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dag-diacylglycerol

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Metformin, AMPK, and liver insulin resistance. Metformin-induced activation...
Published: 16 January 2018
Figure 2 Metformin, AMPK, and liver insulin resistance. Metformin-induced activation of AMPK in the liver suppresses de novo lipogenesis through phosphorylation and inhibition of ACC. Salsalate (a dimer of salicylate) also suppresses de novo lipogenesis by activating AMPK and inducing mitochondria... More
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Possible mechanism of β-cell glucolipotoxicity implicating malonyl-CoA, PPA...
Published: 01 December 2002
FIG. 4. Possible mechanism of β-cell glucolipotoxicity implicating malonyl-CoA, PPAR-α, PPAR-γ, SREBP-1c, and altered lipid partitioning. ACO, acyl-CoA oxidase; DAG, diacylglycerol; detox, detoxification; G3P, glycerol 3-phosphate; PL, phospholipid; UCP2, uncoupling protein 2. FIG. 4. Possible m... More
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Schematic diagram summarizing a proposed molecular model for SMIT1 and PI s...
Published: 15 February 2017
Figure 8 Schematic diagram summarizing a proposed molecular model for SMIT1 and PI signaling in pancreatic β-cells. SMIT1 transports MI into β-cells and in turn regulates the intracellular PIP2 level and its subsequent downstream signaling cascades. PIP2 potentiates insulin secretion by modulating the intracellular Ca2+ level, whereas PIP3 regulates β-cell function and survival through activation of PI3K/Akt signaling pathway. DAG, diacylglycerol. Figure 8. Schematic diagram summarizing a proposed molecular model for SMIT1 and PI signaling in pancreatic β-cells. SMIT1 transports MI into β-cells and in turn regulates the intracellular PIP2 level and its subsequent downstream signaling cascades. PIP2 potentiates insulin secretion by modulating the intracellular Ca2+ level, whereas PIP3 regulates β-cell function and survival through activation of PI3K/Akt signaling pathway. DAG, diacylglycerol. More
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Investigational drugs for treating NASH. The proposed sites of action of va...
Published: 13 November 2018
Figure 3 Investigational drugs for treating NASH. The proposed sites of action of various experimental NASH therapeutics are shown. Agonists for the PPARs, TRβ, and FXR nuclear receptors likely work by stimulating mitochondrial fatty acid oxidation. MPC inhibitors (MPCi) work by attenuating flux o... More
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Hypothesis on the alterations of muscle energy metabolism in type 1 diabete...
Published: 17 May 2013
FIG. 1. Hypothesis on the alterations of muscle energy metabolism in type 1 diabetes. Insulin deficiency leads to hyperglycemia and elevated lipolysis with increased free fatty acids, which are oxidized and stored as TAG or converted to lipotoxic DAG or ceramides, which can induce insulin resistan... More
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Model illustrating the role of the anaplerotic/lipid-signaling pathway in β...
Published: 01 December 2002
FIG. 3. Model illustrating the role of the anaplerotic/lipid-signaling pathway in β-cell metabolic signal transduction in health and diabetes. When transiently stimulated, the Ac-CoA/Ca2+ and anaplerotic/lipid-signaling pathways synergize to promote insulin secretion. Chronic stimulation of the same pathways results in β-cell dysfunction, exhaustion, and death. AcCoAc, cytosolic acetyl-CoA; AcCoAm, mitochondrial acetyl-CoA; DAG, diacylglycerol, LPA, lysophosphatidic acid; βox, β oxidation of fatty acids; PA, phosphatidic acid; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase. FIG. 3. Model illustrating the role of the anaplerotic/lipid-signaling pathway in β-cell metabolic signal transduction in health and diabetes. When transiently stimulated, the Ac-CoA/Ca2+ and anaplerotic/lipid-signaling pathways synergize to promote insulin secretion. Chronic stimulation of the same pathways results in β-cell dysfunction, exhaustion, and death. AcCoAc, cytosolic acetyl-CoA; AcCoAm, mitochondrial acetyl-CoA; DAG, diacylglycerol, LPA, lysophosphatidic acid; βox, β oxidation of fatty acids; PA, phosphatidic acid; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase. More
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Simplified, “classic” model of the pathogenesis of glomerulosclerosis. High...
Published: 01 June 2008
FIG. 1. Simplified, “classic” model of the pathogenesis of glomerulosclerosis. High extracellular glucose leads to increased mesangial cell glucose uptake via enhanced expression of the facilitative glucose transporter GLUT1, activating metabolic pathways that result in increased ROS and AGE gener... More
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The molecular mechanism of fat-induced insulin resistance in skeletal muscl...
