Inhibition of cellular responses to insulin in a rat liver cell line. A role for PKC in insulin resistance

Puljak, Livia; Pagliassotti, Michael J.; Wei, Yu; Qadri, Ishtiaq; Parameswara, Vinay; Esser, Victoria; Fitz, John; Kilic, Gordan

doi:10.1113/jphysiol.2004.080333

Cited by 10 publications

(10 citation statements)

References 63 publications

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“…In support of this notion, we observed up-regulation of several inflammatory markers in both liver and adipose tissue already after 1 week of HFD feeding [63]. Alternatively, increased availability of C20:4 may affect insulin signaling directly, for example through activating PKC as shown in a rat liver cell line [64]. On the other hand, low PUFA content in phospholipids has been proposed as an insulin resistance mechanism (see below).…”

Section: Discussionsupporting

confidence: 66%

Liver TAG Transiently Decreases While PL n‐3 and n‐6 Fatty Acids are Persistently Elevated in Insulin Resistant Mice

Scheja

Toedter

Mohr

et al. 2008

Lipids

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Changes in fatty acid metabolism associated with insulin resistance have been described in rats and humans but have not been well characterized in the frequently used mouse model of diet-induced obesity. To analyse the early phase as well as established insulin resistance, C57BL/6 mice were placed for 1 or 16 weeks on a high fat diet (1w-HFD, 16w-HFD). Endocrine and metabolic parameters indicated that 1w-HFD mice showed a moderate but significant induction of insulin resistance while 16w-HFD mice exhibited profound obesity-associated insulin resistance and dyslipidemias. Significant alterations in fatty acid composition were observed in plasma and liver in both groups. Liver phospholipid-associated arachidonate and docosahexaenoate were increased in both 1w-HFD and 16w-HFD mice, possibly due to increased expression of the desaturases Fads1 and Fads2. Unexpectedly, SCD1 activity and gene expression in liver were decreased in the 1w-HFD group accompanied by diminished total hepatic lipid levels, while they were increased in chronically fed mice. Our data indicate that the early phase of HFD-induced insulin resistance is not associated with elevated liver lipid concentration. Furthermore, the early and persistent rise of arachidonate and docosahexaenoate indicates that insulin resistance is not due to insufficient availability (or concentrations) of polyunsaturated fatty acids as postulated previously.

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Section: Discussionsupporting

confidence: 66%

Liver TAG Transiently Decreases While PL n‐3 and n‐6 Fatty Acids are Persistently Elevated in Insulin Resistant Mice

Scheja

Toedter

Mohr

et al. 2008

Lipids

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“…Hepatocytes are generally considered to be constitutive secretory cells in which exocytosis occurs at a constant rate. However, our recent studies have demonstrated that liver cells are also capable of regulated exocytosis [10,11]. Based on these considerations, the purpose of these studies was to assess the potential role of AMPK in the regulation of constitutive exocytosis of lipoproteins.…”

Section: Introductionmentioning

confidence: 99%

Evidence for AMPK-dependent regulation of exocytosis of lipoproteins in a model liver cell line

Puljak

Parameswara

Dolovcak

et al. 2008

Experimental Cell Research

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5'-AMP-activated kinase (AMPK) plays a key role in the regulation of cellular lipid metabolism. The contribution of vesicular exocytosis to this regulation is not known. Accordingly, we studied the effects of AMPK on exocytosis and intracellular lipid content in a model liver cell line. Activation of AMPK by metformin or 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) increased the rates of constitutive exocytosis by about 2-fold. Stimulation of exocytosis by AMPK occurred within minutes, and persisted after overnight exposure to metformin or AICAR. Activation of AMPK also increased the amount of triacylglycerol (TG) and apolipoprotein B (apoB) secreted from lipid-loaded cells. These effects were accompanied by a decrease in the intracellular lipid content indicating that exocytosis of lipoproteins was involved in these lipid-lowering effects. While AMPK increased the rates of fatty acid oxidation (FAO), the lipid-lowering effects were quantitatively significant even after inhibition of FAO with R-etomoxir. These results suggest that hepatic AMPK stimulates constitutive exocytosis of lipoproteins, which may function in parallel with FAO to regulate intracellular lipid content.

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“…The procedure for cell preparation has been previously described [11, 12]. Cells were used within 24 h after plating.…”

Section: Methodsmentioning

confidence: 99%

“…[Ca 2+ ] i was measured using a Ca 2+ -sensitive fluorescent dye Fluo-3 AM (Molecular Probes, Eugene OR) as previously described [12]. Fluo-3 AM was dissolved in DMSO with equal amounts of Pluronic solution (10 % in DMSO).…”

Section: Methodsmentioning

confidence: 99%

Copper inhibits P2Y2-dependent Ca2+ signaling through the effects on thapsigargin-sensitive Ca2+ stores in HTC hepatoma cells

Dolovcak

Waldrop

Fitz

et al. 2010

Biochemical and Biophysical Research Communications

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Purinergic P2Y 2 G-protein coupled receptors play a key role in the regulation of hepatic Ca 2+ signaling by extracellular ATP. The concentration of copper in serum is about 20 μM. Since copper accumulates in the liver in certain disease states, the purpose of these studies was to assess the effects of copper on P2Y 2 receptors in a model liver cell line. Exposure to a P2Y 2 agonist UTP increased [Ca 2+ ] i by stimulating Ca 2+ release from thapsigargin-sensitive Ca 2+ stores. Pretreatment of HTC cells for several minutes with copper did not affect cell viability, but potently inhibited increases in [Ca 2+ ] i evoked by UTP and thapsigargin. During this pretreatment, copper was not transported into the cytosol, and inhibited P2Y 2 receptors in a concentration-dependent manner with the IC 50 of about 15 μM. These results suggest that copper inhibits P2Y 2 receptors through the effects on thapsigargin-sensitive Ca 2+ stores by acting from an extracellular side. Further experiments indicated that these effect of copper may lead to inhibition of regulatory volume decrease (RVD) evoked by hypotonic solution. Thus, copper may contribute to defective regulation of purinergic signaling and liver cell volume in diseases associated with the increased serum copper concentration.

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Inhibition of cellular responses to insulin in a rat liver cell line. A role for PKC in insulin resistance

Cited by 10 publications

References 63 publications

Liver TAG Transiently Decreases While PL n‐3 and n‐6 Fatty Acids are Persistently Elevated in Insulin Resistant Mice

Liver TAG Transiently Decreases While PL n‐3 and n‐6 Fatty Acids are Persistently Elevated in Insulin Resistant Mice

Evidence for AMPK-dependent regulation of exocytosis of lipoproteins in a model liver cell line

Copper inhibits P2Y2-dependent Ca2+ signaling through the effects on thapsigargin-sensitive Ca2+ stores in HTC hepatoma cells

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