Galanin receptor 2 mediates antifibrogenic effects of galanin on hepatic stellate cells

Abstract

Abstract.Galanin is an endogenous factor involved in the negative regulation of the biological effects of leptin in bioenergetic metabolism. Leptin promotes fibrogenic effects in hepatic stellate cells (HSCs), however, little is known about the effects of galanin on HSCs. In the present study, the biological functions of galanin and its receptors (GalRs) in HSCs were investigated using cell culture in vitro. It was found that galanin and GalR3 mRNA are expressed in quiescent and activated HSCs. GalR2 expression was undetectable in quiescent HSCs but was markedly induced in activated HSCs. In the HSC-T6 cell line, which is an activated rat HSC cell line, treatment with 100 nmol/l galanin significantly inhibited cell proliferation. It also inhibited transforming growth factor (TGF)-β1 and α-smooth muscle actin (SMA) expression and upregulated peroxisome proliferator-activated receptor (PPAR)-γ expression. Following the knockdown of GalR2 by specific small interfering RNA, the activation of GalR3 by galanin does not influence these effects of galanin on HSCs. However, activation of GalR2 alone by galanin following the knockdown of GalR3 inhibits HSC proliferation and TGF-β1 and α-SMA expression, in addition to inducing PPAR-γ expression. These data suggest that galanin inhibits HSC activation and suppresses the profibrogenic features of these cells, and these effects might be mediated by GalR2. Thus, galanin is a potential endogenous factor in the inhibition of liver fibrosis. IntroductionGalanin is a 29-amino acid peptide naturally present in the tissues and fluids of humans and animals (1). To date three galanin receptors (GalR1, GalR2 and GalR3) have been discovered to be widely distributed in the mammalian central and peripheral nervous system (2). It is acknowledged that galanin has a critical role in the regulation of energy homeostasis (3). Leptin, another adipocyte-derived hormone, is also a key factor in the regulation of body weight and energy expenditure and acts in rodents via hypothalamus receptors to inhibit feeding and increase thermogenesis (4). Notably, a previous study confirmed that galanin inhibits leptin expression and secretion in rat adipose tissue and 3T3-L1 adipocytes (5). Leptin has been shown to possess direct profibrogenic activity in the liver, and the absence of leptin is associated with a marked attenuation of the hepatic response to a diverse range of fibrotic stimuli (6). It has been hypothesized that leptin acts directly on hepatic stellate cells (HSCs) to trigger downstream response pathways that ultimately lead to the deposition of extracellular matrix (ECM) (7). However, little is known about the effects of galanin on HSCs. Since the activation and proliferation of HSCs are the key factors in the progress of liver fibrosis, in view of the counteracting effect of galanin on leptin in food intake and energy metabolism, the effect of galanin on the proliferation of HSCs becomes an interesting research topic.It may be hypothesized that galanin is able to inhibit the activation and p...

Coordinated Targeting of Galanin Receptors on Cholangiocytes and Hepatic Stellate Cells Ameliorates Liver Fibrosis in Multidrug Resistance Protein 2 Knockout Mice

“…21 The molecular mechanisms of Gal-induced activation of HSCs are still to be explored. Our findings related to GalR2 being the main Gal receptor expressed in HSCs in vivo are in agreement with a study made by He et al, 30 using HSC T6 cell line in vitro. However, unlike the results obtained with T6 cell line where GalR2 activation was antifibrotic, the data from both in vivo and in vitro experiments indicate that GalR2 in HSCs contributes to Gal-induced fibrogenesis.…”

The Agonists of Peroxisome Proliferator-Activated Receptor-γ for Liver Fibrosis

“… 57 Galanin and vitamin C, endogenous factors that negatively regulate the biological effects of LP bioenergy metabolism, inhibit the proliferation of HSCs and the expression of α-SMA by increasing PPAR-γ, which may be of potential significance for elucidating the detailed mechanisms underlying liver fibrosis in diseases with elevated circulating LP levels, such as non-alcoholic fatty hepatitis in obese patients. 54 , 58 , 59 …”

Caffeic acid phenethyl ester up-regulates antioxidant levels in hepatic stellate cell line T6viaan Nrf2-mediated mitogen activated protein kinases pathway

“…Oxidative stress can stimulate the activation of hepatic stellate cells (HSCs) through paracrine and autocrine mechanisms, leading to the formation of liver fibrosis[ 1 , 2 ]. HSC-T6 cells, a well-differentiated transformed cell line[ 3 , 4 ], were used in this study to observe the role of HSC in liver fibrosis.…”