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

Liu, Hui Yu; Collins, Qu Fan; Xiong, Yan; Moukdar, Fatiha; Lupo, Edgar G.; Liu, Zhenqi; Cao, Wenhong

doi:10.1074/jbc.m609701200

Cited by 68 publications

(41 citation statements)

References 56 publications

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“…In parallel to the assessment of lipid accumulation under basal culture conditions, we exposed the cells to OA, known to efficiently induce steatosis in vitro [14][15][16][17]. As expected, OA supplementation increased Oil Red O staining in all cells; however, lipid deposition remained substantially higher in STK25-overexpressing cells compared with vector control (Fig.…”

Section: Resultsmentioning

confidence: 62%

Protein kinase STK25 controls lipid partitioning in hepatocytes and correlates with liver fat content in humans

et al. 2015

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Aims/hypothesis Type 2 diabetes is closely associated with pathological lipid accumulation in the liver, which is suggested to actively contribute to the development of insulin resistance. We recently identified serine/threonine protein kinase 25 (STK25) as a regulator of liver steatosis, whole-body glucose tolerance and insulin sensitivity in a mouse model system. The aim of this study was to assess the role of STK25 in the control of lipid metabolism in human liver. Methods Intracellular fat deposition, lipid metabolism and insulin sensitivity were studied in immortalised human hepatocytes (IHHs) and HepG2 hepatocellular carcinoma cells in which STK25 was overexpressed or knocked down by small interfering RNA. The association between STK25 mRNA expression in human liver biopsies and hepatic fat content was analysed.Results Overexpression of STK25 in IHH and HepG2 cells enhanced lipid deposition by suppressing β-oxidation and triacylglycerol (TAG) secretion, while increasing lipid synthesis. Conversely, knockdown of STK25 attenuated lipid accumulation by stimulating β-oxidation and TAG secretion, while inhibiting lipid synthesis. Furthermore, TAG hydrolase activity was repressed in hepatocytes overexpressing STK25 and reciprocally increased in cells with STK25 knockdown. Insulin sensitivity was reduced in STK25-overexpressing cells and enhanced in STK25-deficient hepatocytes. We also found a statistically significant positive correlation between STK25 mRNA expression in human liver biopsies and hepatic fat content. Conclusions/interpretation Our data suggest that STK25 regulates lipid partitioning in human liver cells by controlling TAG synthesis as well as lipolytic activity and thereby NEFA release from lipid droplets for β-oxidation and TAG secretion. Our findings highlight STK25 as a potential drug target for the prevention and treatment of type 2 diabetes.

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Section: Resultsmentioning

confidence: 62%

Protein kinase STK25 controls lipid partitioning in hepatocytes and correlates with liver fat content in humans

et al. 2015

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“…Serine phosphorylation of IRS-1 reduces insulin signaling through the PI 3-kinase/Akt pathway, and insulin exerts its many metabolic and pro-survival effects mainly via this pathway (3,12,13,16,28,29,31,33). We have previously demonstrated in cultured endothelial cells and hepatocytes that p38 MAPK plays a critical role in free fatty acid and tumor necrosis factor-␣-induced insulin resistance by increasing serine phosphorylation and decreasing tyrosine phosphorylation of IRS-1 (17,19). As stated above, the effect of p38 MAPK may also be related to increased cell apoptosis as it mediates the apoptotic process (36), and we (6) have recently demonstrated that p38 MAPK plays pivotal role in palmitateinduced apoptosis in cultured endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…We have recently demonstrated that p38 MAPK plays a central role in palmitate-induced apoptosis (6) and tumor necrosis factor-␣-induced insulin resistance (17) in endothelial cells, and in fatty acid-induced insulin resistance in hepatocytes (19). Since ischemia-reperfusion, especially reperfusion, potently activates p38 MAPK (2,22,35), we examined in the present study whether p38 MAPK modulates insulin-mediated cardioprotection against ischemia-reperfusion injury in vivo.…”

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confidence: 96%

Activation of p38 mitogen-activated protein kinase abolishes insulin-mediated myocardial protection against ischemia-reperfusion injury