Published: 01 December 2006
FIG. 1. The molecular mechanism of fat-induced insulin resistance in skeletal muscle (A) and liver (B). A: Increases in intramyocellular fatty acyl CoAs and diacylglycerol due to increased delivery from plasma and/or reduced β-oxidation due to mitochondrial dysfunction activate serine/threonine kinases such as protein kinase C (PKC-θ rodents, PKC-β and -δ humans) in skeletal muscle. The activated kinases phosphorylate serine residues on IRS-1 and inhibit insulin-induced PI 3-kinase activity, resulting in reduced insulin-stimulated AKT2 activity. Lowered AKT2 activity fails to activate GLUT4 translocation, and other downstream AKT2-dependent events, and consequently insulin-induced glucose uptake is reduced. B: Increases in hepatic diacylglycerol content due to increased delivery of fatty acids from the plasma and/or increased de novo lipid synthesis and/or reduced β-oxidation activate protein kinase C-ε (and potentially other serine kinases), leading to reduced insulin receptor kinase activity and reduced IRS-2 tyrosine phosphorylation, resulting in reduced insulin stimulation of glycogen synthase activation and decreased phosphorylation of forkhead box protein O (FOXO), leading to increased hepatic gluconeogenesis. DAG, diacylglycerol; PTB, phosphotyrosine binding domain; PH, pleckstrin homology domain; SH2, src homology domain; GSK3, glycogen synthase kinase-3. FIG. 1. The molecular mechanism of fat-induced insulin resistance in skeletal muscle (A) and liver (B). A: Increases in intramyocellular fatty acyl CoAs and diacylglycerol due to increased delivery from plasma and/or reduced β-oxidation due to mitochondrial dysfunction activate serine/threonine kinases such as protein kinase C (PKC-θ rodents, PKC-β and -δ humans) in skeletal muscle. The activated kinases phosphorylate serine residues on IRS-1 and inhibit insulin-induced PI 3-kinase activity, resulting in reduced insulin-stimulated AKT2 activity. Lowered AKT2 activity fails to activate GLUT4 translocation, and other downstream AKT2-dependent events, and consequently insulin-induced glucose uptake is reduced. B: Increases in hepatic diacylglycerol content due to increased delivery of fatty acids from the plasma and/or increased de novo lipid synthesis and/or reduced β-oxidation activate protein kinase C-ε (and potentially other serine kinases), leading to reduced insulin receptor kinase activity and reduced IRS-2 tyrosine phosphorylation, resulting in reduced insulin stimulation of glycogen synthase activation and decreased phosphorylation of forkhead box protein O (FOXO), leading to increased hepatic gluconeogenesis. DAG, diacylglycerol; PTB, phosphotyrosine binding domain; PH, pleckstrin homology domain; SH2, src homology domain; GSK3, glycogen synthase kinase-3. More
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Regulation of cellular fatty acid partitioning and metabolism by AMPK. <ita
Published: 01 December 2006
FIG. 2. Regulation of cellular fatty acid partitioning and metabolism by AMPK. A: AMPK neutral. By inhibiting CPT-1, malonyl-CoA, which is derived from glucose, diminishes the entrance of cytosolic FA-CoA into mitochondria where they are oxidized. This makes more cytosolic FA-CoA available for triglyceride (TG), diacylglycerol, and ceramide synthesis; lipid peroxidation; and possibly other events that lead to NKκB activation. B: AMPK activated: AMPK increases fatty acid oxidation acutely by phosphorylating and inhibiting ACC and activating MCD, leading to a decrease in malonyl-CoA. It also does this subacutely by effects on ACC, MCD, and CPT-1 abundance at the level of transcription. In addition, AMPK inhibits serine palmitoyltransferase, the first committed enzyme in the de novo pathway for ceramide synthesis and glycerophosphate acyltransferase, which plays a similar role in glycerolipid synthesis. The basis for the ability of AMPK to inhibit oxidant stress (ROS generation) and nuclear factor (NF)-κB activation (inflammation) is not known. Whether AMPK activation enhances or inhibits a process or an enzyme in this scheme is denoted by plus and minus signs, respectively (see full text for details). ACC, acetyl-CoA carboxylase; CPT1, carnitine palmitoyltransferase 1; DAG, diacylglycerol; FA CoA, cytosolic long-chain fatty acyl-CoA; FFA, free fatty acid; GPAT, glycerophosphate acyltransferase; MCD, malonyl-CoA decarboxylase; ROS, reactive O2 species. Adapted from Ruderman and Prentki ( 17 ). See text for additional details. FIG. 2. Regulation of cellular fatty acid partitioning and metabolism by AMPK. A: AMPK neutral. By inhibiting CPT-1, malonyl-CoA, which is derived from glucose, diminishes the entrance of cytosolic FA-CoA into mitochondria where they are oxidized. This makes more cytosolic FA-CoA available for triglyceride (TG), diacylglycerol, and ceramide synthesis; lipid peroxidation; and possibly other events that lead to NKκB activation. B: AMPK activated: AMPK increases fatty acid oxidation acutely by phosphorylating and inhibiting ACC and activating MCD, leading to a decrease in malonyl-CoA. It also does this subacutely by effects on ACC, MCD, and CPT-1 abundance at the level of transcription. In addition, AMPK inhibits serine palmitoyltransferase, the first committed enzyme in the de novo pathway for ceramide synthesis and glycerophosphate acyltransferase, which plays a similar role in glycerolipid synthesis. The basis for the ability of AMPK to inhibit oxidant stress (ROS generation) and nuclear factor (NF)-κB activation (inflammation) is not known. Whether AMPK activation enhances or inhibits a process or an enzyme in this scheme is denoted by plus and minus signs, respectively (see full text for details). ACC, acetyl-CoA carboxylase; CPT1, carnitine palmitoyltransferase 1; DAG, diacylglycerol; FA CoA, cytosolic long-chain fatty acyl-CoA; FFA, free fatty acid; GPAT, glycerophosphate acyltransferase; MCD, malonyl-CoA decarboxylase; ROS, reactive O2 species. Adapted from Ruderman and Prentki (17). See text for additional details. More
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Hepatic lipid deposition in <em>Stk25</em> knockout mice and wild-t...
