Oleate-induced decrease in hepatocyte insulin binding is mediated by PKC-δ

Shu, Chen; Lam, Tony K.T.; Park, Edward; Burdett, Elena; Wang, Penny Y.T.; Wiesenthal, Stephanie R.; Lam, Loretta; Tchipashvili, Vaja; Fantus, I. George; Giacca, Adria

doi:10.1016/j.bbrc.2006.05.190

Cited by 10 publications

(11 citation statements)

References 25 publications

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“…The activation of hypothalamic K ATP channels by an approximately twofold elevation of circulating LCFA (induced by intravenous intralipid infusion) was recently demonstrated to inhibit glycogenolysis and compensate for the induction in gluconeogenesis (10). In light of the fact that 1) LCFAs activate PKC in liver and muscle (11)(12)(13)(14)(15)(16) and 2) hypothalamic PKC-K ATP channel activation lowers glucose production (demonstrated in the current study), we tested, using the same intravenous intralipidinfused model (10), whether activation of hypothalamic PKC is required for circulating LCFA to lower glucose production. We inhibited hypothalamic PKC activation with either MBH BIM (60 mol/l) or Rot (60 mol/l) administration to rats that received intravenous intralipid.…”

Section: Resultsmentioning

confidence: 99%

“…In the peripheral tissues such as the liver and muscle, an elevation of lipids (especially the long-chain fatty acids [LCFAs]) activates the novel isoforms of protein kinase C (PKC) (i.e., -␦, -ε, and -) to induce insulin resistance during hyperinsulinemic-euglycemic clamps (11)(12)(13)(14)(15)(16). Although novel isoforms of PKC (especially -␦ and -ε) are expressed in the brain (17), it is currently unknown whether LCFAs activate hypothalamic, novel isoforms of PKC to regulate glucose production.…”

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confidence: 99%

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Hypothalamic Protein Kinase C Regulates Glucose Production

et al. 2008

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OBJECTIVE-A selective rise in hypothalamic lipid metabolism and the subsequent activation of SUR1/Kir6.2 ATP-sensitive K ϩ (K ATP ) channels inhibit hepatic glucose production. The mechanisms that link the ability of hypothalamic lipid metabolism to the activation of K ATP channels remain unknown.RESEARCH DESIGN AND METHODS-To examine whether hypothalamic protein kinase C (PKC) mediates the ability of central nervous system lipids to activate K ATP channels and regulate glucose production in normal rodents, we first activated hypothalamic PKC in the absence or presence of K ATP channel inhibition. We then inhibited hypothalamic PKC in the presence of lipids. Tracer-dilution methodology in combination with the pancreatic clamp technique was used to assess the effect of hypothalamic administrations on glucose metabolism in vivo.RESULTS-We first reported that direct activation of hypothalamic PKC via direct hypothalamic delivery of PKC activator 1-oleoyl-2-acetyl-sn-glycerol (OAG) suppressed glucose production. Coadministration of hypothalamic PKC-␦ inhibitor rottlerin with OAG prevented the ability of OAG to activate PKC-␦ and lower glucose production. Furthermore, hypothalamic dominantnegative Kir6.2 expression or the delivery of the K ATP channel blocker glibenclamide abolished the glucose production-lowering effects of OAG. Finally, inhibition of hypothalamic PKC eliminated the ability of lipids to lower glucose production.CONCLUSIONS-These studies indicate that hypothalamic PKC activation is sufficient and necessary for lowering glucose production.

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Section: Resultsmentioning

confidence: 99%

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Hypothalamic Protein Kinase C Regulates Glucose Production

et al. 2008

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“…As pointed out earlier, translocation of PKCd to the plasma membrane is not the sole or even major indication of its activation [see Quest, 1996;Steinberg, 2004]. Moreover, direct measurements of activity in immunoprecipitated PKCd were not reported by Probst et al The importance of PKCd in insulin-induced pyruvate dehydrogenase complex activity in liver cells was conclusively demonstrated [Caruso et al, 2001], as well as in other diabetes-related effects on liver cells [Chen et al, 2006]. In this respect, Caruso et al [2001] showed clear translocation of PKCd to mitochondria induced by insulin.…”

Section: Discussionmentioning

confidence: 98%

“…Some studies have been indirect and have relied on use of PKC activators to mimic or otherwise modulate insulin-induced effects without identification of the specific PKC isoforms involved [Donchenko et al, 1994;Probst et al, 2003]. A role for PKCd has been both implicated [Caruso et al, 2001;Chen et al, 2006] and denied [Probst et al, 2003] in certain insulin-induced effects in hepatic cells. Other isoforms were not studied.…”

