Abstract
Background Sympathetic nervous system (SNS) signalling regulates murine hepatic fibrogenesis through effects on hepatic stellate cells (HSC), and obesity-related hypertension with SNS activation accelerates progression of non-alcoholic fatty liver disease (NAFLD), the commonest cause of chronic liver disease. NAFLD may lead to cirrhosis. The effects of the SNS neurotransmitters norepinephrine (NE), epinephrine (EPI) and neuropeptide Y (NPY) on human primary HSC (hHSC) function and in NAFLD pathogenesis are poorly understood.Aimsto determine the mechanistic effects of NE/EPI/NPY on phenotypic changes in cultured hHSC, and to study SNS signalling in human NAFLD livers.MethodsFreshly isolated hHSC were assessed for expression of cathecholamine/neuropeptide Y receptors and for the synthesis of NE/EPI. The effects of NE/EPI/NPY and adrenoceptor antagonists prazosin (PRZ)/propranolol (PRL) on hHSC fibrogenic functions and the involved kinases and interleukin pathways were examined. Human livers with proven NAFLD were then assessed for upregulation of SNS signalling components.ResultsActivated hHSC express functional α/β-adrenoceptors and NPY receptors, which are upregulated in the livers of patients with cirrhotic NAFLD. hHSC in culture synthesize and release NE/EPI, required for their optimal basal growth and survival. Exogenous NE/EPI and NPY dose-dependently induced hHSC proliferation, mediated via p38 MAP, PI3K and MEK signalling. NE and EPI but not NPY increased expression of collagen-1α2 via TGF-β without involvement of the pro-fibrogenic cytokines leptin, IL-4 and IL-13 or the anti-fibrotic cytokine IL-10.ConclusionshHSC synthesize and require cathecholamines for optimal survival and fibrogenic functionality. Activated hHSC express directly fibrogenic α/β-adrenoceptors and NPY receptors, upregulated in human cirrhotic NAFLD. Adrenoceptor and NPY antagonists may be novel anti-fibrotic agents in human NAFLD.
Highlights
The sympathetic nervous system (SNS), a major branch of the autonomic nervous system, is responsible for up- and downregulating many homeostatic mechanisms in living organisms
Activated human primary HSC (hHSC) express functional a/b-adrenoceptors and neuropeptide Y (NPY) receptors, which are upregulated in the livers of patients with cirrhotic non-alcoholic fatty liver disease (NAFLD). hHSC in culture synthesize and release NE/EPI, required for their optimal basal growth and survival
Characteristics of cultured hHSC Upon isolation, primary hHSC cell identity and activation was confirmed by their expression of established indicators, alpha smooth muscle actin (ASMA) and glial fibrillary acidic protein (GFAP), verified at day 4 by immunocytochemistry (Figure 1a)
Summary
The sympathetic nervous system (SNS), a major branch of the autonomic nervous system, is responsible for up- and downregulating many homeostatic mechanisms in living organisms. Neuropeptide Y (NPY), co-released with cathecholamines at SNS nerve terminals modulates in turn cathecholamine release [6,7] and induces murine HSC proliferation but not collagen expression [5]. The applicability of these findings to human liver fibrosis is unknown. Sympathetic nervous system (SNS) signalling regulates murine hepatic fibrogenesis through effects on hepatic stellate cells (HSC), and obesity-related hypertension with SNS activation accelerates progression of non-alcoholic fatty liver disease (NAFLD), the commonest cause of chronic liver disease. The effects of the SNS neurotransmitters norepinephrine (NE), epinephrine (EPI) and neuropeptide Y (NPY) on human primary HSC (hHSC) function and in NAFLD pathogenesis are poorly understood
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