Published: 06 April 2015
Figure 3 Hepatic lipid deposition in Stk25 knockout mice and wild-type littermates challenged with a high-fat diet for 20 weeks compared with chow-fed controls. A: Representative images of whole liver. B: Representative liver sections stained with H-E or Oil Red O for lipids. Scale bar = 100 μm. C and D: Total lipid area (C) and lipid droplet number and size distribution (D) in liver sections. E: Liver lipid profiling. One outlier, located outside the 99% confidence band, was removed from the analysis. For CE, data are mean ± SEM from 6–10 mice per genotype and diet group. *P < 0.05, **P < 0.01 for Stk25−/− mice vs. corresponding wild-type littermates; †P < 0.05, ††P < 0.01 for wild-type mice fed high-fat vs. chow diet; #P < 0.05, ##P < 0.01 for Stk25−/− mice fed high-fat vs. chow diet. CD, chow diet; CE, cholesteryl ester; CER, ceramide; DAG, diacylglycerol; HFD, high-fat diet; KO, knockout; LD, lipid droplet; LPC, lysophosphatidylcholine; PC, phosphatidylcholine; PE, phosphatidylethanolamine; SM, sphingomyelin; TAG, triacylglycerol; WT, wild type. Figure 3. Hepatic lipid deposition in Stk25 knockout mice and wild-type littermates challenged with a high-fat diet for 20 weeks compared with chow-fed controls. A: Representative images of whole liver. B: Representative liver sections stained with H-E or Oil Red O for lipids. Scale bar = 100 μm. C and D: Total lipid area (C) and lipid droplet number and size distribution (D) in liver sections. E: Liver lipid profiling. One outlier, located outside the 99% confidence band, was removed from the analysis. For C–E, data are mean ± SEM from 6–10 mice per genotype and diet group. *P < 0.05, **P < 0.01 for Stk25−/− mice vs. corresponding wild-type littermates; †P < 0.05, ††P < 0.01 for wild-type mice fed high-fat vs. chow diet; #P < 0.05, ##P < 0.01 for Stk25−/− mice fed high-fat vs. chow diet. CD, chow diet; CE, cholesteryl ester; CER, ceramide; DAG, diacylglycerol; HFD, high-fat diet; KO, knockout; LD, lipid droplet; LPC, lysophosphatidylcholine; PC, phosphatidylcholine; PE, phosphatidylethanolamine; SM, sphingomyelin; TAG, triacylglycerol; WT, wild type. More
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Hypothetical model illustrating the molecular basis of insulin-induced meta...
