Resistin as an Intrahepatic Cytokine

Abstract

Obesity and insulin resistance accelerate the progression of fibrosis during chronic liver disease. Resistin antagonizes insulin action in rodents, but its role in humans is still controversial. The aims of this study were to investigate resistin expression in human liver and to evaluate whether resistin may affect the biology of activated human hepatic stellate cells (HSCs), key modulators of hepatic fibrogenesis. Resistin gene expression was low in normal human liver but was increased in conditions of severe fibrosis. Up-regulation of resistin during chronic liver damage was confirmed by immunohistochemistry. In a group of patients with alcoholic hepatitis, resistin expression correlated with inflammation and fibrosis, suggesting a possible action on HSCs. Exposure of cultured HSCs to recombinant resistin resulted in increased expression of the proinflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8, through activation of nuclear factor (NF)-B. Resistin induced a rapid increase in intracellular calcium concentration , mainly through calcium release from intracellular inositol triphosphate-sensitive pools. The intracellular calcium chelator BAPTA-AM blocked resistin-induced NF-B activation and monocyte chemoattractant protein-1 expression. In conclusion, this study shows a role for resistin as an intrahepatic cytokine exerting proinflammatory actions in HSCs, via a Ca 2؉ /NF-B-dependent pathway and suggests involvement of this adipokine in the pathophysiology of liver fibrosis.

Cellular and molecular mechanisms in liver fibrogenesis

“…Indeed, in rodents resistin is up-regulated in dietinduced or genetic obesity [70] whereas in humans seems to have a role in sustaining inflammation, as shown by studies in which resistin is up-regulated in monocytes exposed to proinflammatory stimuli and in conditions of experimentally induced endotoxemia [71,72]. In relation to liver fibrogenesis, it has been shown that resistin expression during liver injury positively correlates with infiltration of inflammatory cells, which may represent the principal source of intrahepatic resistin [73]. Indeed, resistin expression was found to co-localize with the inflammatory cell marker CD43 in liver specimens from patients with alcoholic hepatitis.…”

“…Indeed, resistin expression was found to co-localize with the inflammatory cell marker CD43 in liver specimens from patients with alcoholic hepatitis. However, resistin is apparently expressed only in quiescent HSCs isolated from rats, but not in activated HSCs isolated from either rodents or humans [73]. Human HSC, however, respond to recombinant resistin by up-regulating expression of CCL2 and IL-8 in a NF-kB-dependent manner [73].…”

The role of resistin as a regulator of inflammation: Implications for various human pathologies

“…This effect may occur through resistin-mediated phosphorylation of the inhibitory protein IκBα and the p65 subunit of NF-κB [40]. Resistin increased the cytosolic calcium concentration via an influx of calcium from the extracellular environment and activation of phospholipase C (PLC), leading to the release of calcium from intracellular pools [41].…”

“…Recombinant human resistin is also capable of increasing the production of the proinflammatory cytokines IL-8 and monocyte chemoattractant protein (MCP)-1 via the activation of NF-κB [42]. Both mitogen-activated protein kinases (MAPKs), such as Erk or p38, and Akt, as a downstream substrate of phosphatidylinositol 3-kinase (PI3K), can be phosphorylated by resistin in several cell lines [41,[43][44][45]. The intracellular signaling pathways of resistin are shown in Figure 1.…”

EFFECT OF <i>CATHA EDULIS</i> ON INSULIN, RESISTIN AND CORTISOL LEVELS IN TYPE-2 DIABETICS AND NON-DIABETICS

“…An increased serum calcium level led to an increased cytosolic calcium level (Aoki and Miyagawa, 1990), which diminish cellular sensitivity to insulin and might participate in the pathogenesis of insulin resistance in type 2 diabetes. calcium was shown to be significantly correlated with resistin; it has been shown that resistin increases cytosolic calcium concentration in hepatic stellate cells (Bertolani et al, 2006). In addition, Yamaguchi et al (2011) who stated that serum calcium is positively correlated with fasting plasma glucose and insulin resistance, independent of parathyroid hormone, in male patients with type 2 diabetes mellitus.…”