Chai¹,

Wu²,

Li³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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. Activation of p38 mitogen-activated protein kinase abolishes insulin-mediated myocardial protection against ischemia-reperfusion injury. Am J Physiol Endocrinol Metab 294: E183-E189, 2008. First published November 14, 2007 doi:10.1152/ajpendo.00571.2007.-Myocardial ischemiareperfusion injury contributes significantly to morbidity and mortality in patients with diabetes. Insulin decreases myocardial infarct size in animals and the rate of apoptosis in cultured cells. Ischemia-reperfusion activates p38 mitogen-activated protein kinase (MAPK), which regulates cellular apoptosis. To examine whether p38 MAPK affects insulin's cardioprotection against ischemia-reperfusion injury, we studied overnight-fasted adult male rats by use of an in vivo rat model of myocardial ischemia-reperfusion. A euglycemic clamp (3 mU ⅐ min Ϫ1 ⅐ kg Ϫ1 ) was begun either 10 min before ischemia (Insulin BI), 5 min before reperfusion (InsulinBR), or 30 min after the onset of reperfusion (Insulin AR ), and continued until the end of the study. Compared with saline control, insulin decreased the infarct size in both Insulin BI (P Ͻ 0.001) and InsulinBR (P Ͻ 0.02) rats but not in Insulin AR rats. The ischemic area showed markedly increased phosphorylation of p38 MAPK compared with the nonischemic area in saline animals. Acute activation of p38 MAPK with anisomycin (2 mg/kg iv 10 min before ischemia) had no effect on infarct size in saline rats. However, it completely abolished insulin's protective effect in Insulin BI and InsulinBR rats. Activation of p38 MAPK by anisomycin was associated with marked and persistent elevation in IRS-1 serine phosphorylation. Treatment of animals with SB-239063, a potent and specific inhibitor of p38 MAPK, 10 min before reperfusion enabled insulin-mediated myocardial protection in Insulin AR rats. We conclude that insulin protects myocardium against ischemiareperfusion injury when given prior to ischemia or reperfusion, and activation of p38 MAPK abolishes insulin's cardioprotective effect.

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“…Measurement of Glucose Production in Primary Hepatocytes-The glucose production from primary hepatocytes was measured as previously described (22,23). Briefly, cells were treated with EGCG for 3 h at concentrations as noted in the serum-free Williams' E medium.…”

Section: Methodsmentioning

confidence: 99%

Epigallocatechin-3-gallate (EGCG), A Green Tea Polyphenol, Suppresses Hepatic Gluconeogenesis through 5′-AMP-activated Protein Kinase

Collins

Liu

et al. 2007

Journal of Biological Chemistry

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306

224

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Epigallocatechin-3-gallate (EGCG), a main catechin of green tea, has been suggested to inhibit hepatic gluconeogenesis. However, the exact role and related mechanism have not been established. In this study, we examined the role of EGCG in hepatic gluconeogenesis at concentrations that are reachable by ingestion of pure EGCG or green tea, and are not toxic to hepatocytes. Our results show in isolated hepatocytes that EGCG at relatively low concentrations (<1 M) inhibited glucose production via gluconeogenesis and expression of key gluconeogenic genes. EGCG was not toxic at these concentrations while demonstrating significant cytotoxicity at 10 M and higher concentrations. EGCG at 1 M or lower concentrations effective in suppressing hepatic gluconeogenesis did not activate the insulin signaling pathway, but activated 5-AMP-activated protein kinase (AMPK). The EGCG suppression of hepatic gluconeogenesis was prevented by blockade of AMPK activity. In defining the mechanism by which EGCG activates AMPK, we found that the EGCG activation of AMPK was mediated by the Ca 2؉ /calmodulin-dependent protein kinase kinase (CaMKK). Furthermore, our results show that the EGCG activation of AMPK and EGCG suppression of hepatic gluconeogenesis were both dependent on production of reactive oxygen species (ROS), which was a known activator of CaMKK. Together, our results demonstrate an inhibitory role for EGCG in hepatic gluconeogenesis and shed new light on the mechanism by which EGCG suppresses gluconeogenesis.

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

Cited by 68 publications

References 56 publications

Protein kinase STK25 controls lipid partitioning in hepatocytes and correlates with liver fat content in humans

Protein kinase STK25 controls lipid partitioning in hepatocytes and correlates with liver fat content in humans

Activation of p38 mitogen-activated protein kinase abolishes insulin-mediated myocardial protection against ischemia-reperfusion injury

Epigallocatechin-3-gallate (EGCG), A Green Tea Polyphenol, Suppresses Hepatic Gluconeogenesis through 5′-AMP-activated Protein Kinase

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