Published: 17 February 2015
Figure 1 Hypothetical model illustrating the molecular basis of insulin-induced metabolic stress in patients with poorly controlled T2D in which both blood glucose and FFA levels are persistently elevated. Depicted here is a cell in which (A) IR protects from nutrient overload and metabolic stress by limiting glucose flux into the cell and (B) the IR protection is overridden by a high dose of exogenous insulin therapy, which promotes excess glucose uptake and glucolipotoxicity. Excess glucose supply to the mitochondria results in reducing equivalent overload of the electron transfer chain and enhanced production of ATP and ROS, resulting in oxidative damage. The resulting increased ATP/AMP ratio inhibits AMPK, which has the effect of decreasing FFA oxidation (limiting nutrient detoxification) favoring fat deposition. Enhanced glucose uptake can also result in excessive glycogen deposition and increased activities of the toxic polyol, hexosamine, and AGE formation pathways. Glucose that is metabolized via the anaplerosis pathway can also increase cytosolic acetyl-CoA (AcCoA) and malonyl-CoA (MalCoA). AcCoA and MalCoA are then available for cholesterol and fatty acid synthesis, increasing the lipid load on the cell. MalCoA also inhibits fatty acyl-CoA (FACoA) entry into the mitochondria such that FACoA is more available for synthesis of complex lipids, including glycerolipids (phospholipids, diacylglycerols, and triglycerides) and ceramides. This can result in endoplasmic reticulum stress and the accumulation of lipid droplets (steatosis). Increased ROS production, toxic lipid accumulation, and reduced AMPK activity are factors that also activate the inflammasome contributing to cardiac injury. The overall effect is nutrient overload and metabolic stress causing cell dysfunction or death and cardiac inflammation. CD36, free fatty acid transporter; DAG, diacylglycerols; ER, endoplasmic reticulum; ETC, electron transport chain; GLUT4, facilitative glucose transporter 4; IRc, insulin receptor; MITO DYSF, mitochondrial dysfunction; OXID STRESS, oxidative stress; Pyr, pyruvate; PL, phospholipids; TG, triglycerides; Tx, treatment. Figure 1. Hypothetical model illustrating the molecular basis of insulin-induced metabolic stress in patients with poorly controlled T2D in which both blood glucose and FFA levels are persistently elevated. Depicted here is a cell in which (A) IR protects from nutrient overload and metabolic stress by limiting glucose flux into the cell and (B) the IR protection is overridden by a high dose of exogenous insulin therapy, which promotes excess glucose uptake and glucolipotoxicity. Excess glucose supply to the mitochondria results in reducing equivalent overload of the electron transfer chain and enhanced production of ATP and ROS, resulting in oxidative damage. The resulting increased ATP/AMP ratio inhibits AMPK, which has the effect of decreasing FFA oxidation (limiting nutrient detoxification) favoring fat deposition. Enhanced glucose uptake can also result in excessive glycogen deposition and increased activities of the toxic polyol, hexosamine, and AGE formation pathways. Glucose that is metabolized via the anaplerosis pathway can also increase cytosolic acetyl-CoA (AcCoA) and malonyl-CoA (MalCoA). AcCoA and MalCoA are then available for cholesterol and fatty acid synthesis, increasing the lipid load on the cell. MalCoA also inhibits fatty acyl-CoA (FACoA) entry into the mitochondria such that FACoA is more available for synthesis of complex lipids, including glycerolipids (phospholipids, diacylglycerols, and triglycerides) and ceramides. This can result in endoplasmic reticulum stress and the accumulation of lipid droplets (steatosis). Increased ROS production, toxic lipid accumulation, and reduced AMPK activity are factors that also activate the inflammasome contributing to cardiac injury. The overall effect is nutrient overload and metabolic stress causing cell dysfunction or death and cardiac inflammation. CD36, free fatty acid transporter; DAG, diacylglycerols; ER, endoplasmic reticulum; ETC, electron transport chain; GLUT4, facilitative glucose transporter 4; IRc, insulin receptor; MITO DYSF, mitochondrial dysfunction; OXID STRESS, oxidative stress; Pyr, pyruvate; PL, phospholipids; TG, triglycerides; Tx, treatment. More
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HSP72-KO promotes glucose intolerance and insulin resistance in male mice. ...
Published: 12 April 2014
