids ◽

Biologically Active ◽

Coleus Amboinicus

Abstract Background: This study aimed to investigate the effect of biologically active compounds (BAC) of Coleus amboinicus Lour. (CAL) herb fed to growing lambs on ruminal methane production, ruminal biohydrogenation of unsaturated fatty acids and meat characteristics. An in vitro trial (Experiment 1) comprising of control and three experimental diets (CAL constituting 10%, 15%, and 20% of the total diet) was conducted to determine an effective dose for in vivo experiments. After the in vitro trial, two in vivo experiments were conducted on six growing, rumen-cannulated lambs (Experiment 2) and 16 growing lambs (Experiment 3), which were assigned into the control (CON) and one experimental diet (20% of CAL). Several parameters were examined in vitro (pH, ammonia and VFA concentrations, protozoa, methanogens and select bacteria populations) and in vivo (methane production, digestibility, ruminal microorganism populations, meat quality, fatty acids profiles in rumen fluid and meat, transcript expression of 5 genes in meat). Results: The CAL lowered in vitro methane production by 51%. In the in vivo experiments, lambs fed CAL decreased methane production by 20% compared with the CON animals (Experiment 3), which corresponded to the reduced total methanogens counts in all experiments up to 28%, notably Methanobacteriales. In Experiment 3, CAL increased or tended to increase the numbers of Ruminococcus albus, Megasphaeraelsdenii, Butyrivibrioproteoclasticus, and Butyrivibriofibrisolvens. Dietary CAL suppressed the Holotricha population, but increased or tended to increase Entodiniomorpha population in Experiments 2 and 3. An increase in the polyunsaturated fatty acid (PUFA) proportion in the rumen of lambs was noted in response to the CAL diet, which was mainly attributable to the increase in C18:3 cis-9 cis-12 cis-15 (LNA) proportion. The CAL reduced the mRNA expressions of four investigated genes in meat (fatty acid synthase, stearoyl-CoA desaturase, lipoprotein lipase, and fatty acid desaturase 1). Conclusions:Summarizing, polyphenols of CAL (20% in diet) origin can mitigate ruminal methane production by inhibiting the methanogens communities. Supplementation of CAL also provides favorable conditions in the rumen by modulating ruminal bacteria involved in fermentation and biohydrogenation of fatty acids. CAL elevated the LNA concentration, which led to improved meat quality through increased deposition of n-3 PUFA.

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In vivo Cerebral Incorporation of Radiolabeled Fatty Acids after Acute Unilateral Orbital Enucleation in Adult Hooded Long-Evans Rats

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1994.38 ◽

1994 ◽

Vol 14 (2) ◽

pp. 312-323 ◽

Cited By ~ 22

Author(s):

S. Wakabayashi ◽

L. M. Freed ◽

J. M. Bell ◽

S. I. Rapoport

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Unsaturated Fatty Acids ◽

Visual Stimulation ◽

Lateral Geniculate Body ◽

Brain Regions ◽

Visual Areas ◽

Awake Rat ◽

Long Evans

We examined effects of acute unilateral enucleation on incorporation from blood of intravenously injected unsaturated [1-14C]arachidonic acid ([14C]AA) and [1-14C]docosahexaenoic acid ([14C]DHA), and of saturated [9,10-3H]palmitic acid ([3H]PA), into visual and nonvisual brain areas of awake adult Long-Evans hooded rats. Regional cerebral metabolic rate for glucose (rCMRglc) values also were assessed with 2-deoxy-d-[1-14C]glucose ([14C]DG). One day after unilateral enucleation, an awake rat was placed in a brightly lit visual stimulation box with black and white striped walls, and a radiolabeled fatty acid was infused for 5 min or [14C]DG was injected as a bolus. [14C]DG also was injected in a group of rats kept in the dark for 4 h. Fifteen minutes after starting an infusion of a radiolabeled fatty acid, or 45 min after injecting [14C]DG, the rat was killed and the brain was prepared for quantitative autoradiography. Incorporation coefficients k* of fatty acids, or rCMRglc values, were calculated in homologous brain regions contralateral and ipsilateral to enucleation. As compared with ipsilateral regions, rCMRglc was reduced significantly (by as much as - 39%) in contralateral visual areas, including the superior colliculus, lateral geniculate body, and layers I, IV, and V of the primary (striate) and secondary (association, extrastriate) visual cortices. Enucleation did not affect incorporation of [3H]PA into contralateral visual regions, but reduced incorporation of [14C]AA and of [14C]DHA by - 18.5 to - 2.1%. Percent reductions were correlated with percent reductions in rCMRglc in most but not all regions. No effects were noted at any of nine nonvisual structures that were examined. These results indicate that enucleation acutely reduces neuronal activity in contralateral visual areas of the awake rat and that the reductions are coupled to reduced incorporation of unsaturated fatty acids into sn-2 regions of phosphatidylcholine, phosphatidylinositol, and phosphatidylethanolamine. Reduced fatty acid incorporation likely reflects reduced activity of phospholipases A2 and/or phospholipase C.