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Protein kinase Cδ but not PKCα is involved in insulin‐induced glucose metabolism in hepatocytes

Brutman-Barazani

Horovitz-Fried

Aga-Mizrachi

et al. 2012

J of Cellular Biochemistry

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The liver is a major insulin-responsive tissue responsible for glucose regulation. One important mechanism in this phenomenon is insulin-induced glycogen synthesis. Studies in our laboratory have shown that protein kinase Cs delta (PKCδ) and alpha (α) have important roles in insulin-induced glucose transport in skeletal muscle, and that their expression and activity are regulated by insulin. Their importance in glucose regulation in liver cells is unclear. In this study we investigated the possibility that these isoforms are involved in the mediation of insulin-induced glycogen synthesis in hepatocytes. Studies were done on rat hepatocytes in primary culture and on the AML-12 (alpha mouse liver) cell line. Insulin increased activity and tyrosine phosphorylation of PKCδ within 5 min. In contrast, activity and tyrosine phosphorylation of PKCα were not increased by insulin. PKCδ was constitutively associated with IR, and this was increased by insulin stimulation. Suppression of PKCδ expression by transfection with RNAi, or overexpression of kinase dead (dominant negative) PKCδ reduced both the insulin-induced activation of PKB/Akt and the phosphorylation of glycogen synthase kinase 3 (GSK3) and reduced significantly insulin-induced glucose uptake. In addition, treatment of primary rat hepatocytes with rottlerin abrogated insulin-induced increase in glycogen synthesis. Neither overexpression nor inhibition of PKCα appeared to alter activation of PKB, phosphorylation of GSK3 or glucose uptake in response to insulin. We conclude that PKCδ, but not PKCα, plays an essential role in insulin-induced glucose uptake and glycogenesis in hepatocytes.

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“…FFA can activate PKC␦ in isolated hepatocytes and liver (13,20). Furthermore, PKC␦ is probably involved in FFA-induced insulin resistance (13) and FFA-induced decrease of insulin binding in hepatocytes (21). Finally, p38 has been shown to mediate FFA-induced insulin resistance in various cell types (22)(23)(24)(25), but its role in hepatic insulin resistance is unclear.…”

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Prolonged Treatment of Primary Hepatocytes with Oleate Induces Insulin Resistance through p38 Mitogen-activated Protein Kinase

Liu

Collins

Xiong

et al. 2007

Journal of Biological Chemistry

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Free fatty acid (FFA) is believed to be a major environmental factor linking obesity to Type II diabetes. We have recently reported that FFA can induce gluconeogenesis in hepatocytes through p38 mitogen-activated protein kinase (p38). In this study, we have investigated the role of p38 in oleate-induced hepatic insulin resistance. Our results show that a prolonged treatment of primary hepatocytes with oleate blunted insulin suppression of hepatic gluconeogenesis, and decreased insulin-induced phosphorylation of Akt in a p38-dependent manner. Reduction of the insulin-induced Akt phosphorylation by oleate correlated with activation of p38. In the presence of p38 inhibition, prolonged exposure of hepatocytes to oleate failed to reduce insulin-stimulated phosphorylation of Akt. An siRNA against p38␣ prevented oleate suppression of the insulin-induced phosphorylation of Akt. Furthermore, a prolonged exposure of hepatocytes to oleate decreased insulininduced tyrosine phosphorylation of IRS1/2, while slightly increasing serine phosphorylation of IRS. The decrease of insulin-stimulated tyrosine phosphorylation of IRS1/2 in hepatocytes by oleate was reversed by the inhibition of p38. We further show that a prolonged exposure of primary hepatocytes to oleate elevated the protein level of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in a p38-dependent manner, but had no effect on the mRNA level of PTEN. Knocking down the PTEN gene prevented oleate to inhibit insulin activation of Akt and insulin suppression of gluconeogenesis. Together, results from this study demonstrate a critical role for p38 in oleate-induced hepatic insulin resistance.

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Oleate-induced decrease in hepatocyte insulin binding is mediated by PKC-δ

Cited by 10 publications

References 25 publications

Hypothalamic Protein Kinase C Regulates Glucose Production

Hypothalamic Protein Kinase C Regulates Glucose Production

Protein kinase Cδ but not PKCα is involved in insulin‐induced glucose metabolism in hepatocytes

Prolonged Treatment of Primary Hepatocytes with Oleate Induces Insulin Resistance through p38 Mitogen-activated Protein Kinase

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