Figure 1 HSP72-KO promotes glucose intolerance and insulin resistance in male mice. A: Immunoblot analyses performed on glucoregulatory tissues (white adipose tissue, liver, and muscle) confirms deletion of HSP72 in HSP72-KO tissues under basal and heat shock conditions. B: Glucose tolerance is impaired in KO mice (closed circles, dotted line) compared with WT (open circles, solid line; n = 10 mice/genotype). Hyperinsulinemic-euglycemic clamp studies show skeletal muscle and hepatic insulin resistance in HSP72-KO mice (closed bars; n = 8) as (C) insulin-stimulated glucose disposal rate and (D) hepatic glucose production (HGP) percentage suppression was significantly reduced compared with WT (open bars; n = 7 mice). E: Studies in isolated skeletal muscle (soleus) show impaired insulin-stimulated glucose uptake (n = 8 mice/genotype) and (F) reduced insulin-stimulated phosphorylation of Akt in HSP72-KO (closed bars) versus WT (open bars). G: Fatty acid oxidation was reduced, and (H) fatty acid esterification increased in isolated soleus muscles from HSP72-KO (closed bars) compared with WT (open bars) mice (n = 6/genotype). I: AMPK activity in quadriceps from WT and HSP72-KO mice (n = 6 mice/genotype). J: Diacylglycerol and triacylglycerol levels were elevated significantly in muscle from HSP72-KO (closed bars) versus WT (open bars; n = 6 mice/genotype) as measured by mass spectrometry. Values are expressed as means ± SEM. *, significance, P < 0.05, between genotypes; #, significance, P < 0.05, within genotype, between treatments. WAT, white adipose tissue; AUC, area under the curve; DAG, diacylglycerol; FA, fatty acid; HGP, hepatic glucose production; IS, insulin-stimulated; IS-GDR, insulin-stimulated glucose disposal rate; TAG, triacylglycerol; WAT, white adipose tissue. Figure 1. HSP72-KO promotes glucose intolerance and insulin resistance in male mice. A: Immunoblot analyses performed on glucoregulatory tissues (white adipose tissue, liver, and muscle) confirms deletion of HSP72 in HSP72-KO tissues under basal and heat shock conditions. B: Glucose tolerance is impaired in KO mice (closed circles, dotted line) compared with WT (open circles, solid line; n = 10 mice/genotype). Hyperinsulinemic-euglycemic clamp studies show skeletal muscle and hepatic insulin resistance in HSP72-KO mice (closed bars; n = 8) as (C) insulin-stimulated glucose disposal rate and (D) hepatic glucose production (HGP) percentage suppression was significantly reduced compared with WT (open bars; n = 7 mice). E: Studies in isolated skeletal muscle (soleus) show impaired insulin-stimulated glucose uptake (n = 8 mice/genotype) and (F) reduced insulin-stimulated phosphorylation of Akt in HSP72-KO (closed bars) versus WT (open bars). G: Fatty acid oxidation was reduced, and (H) fatty acid esterification increased in isolated soleus muscles from HSP72-KO (closed bars) compared with WT (open bars) mice (n = 6/genotype). I: AMPK activity in quadriceps from WT and HSP72-KO mice (n = 6 mice/genotype). J: Diacylglycerol and triacylglycerol levels were elevated significantly in muscle from HSP72-KO (closed bars) versus WT (open bars; n = 6 mice/genotype) as measured by mass spectrometry. Values are expressed as means ± SEM. *, significance, P < 0.05, between genotypes; #, significance, P < 0.05, within genotype, between treatments. WAT, white adipose tissue; AUC, area under the curve; DAG, diacylglycerol; FA, fatty acid; HGP, hepatic glucose production; IS, insulin-stimulated; IS-GDR, insulin-stimulated glucose disposal rate; TAG, triacylglycerol; WAT, white adipose tissue. More
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Proposed general theory of how elevated glucose and possibly FFA levels con...
Published: 01 January 2003
FIG. 1. Proposed general theory of how elevated glucose and possibly FFA levels contribute to the pathophysiology of diabetes via the generation of ROS and consequent activation of numerous stress-sensitive pathways. The causative link among hyperglycemia, mitochondrial ROS generation, oxidative s... More
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Knockdown of ELOVL1 and ACBP inhibits oleate (OL)-induced β-cell proliferat...
Published: 14 March 2022
Figure 8 Knockdown of ELOVL1 and ACBP inhibits oleate (OL)-induced β-cell proliferation in isolated rat islets. A and B: Isolated rat islets were infected with Adv-shCTL, Adv-shELOVL1 (A) or Adv-shACBP (B) and exposed to 2.8 or 16.7 mmol/L glucose with or without OL (0.5 mmol/L) as indicated. Proliferation of infected (GFP+) β-cells was assessed by flow cytometry following staining for EdU and Ins and presented as the percentage of EdU+/Ins+/GFP+ over total Ins+/GFP+ cells. Data are fold change over the control condition (Adv-shCTL). Data represent individual values and are mean ± SEM. *P < 0.05, **P < 0.01 using mixed-effects analysis with Sidak multiple comparison test compared with the Adv-shCTL condition. C: Proposed mechanism whereby the OL/VLC sphingolipid axis controls β-cell proliferation. In high-glucose conditions when FA oxidation is inhibited, OL transformed in C18:1-CoA in the cell is stabilized by ACBP, thus favoring its elongation to C24:1 by ELOVL1 and the synthesis of C24:1 sphingolipids after acylation by CerS2. The production of C24:1 sphingolipids leads to an increase in β-cell proliferation. Image created with BioRender.com . 3KetoSph, 3-ketosphinganine; Cer, ceramide; CPT1, carnitine palmitoyltransferase 1; DAG, diacylglycerol; dhCER, dihydroceramide; dhSph, sphinganine; ER, endoplasmic reticulum; Ser, serine; SM, sphingomyelin; Sph, sphingosine; SPP, sphingosine-1-phosphate phosphatase; TAG, triacylglycerol. More
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Acyl-CoA (<em>A</em>–<em>D</em>) and <span class="search-highlight">diacylglycerol</span> (<span class="search-highlight">DAG</span>) (...