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Unsaturated fatty acids activate glycogen phosphorylase in cultured rat hepatocytes

Biochemical Journal ◽

10.1042/bj2760209 ◽

1991 ◽

Vol 276 (1) ◽

pp. 209-215 ◽

Cited By ~ 6

Author(s):

A Gomez-Muñoz ◽

P Hales ◽

D N Brindley

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Glycogen Phosphorylase ◽

Unsaturated Fatty Acids ◽

High Fatty Acid ◽

Rat Hepatocytes ◽

Phosphorylase Activity ◽

Cultured Rat Hepatocytes ◽

Glycogen Phosphorylase Activity

Oleate, linoleate, linolenate, arachidonate and eicosapentaenoate, but not myristate, palmitate and stearate, stimulated glycogen phosphorylase activity by 2-8-fold when added to cultured rat hepatocytes. Addition of BSA or Ca2- to the incubation medium decreased the stimulating effects of the unsaturated fatty acids. The combination of oleate or linolenate, with corticosterone, testosterone or estradiol produced synergistic stimulations of phosphorylase activity. The stimulation of glycogen phosphorylase activity by linolenate was inhibited by staurosporine or sphingosine. Staurosporine (80 nM) alone also decreased basal phosphorylase activities by about 60%. The results show that unsaturated fatty acids can be used as model agonists to stimulate phosphorylase activity by a mechanism that probably involves protein kinase C. On the basis of the fatty acid: BSA ratios used, this stimulation should only occur in vivo at high fatty acid concentrations when accompanied by hypoalbuminaemia.

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The effect of dietary fats on the composition of the liver endoplasmic reticulum and oxidative drug metabolism

British Journal Of Nutrition ◽

10.1079/bjn19790061 ◽

1979 ◽

Vol 41 (3) ◽

pp. 465-475 ◽

Cited By ~ 30

Author(s):

Catherine T. Hammer ◽

E. D. Wills

Keyword(s):

Fatty Acids ◽

Endoplasmic Reticulum ◽

Fatty Acid Composition ◽

Fatty Acid ◽

Linoleic Acid ◽

Acid Composition ◽

Unsaturated Fatty Acids ◽

High Rate ◽

Oxidative Demethylation ◽

Maize Oil

1. The dependence of the rate of oxidative demethylation in the liver endoplasmic reticulum on the fatty acid composition of the endoplasmic reticulum has been studied by varying the lipid content of the diet.2. The rate of oxidative demethylation was markedly dependent on the percentage of linoleic acid (18:2) incorporated into the membrane. Feeding diets containing (g/kg) 100 coconut oil, 100 lard or 100 maize oil caused respectively the incorporation of 7.6, 10.3 and 25.1% linoleic acid (18:2) and a demethylation rate of 3.26, 3.15 and 5.03 nmol formaldehyde/min per mg protein. Feeding 100 g herring oil/kg diet caused incorporation of only 5.1% C18:2 but also 27.2% ωw3 unsaturated fatty acids, including 8.7% eicosapentaenoic acid (20:5) and 17.0% docosahexaenoic acid (22.6) and caused a very high rate of oxidative demethylation (6.53 nmol formaldehyde/min per mg protein).3. Destruction of the polyunsaturated fatty acids in herring oil by irradiation with 400 krad caused incorporation of a smaller quantity of ωw3 unsaturated acids into the endoplasmic reticulum and decreased the rate of oxidative demethylation (4.83 nmol formaldehyde/min per mg protein).4. The inductive effects of phenobarbitone on oxidative demethylation were partially dependent on changes in the fatty acid composition of the endoplasmic reticulum. Phenobarbitone (100 mg/kg) increased the percentage of C18:2 from 25.1 to 29.4% in rats given a maize-oil diet, increased the percentage of C20:5 from 8.7 to 10.3% in rats given a herring-oil diet and decreased the percentage of arachidonic acid (20:4) and C22:6 in rats given a lard, maize-oil, herring-oil or irradiated-herring-oil diet.5. Intraperitoneal α-tocopherol (50 mg/kg) increased the percentage of C20:4 from 11.1 to 13.1% in rats given a lard diet and from 5.9 to 7.3% in rats given a herring-oil diet.6. It is concluded that dietary C18:2 is an important factor in the regulation of the rate of oxidative demethylation in the liver endoplasmic reticulum but this may be replaced effectively by dietary C20:5 ω3 and C22:6 ω3 acids. Oxidative demethylation is regulated by changes in the fatty acid composition of the membranes of the liver endoplasmic reticulum.

