neuropeptide-y and Non-alcoholic-Fatty-Liver-Disease

The development of non-alcoholic fatty liver disease (NAFLD) is partially attributed to disturbance in cholesterol metabolism and sympathetic overactivity. Excessive levels of the sympathetic neurotransmitter neuropeptide Y (NPY) positively correlated with both NAFLD and cholesterol accumulation. We wanted to determine, for the first time, whether NPY promotes cholesterol accumulation directly in hepatocytes and elucidate the underlying mechanism.. In vivo, NPY was injected through the hepatic portal vein into SD rats. One hour later, serum and liver tissues were collected. In vitro, BRL-3A hepatocytes were treated with NPY, and with Y1, Y2, Y5, receptor antagonists as well as with extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) antagonist, respectively. Cholesterol content was measured by coupled enzyme method. Precursor sterol-regulatory element binding protein 2 (pSREBP2), mature SREBP2 (mSREBP2), HMG-CoA reductase (HMGCR), ERK1/2, pERK1/2, cAMP-dependent protein kinase (PKA), and pPKA protein expression levels were examined by western blotting.. In rats, intraportal vein injection of NPY activates pSREBP2, mSREBP2, and HMGCR protein expression, and induces hepatic cholesterol accumulation. In BRL-3A cells, we observed that NPY increases cholesterogenic protein expression and cholesterol synthesis through Y1 and Y5 receptors. This effect is mediated by the activation of the ERK1/2 signaling pathway.. We demonstrated, for the first time, that NPY can activate the cholesterogenic pathway and elucidated the underlying mechanism. Thus, NPY and NPY receptors might be new targets for the treatment of NAFLD and dyslipidemia.

Topics: Animals; Cholesterol; Hepatocytes; Hydroxymethylglutaryl CoA Reductases; Male; Neuropeptide Y; Non-alcoholic Fatty Liver Disease; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Sterol Regulatory Element Binding Protein 2

This study was intended to assess the influence of the rs16147 variant of the NPY gene on liver histology in patients with non-alcoholic fatty liver disease (NAFLD).. Eighty-nine patients with NAFLD were recruited into the study. Serum chemistry tests were done including lipid profile, transaminases, adipokines, and insulin resistance. Genotype of polymorphism (rs161477) of the NPY gene was studied.. Twenty-three patients (25.0%) had the GG genotype (wild type) and sixty-six patients (75%) the GA (n=39) or AA (n=27) (mutant) types. Patients with A allele had a lower percentage of lobular inflammation and steatohepatitis (lobular inflammation plus ballooning) than those with wild genotype. Patients with A allele showed lower SAF (Steatosis, Activity, Fibrosis) scores than non-A allele carriers (5.4±2.7 points vs. 4.1±1.1 points; p=0.01). In the analysis without fibrosis (NAS score), the same differences were detected (4.5±1.8 points vs. 3.4±1.8 points; p=0.01). In the logistic regression analysis A allele carriers showed lower odds for inflammation (OR 0.11, 95% CI 0.02-0.84, p=0.03) and steatohepatitis (OR 0.39, 95% CI 0.14-0.86, p=0.04) after adjusting for age, sex, and body mass index.. A variant of polymorphism rs16147 of the NPY gene is independently associated to a lower percentage of steatohepatitis and lobular inflammation in obese subjects with biopsy-proven NAFLD.

Topics: Adipokines; Adiposity; Adult; Blood Glucose; Body Weight; Comorbidity; Female; Genetic Association Studies; Genotype; Humans; Insulin Resistance; Lipids; Liver; Male; Middle Aged; Neuropeptide Y; Non-alcoholic Fatty Liver Disease; Obesity; Polymorphism, Single Nucleotide

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.. to determine the mechanistic effects of NE/EPI/NPY on phenotypic changes in cultured hHSC, and to study SNS signalling in human NAFLD livers.. Freshly 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.. Activated 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.. hHSC 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.

Topics: Base Sequence; Catecholamines; Cells, Cultured; Chromatography, High Pressure Liquid; Collagen; DNA Primers; Fatty Liver; Hepatic Stellate Cells; Humans; Interleukins; Liver Cirrhosis; Neuropeptide Y; Non-alcoholic Fatty Liver Disease; Norepinephrine; Receptors, Adrenergic; Reverse Transcriptase Polymerase Chain Reaction; Sympathetic Nervous System; Transforming Growth Factor beta; Up-Regulation