Published: 01 April 2007
FIG. 2. Acyl-CoA (AD) and diacylglycerol (DAG) (EH) species in livers of PPAR-α null and wild-type (WT) mice. Male PPAR-α null or wild-type mice were fed for 2 weeks with either a control diet or isocaloric high-fat diets containing 27% safflower oil without or with an 8% fish oil replacement, livers freeze-clamped in situ, and lipid metabolites extracted for LC/MS/MS analysis. Total acyl-CoA (A) and diacylglycerol (E) content are displayed as well as selected acyl-CoA (BD) and diacylglycerol species (FH). Results are the means ± SE of six mice per group. BH: □, control diet; , isocaloric high-fat diets containing safflower oil without fish oil; ▪, isocaloric high-fat diets containing safflower oil with fish oil. FIG. 2. Acyl-CoA (A–D) and diacylglycerol (DAG) (E–H) species in livers of PPAR-α null and wild-type (WT) mice. Male PPAR-α null or wild-type mice were fed for 2 weeks with either a control diet or isocaloric high-fat diets containing 27% safflower oil without or with an 8% fish oil replacement, livers freeze-clamped in situ, and lipid metabolites extracted for LC/MS/MS analysis. Total acyl-CoA (A) and diacylglycerol (E) content are displayed as well as selected acyl-CoA (B–D) and diacylglycerol species (F–H). Results are the means ± SE of six mice per group. B–H: □, control diet; , isocaloric high-fat diets containing safflower oil without fish oil; ▪, isocaloric high-fat diets containing safflower oil with fish oil. More
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Acyl-CoA (<em>A</em>–<em>D</em>) and <span class="search-highlight">diacylglycerol</span> (<span class="search-highlight">DAG</span>) (...
Published: 01 April 2007
FIG. 2. Acyl-CoA (AD) and diacylglycerol (DAG) (EH) species in livers of PPAR-α null and wild-type (WT) mice. Male PPAR-α null or wild-type mice were fed for 2 weeks with either a control diet or isocaloric high-fat diets containing 27% safflower oil without or with an 8% fish oil replacement, livers freeze-clamped in situ, and lipid metabolites extracted for LC/MS/MS analysis. Total acyl-CoA (A) and diacylglycerol (E) content are displayed as well as selected acyl-CoA (BD) and diacylglycerol species (FH). Results are the means ± SE of six mice per group. BH: □, control diet; , isocaloric high-fat diets containing safflower oil without fish oil; ▪, isocaloric high-fat diets containing safflower oil with fish oil. FIG. 2. Acyl-CoA (A–D) and diacylglycerol (DAG) (E–H) species in livers of PPAR-α null and wild-type (WT) mice. Male PPAR-α null or wild-type mice were fed for 2 weeks with either a control diet or isocaloric high-fat diets containing 27% safflower oil without or with an 8% fish oil replacement, livers freeze-clamped in situ, and lipid metabolites extracted for LC/MS/MS analysis. Total acyl-CoA (A) and diacylglycerol (E) content are displayed as well as selected acyl-CoA (B–D) and diacylglycerol species (F–H). Results are the means ± SE of six mice per group. B–H: □, control diet; , isocaloric high-fat diets containing safflower oil without fish oil; ▪, isocaloric high-fat diets containing safflower oil with fish oil. More
Journal Articles
Journal: Diabetes
Diabetes 1996;45(Supplement_3):S117–S119
Published: 01 July 1996
...Makoto Kunisaki; Umeda Fumio; Hajime Nawata; George L King Hyperglycemia, a major cause of vascular complications in diabetes, has been shown to activate the diacylglycerol (DAG)-protein kinase C (PKC) pathway in vascular tissues. We have found that D-α-tocopherol (vitamin E) treatment reversed...
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Nutrient detoxification pathways in the β-cell. In order to cope with toxic...
