Insulin resistance in hepatocytes and sinusoidal liver cells: Mechanisms and consequences

Leclercq, Isabelle; Morais, Alain da Silva; Schroyen, Ben; Hul, Noémi Van; Geerts, Albert

doi:10.1016/j.jhep.2007.04.002

Cited by 307 publications

(240 citation statements)

References 126 publications

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“…This study indicates that S1P influences Akt activity in a divergent manner depending on the levels of the S1P receptor subtypes. Several lines of evidence support a role of S1P 1 and S1P 3 in Akt activation in response to S1P or FTY720 [41]. Measurement of the receptor profile in rat and human hepatocytes indicated a predominant expression of the S1P 2 receptor subtype, explaining the inhibitory effect of S1P on insulinmediated Akt activation.…”

Section: Discussionmentioning

confidence: 97%

“…Hepatic insulin resistance is defined clinically in terms of a failure of insulin to maintain glucose homeostasis, leading to hyperglycaemia. Unrestrained hepatic glucose production is a consequence of a reduced efficacy of insulin to suppress hepatic gluconeogenesis and glycogenolysis, while reduced hepatic glucose clearance results from an impaired insulindependent stimulation of glycogen synthesis [3].…”

Section: Introductionmentioning

confidence: 99%

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Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P2 receptor subtype

et al. 2013

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Aims/hypothesis Enhanced plasma levels of NEFA have been shown to induce hepatic insulin resistance, which contributes to the development of type 2 diabetes. Indeed, sphingolipids can be formed via a de novo pathway from the saturated fatty acid palmitate and the amino acid serine. Besides ceramides, sphingosine 1-phosphate (S1P) has been identified as a major bioactive lipid mediator. Therefore, our aim was to investigate the generation and function of S1P in hepatic insulin resistance. Methods The incorporation of palmitate into sphingolipids was performed by rapid-resolution liquid chromatography-MS/MS in primary human and rat hepatocytes. The influence of S1P and the involvement of S1P receptors in hepatic insulin resistance was examined in human and rat hepatocytes, as well as in New Zealand obese (NZO) mice. Results Palmitate induced an impressive formation of extraand intracellular S1P in rat and human hepatocytes. An elevation of hepatic S1P levels was observed in NZO mice fed a high-fat diet. Once generated, S1P was able, similarly to palmitate, to counteract insulin signalling. The inhibitory effect of S1P was abolished in the presence of the S1P 2 receptor antagonist JTE-013 both in vitro and in vivo. In agreement with this, the immunomodulator FTY720-phosphate, which binds to all S1P receptors except S1P 2 , was not able to inhibit insulin signalling. Conclusions/interpretation These data indicate that palmitate is metabolised by hepatocytes to S1P, which acts via stimulation of the S1P 2 receptor to impair insulin signalling. In particular, S1P 2 inhibition could be considered as a novel therapeutic target for the treatment of insulin resistance.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P2 receptor subtype

et al. 2013

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“…It inhibits hepatic glucose production and increases peripheral glucose uptake and glycogen synthesis. The principal signaling pathway ( Figure 1) involves sequential activation of the insulin receptor, insulin receptor substrates (IRS), phosphatidylinositol-3-kinase (PI3K), Akt and protein kinase C isoforms ζ and λ [3,4] . Akt is phosphorylated initially at serine 473 by phosphoinositide-dependent kinase (PDK)2 and Douglas MW et al .…”

Section: Insulin Signaling and Irmentioning

confidence: 99%

Molecular mechanisms of insulin resistance in chronic hepatitis C

Douglas

George²

2009

WJG

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It is now widely recognized that chronic hepatitis C (CHC) is associated with insulin resistance (IR) and type 2 diabetes, so can be considered a metabolic disease. IR is most strongly associated with hepatitis C virus (HCV) genotype 1, in contrast to hepatic steatosis, which is associated with genotype 3 infection. Apart from the well-described complications of diabetes, IR in CHC predicts faster progression to fibrosis and cirrhosis that may culminate in liver failure and hepatocellular carcinoma. More recently, it has been recognized that IR in CHC predicts a poor response to antiviral therapy. The molecular mechanisms for the association between IR and HCV infection are not well defined. This review will elaborate on the clinical associations between CHC and IR and summarize current knowledge regarding the molecular mechanisms that potentially mediate HCV-associated IR.

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“…However, we do not fully understand the biological effects of IR on cancer cells. As the most important target organ of insulin, reduced insulin sensitivity in liver cells is one of the pathological changes of carcinogenesis (Leclercq et al, 2007). The HepG2 cell line is an HCC cell line that possesses some features of normal liver cells including high InsR expression.…”

Section: Discussionmentioning

confidence: 99%

“…Normally, insulin binds to its receptor to initiate signal transduction. Insulin resistance (IR) can be induced by any of the following events: reduction in the number and affinity of insulin receptors, mutations of encoding genes, downregulation of the glucose transporter, and defects in insulin signal transduction (Yoshikawa et al, 2001;Wilcox, 2005;Draznin, 2006;Leclercq et al, 2007). IR refers to a decrease in the sensitivity of the whole organism, organs, tissues, or cells to insulin stimulation.…”

Section: Introductionmentioning

confidence: 99%

Insulin Resistance Reduces Sensitivity to Cis-Platinum and Promotes Adhesion, Migration and Invasion in HepG2 Cells

Li²,

Wei³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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The liver is normally the major site of glucose metabolism in intact organisms and the most important target organ for the action of insulin. It has been widely accepted that insulin resistance (IR) is closely associated with postoperative recurrence of hepatocellular carcinoma (HCC). However, the relationship between IR and drug resistance in liver cancer cells is unclear. In the present study, IR was induced in HepG2 cells via incubation with a high concentration of insulin. Once the insulin-resistant cell line was established, the stability of HepG2/ IR cells was further tested via incubation in insulin-free medium for another 72h. Afterwards, the biological effects of insulin resistance on adhesion, migration, invasion and sensitivity to cis-platinum (DDP) of cells were determined. The results indicated that glucose consumption was reduced in insulin-resistant cells. In addition, the expression of the insulin receptor and glucose transportor-2 was downregulated. Furthermore, HepG2/IR cells displayed markedly enhanced adhesion, migration, and invasion. Most importantly, these cells exhibited a lower sensitivity to DDP. By contrast, HepG2/IR cells exhibited decreased adhesion and invasion after treatment with the insulin sensitizer pioglitazone hydrochloride. The results suggest that IR is closely related to drug resistance as well as adhesion, migration, and invasion in HepG2 cells. These findings may help explain the clinical observation of limited efficacy for chemotherapy on a background of IR, which promotes the invasion and migration of cancer cells.

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Insulin resistance in hepatocytes and sinusoidal liver cells: Mechanisms and consequences

Cited by 307 publications

References 126 publications

Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P2 receptor subtype

Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P2 receptor subtype

Molecular mechanisms of insulin resistance in chronic hepatitis C

Insulin Resistance Reduces Sensitivity to Cis-Platinum and Promotes Adhesion, Migration and Invasion in HepG2 Cells

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