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A Bi-Enzymatic Cascade Pathway Towards FAHFAs

10.26434/chemrxiv.13650629.v1 ◽

2021 ◽

Author(s):

Yan Zhang ◽

Bekir Engin Eser ◽

Zheng Guo

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Unsaturated Fatty Acids ◽

Operation Mode ◽

Hydroxy Fatty Acids ◽

Fatty Acid Esters ◽

One Pot ◽

Preparative Scale

Recently discovered endogenous mammalian lipids fatty acid esters of hydroxy fatty acids (FAHFAs), proved to <a></a><a>have anti-inflammatory and anti-diabetic effects</a>. Due to their extremely low abundancies in vivo, forging a feasible scenario for FAHFA synthesis is critical for their use in uncovering biological mechanism or clinical trials. Here, we showcase a fully enzymatic approach, a novel in vitro bi-enzymatic cascade system, enabling an effective conversion of nature-abundant fatty acid into FAHFAs. Two hydratases <a></a><a>from L. acidophilus </a>were used for converting unsaturated fatty acids to various stereospecific hydroxy fatty acids, followed by esterification with another fatty acid catalyzed by C. antarctica lipase A (CALA). Various FAHFAs were synthesized in a preparative scale using this bi-enzymatic approach in a one-pot two-step operation mode. In all, we demonstrated that hydratase-CALA system promises a sustainable solution to the synthesis of structure-diverse stereospecific FAHFAs.

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Palmitate modulates intracellular signaling, induces endoplasmic reticulum stress, and causes apoptosis in mouse 3T3-L1 and rat primary preadipocytes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00523.2006 ◽

2007 ◽

Vol 293 (2) ◽

pp. E576-E586 ◽

Cited By ~ 156

Author(s):

Wen Guo ◽

Siu Wong ◽

Weisheng Xie ◽

Tianluo Lei ◽

Zhijun Luo

Keyword(s):

Fatty Acids ◽

Endoplasmic Reticulum ◽

Fatty Acid ◽

Er Stress ◽

Intracellular Signaling ◽

Unsaturated Fatty Acids ◽

Glycogen Synthase ◽

Prolonged Incubation ◽

Apoptotic Effect ◽

Induced Apoptosis

Although fatty acids enhance preadipocyte differentiation in the presence of adequate hormone cocktails, little is known regarding their effects in the absence of these hormones. We have now shown that palmitate, a common long-chain saturated fatty acid, induced apoptosis in both mouse 3T3-L1 and rat primary preadipocytes grown in a normal serum-containing medium. Treatment of preadipocytes with palmitate induced multiple endoplasmic reticulum (ER) stress responses, evidenced by increased protein content of CHOP and GRP78 and splicing of XBP-1 mRNA, as well as altered phosphorylation of eIF2α and increased phosphorylation of JNK and Erk1/2. Intriguingly, palmitate induced an early activation of Akt but diminished both Akt activation and its protein mass after prolonged incubation (>6 h). In association with these changes, palmitate reduced expression of β-catenin and its downstream target, c-Myc and cyclin D1, two key prosurvival proteins. Overexpression of constitutively active Akt did not block the apoptotic effect of palmitate. Cotreatment with unsaturated fatty acids (oleate, linoleate) or with LiCl (a glycogen synthase kinase-3β inhibitor) attenuated the palmitate-induced apoptosis. Subsequent analysis suggested that the unsaturated fatty acids probably counteracted palmitate by reducing, not eliminating, ER stress, whereas LiCl probably improved viability by activating the Wnt signaling pathway. Cotreatment of palmitate with a standard adipogenic hormone cocktail also abolished the apoptotic effect and promoted adipocyte differentiation. Collectively, our results suggest that palmitate causes multiple cellular stresses that may lead to apoptosis in preadipocytes in the absence of adipogenic stimuli, highlighting the importance of exogenous hormones in directing cell fate in response to increased fatty acid influx.

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