Published: 13 February 2020
Figure 3 Nutrient detoxification pathways in the β-cell. In order to cope with toxic levels of fuel surplus, β-cells employ multiple detoxification pathways. Glucose entering the β-cell is converted by glucokinase (GK) to glucose 6-phosphate (glucose-6-P), which enters the glycolytic pathway. However, when excess glucose becomes available, some of the glucose-6-phosphate is hydrolyzed by glucose-6-phosphatase (G6Pase), resulting in a futile cycle of net ATP hydrolysis and heat generation. In addition, some of the glucose-6-P also is sequestered as glycogen, which is a relatively inert form of stored energy, at least when the accumulation is reasonable. Glycolysis-derived pyruvate through its participation in Krebs cycle (KC) generates citrate, a significant portion of which enters into cytosol (cataplerosis). Citrate, when produced in excess, may leave the β-cell or is converted to acetyl-CoA, which is the precursor for fatty acids (FFA) and cholesterol (Chol). Cholesterol, being toxic to the cell, is also transported out of the cell via ABCA1 transporter or is converted to cholesterol esters (CE) and stored away in lipid droplets. Part of the glucose carbons are also oxidized to CO2 in KC and leave the cell as HCO3. The Krebs cycle also generates α-ketoglutarate, which is transaminated to glutamate that can exit from β-cells. FFA entering the cells after conversion to fatty acyl-CoA participate in the GL/FFA cycle and through the action of lipogenic enzymes generate TG, which is sequestered in lipid droplets. Sequential hydrolysis of TG gives rise to FFA, which either leave the cell or recycle into the futile GL/FFA cycle, and glycerol, which can leave the cell through aquaporin-7 (AQP7). Gro-3-P, formed during glycolysis, and fatty acyl-CoA are the starting substrates for GL/FFA cycle, which, when fully operational, results in a net hydrolysis of 7 ATP molecules per turn and heat production and leads to the elimination of glucose carbons as glycerol and sequestration of TG into lipid droplets. A significant proportion of Gro-3-P, when produced in elevated levels at high glucose concentrations, is directly hydrolyzed by Gro-3-P phosphatase (G3PP), producing glycerol, which leaves the β-cell and thus helps in detoxifying excess glucose. When the β-oxidation pathway in mitochondria is flooded with excess availability of FFA, not only is there enhanced CO2 production and HCO3 efflux, but fatty acylcarnitines produced by CPT1 can also leave the cell, thereby detoxifying excess FFA. ABCA1, ATP-binding cassette transporter-A1; β-Ox, β-oxidation; DAG, diacylglycerol; FACarn, fatty acylcarnitine; LPA, lysophosphatidic acid; MAG, monoacylglycerol; Pyr, pyruvate. Figure 3. Nutrient detoxification pathways in the β-cell. In order to cope with toxic levels of fuel surplus, β-cells employ multiple detoxification pathways. Glucose entering the β-cell is converted by glucokinase (GK) to glucose 6-phosphate (glucose-6-P), which enters the glycolytic pathway. However, when excess glucose becomes available, some of the glucose-6-phosphate is hydrolyzed by glucose-6-phosphatase (G6Pase), resulting in a futile cycle of net ATP hydrolysis and heat generation. In addition, some of the glucose-6-P also is sequestered as glycogen, which is a relatively inert form of stored energy, at least when the accumulation is reasonable. Glycolysis-derived pyruvate through its participation in Krebs cycle (KC) generates citrate, a significant portion of which enters into cytosol (cataplerosis). Citrate, when produced in excess, may leave the β-cell or is converted to acetyl-CoA, which is the precursor for fatty acids (FFA) and cholesterol (Chol). Cholesterol, being toxic to the cell, is also transported out of the cell via ABCA1 transporter or is converted to cholesterol esters (CE) and stored away in lipid droplets. Part of the glucose carbons are also oxidized to CO2 in KC and leave the cell as HCO3−. The Krebs cycle also generates α-ketoglutarate, which is transaminated to glutamate that can exit from β-cells. FFA entering the cells after conversion to fatty acyl-CoA participate in the GL/FFA cycle and through the action of lipogenic enzymes generate TG, which is sequestered in lipid droplets. Sequential hydrolysis of TG gives rise to FFA, which either leave the cell or recycle into the futile GL/FFA cycle, and glycerol, which can leave the cell through aquaporin-7 (AQP7). Gro-3-P, formed during glycolysis, and fatty acyl-CoA are the starting substrates for GL/FFA cycle, which, when fully operational, results in a net hydrolysis of 7 ATP molecules per turn and heat production and leads to the elimination of glucose carbons as glycerol and sequestration of TG into lipid droplets. A significant proportion of Gro-3-P, when produced in elevated levels at high glucose concentrations, is directly hydrolyzed by Gro-3-P phosphatase (G3PP), producing glycerol, which leaves the β-cell and thus helps in detoxifying excess glucose. When the β-oxidation pathway in mitochondria is flooded with excess availability of FFA, not only is there enhanced CO2 production and HCO3− efflux, but fatty acylcarnitines produced by CPT1 can also leave the cell, thereby detoxifying excess FFA. ABCA1, ATP-binding cassette transporter-A1; β-Ox, β-oxidation; DAG, diacylglycerol; FACarn, fatty acylcarnitine; LPA, lysophosphatidic acid; MAG, monoacylglycerol; Pyr, pyruvate. More
Journal Articles
Journal: Diabetes
Diabetes 1996;45(Supplement_3):S105–S108
Published: 01 July 1996
... that hyperglycemia is mediating its adverse effects through multiple mechanisms. We have summarized some of these mechanisms in this review, with particular attention to the effect of hyperglycemia on the activation of diacylglycerol (DAG)-protein kinase C (PKC) pathway. We have reviewed existing information...
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<em>A</em>: General overview of intracellular signaling by C-peptid...
Published: 14 March 2012
FIG. 2. A: General overview of intracellular signaling by C-peptide. C-peptide interaction with cell membranes is accompanied by activation of a pertussis toxin–sensitive G-protein. Subsequently, there is influx of Ca2+ and activation of eNOS, resulting in NO formation. PLC and specific isomers of PKC are also activated, as well as the MAPK complex. As a result, there is activation and induction of Na+,K+-ATPase, as well as DNA binding of several transcription factors, resulting in augmented eNOS mRNA formation and increased eNOS protein synthesis. Phosphoinositide 3-kinase (PI3-K)γ is also activated, giving rise to PPAR-γ–mediated transcriptional activity. In addition, there is evidence to indicate that C-peptide may interact synergistically with the insulin signaling pathway, as indicated by dashed lines. IRS-1, insulin receptor substrate 1; GS, glycogen synthesis; AA, amino acid uptake; DAG, diacylglycerol; FAK, focal adhesion kinase. B: Representation of [Ca2+]i in fura-2/AM-loaded human renal tubular cells stimulated with 5 nmol/L human C-peptide. Top panel: Tracing of the 340:380 fluorescence ratio before and during C-peptide exposure; bottom panel: cell images in transmission light (first panel) and in color code (next three panels) representing [Ca2+]i at the time points shown by the spot indicators (red) in the trace above. Reprinted with permission from Shafqat et al. ( 14 ). C: Effect of varying concentrations of C-peptide on ERK1/2 phosphorylation. Top panel: Human renal tubular cells were serum starved overnight and stimulated with human C-peptide, and cell lysates were subjected to Western blot analyses to determine ERK1/2 phosphorylation. Amount of phosphorylated (p-)ERK1/2 in the densitometric quantification is expressed as fold increase vs. control. Reprinted with permission from Zhong et al. ( 15 ). D: Effect of C-peptide and inhibitors on ouabain-sensitive 86Rb+ uptake indicating Na+,K+-ATPase activity. Primary human renal tubular cells were incubated with C-peptide (red bar), scrambled C-peptide (orange bar), or C-peptide plus pertussis toxin (PTX) (green bar) for 10 min. **P < 0.01 vs. control (blue bar). Data are from Ref. 25 . E: Effect of C-peptide on the NO release from bovine aortic endothelial cells in the presence and absence of Ca2+. ***P < 0.001 vs. control. Data are from Ref. 28 . (A high-quality digital representation of this figure is available in the online issue.) FIG. 2. A: General overview of intracellular signaling by C-peptide. C-peptide interaction with cell membranes is accompanied by activation of a pertussis toxin–sensitive G-protein. Subsequently, there is influx of Ca2+ and activation of eNOS, resulting in NO formation. PLC and specific isomers of PKC are also activated, as well as the MAPK complex. As a result, there is activation and induction of Na+,K+-ATPase, as well as DNA binding of several transcription factors, resulting in augmented eNOS mRNA formation and increased eNOS protein synthesis. Phosphoinositide 3-kinase (PI3-K)γ is also activated, giving rise to PPAR-γ–mediated transcriptional activity. In addition, there is evidence to indicate that C-peptide may interact synergistically with the insulin signaling pathway, as indicated by dashed lines. IRS-1, insulin receptor substrate 1; GS, glycogen synthesis; AA, amino acid uptake; DAG, diacylglycerol; FAK, focal adhesion kinase. B: Representation of [Ca2+]i in fura-2/AM-loaded human renal tubular cells stimulated with 5 nmol/L human C-peptide. Top panel: Tracing of the 340:380 fluorescence ratio before and during C-peptide exposure; bottom panel: cell images in transmission light (first panel) and in color code (next three panels) representing [Ca2+]i at the time points shown by the spot indicators (red) in the trace above. Reprinted with permission from Shafqat et al. (14). C: Effect of varying concentrations of C-peptide on ERK1/2 phosphorylation. Top panel: Human renal tubular cells were serum starved overnight and stimulated with human C-peptide, and cell lysates were subjected to Western blot analyses to determine ERK1/2 phosphorylation. Amount of phosphorylated (p-)ERK1/2 in the densitometric quantification is expressed as fold increase vs. control. Reprinted with permission from Zhong et al. (15). D: Effect of C-peptide and inhibitors on ouabain-sensitive 86Rb+ uptake indicating Na+,K+-ATPase activity. Primary human renal tubular cells were incubated with C-peptide (red bar), scrambled C-peptide (orange bar), or C-peptide plus pertussis toxin (PTX) (green bar) for 10 min. **P < 0.01 vs. control (blue bar). Data are from Ref. 25. E: Effect of C-peptide on the NO release from bovine aortic endothelial cells in the presence and absence of Ca2+. ***P < 0.001 vs. control. Data are from Ref. 28. (A high-quality digital representation of this figure is available in the online issue.) More