title: Chronic alcohol consumption disrupted cholesterol homeostasis in rats: down-regulation of low-density lipoprotein receptor and enhancement of cholesterol biosynthesis pathway in the liver.
abstract: BACKGROUND
  Chronic alcohol consumption causes alcoholic liver disease, which is associated, or initiated, with dysregulated lipid metabolism. Very recent evidence suggested that dysregulated cholesterol metabolism plays an important role in the pathogenesis of alcoholic fatty liver diseases, however, the effects of chronic alcohol exposure on cholesterol homeostasis have not been well studied and underlying mechanisms behind are still elusive.
  
  
  METHODS
  Male Sprague-Dawley rats weighing 250 +/- 5.5 g (mean +/- SEM) divided into 2 groups (8 rats per group) and pair-fed with liquid diets containing (in percent of energy intake) 18% protein, 35% fat, 12% carbohydrate, and 35% either ethanol (ethanol diet) or an isocaloric maltose-dextrin mixture (control diet), according to Lieber and De Carli, for 4 weeks.
  
  
  RESULTS
  Long-term excessive alcohol feeding to rats caused fatty liver and liver injury, which was associated with disrupted cholesterol homeostasis, characterized by increased hepatic cholesterol levels and hypercholesterolemia. Hepatic cholesterol increases were concomitant with constantly activated sterol regulatory element-binding protein-2 (SREBP-2) in the liver and increased expression of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, a rate-limiting enzyme for cholesterol de novo synthesis, indicating enhanced cholesterol biosynthesis. Alcohol-induced hypercholesterolemia was accompanied by decreased LDL receptor (LDLr) levels in the liver. Further investigations revealed that chronic alcohol exposure increased hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) contents to down-regulate LDLr via a post-translational mechanism. Moreover, alcohol feeding suppressed extracellular signal-regulated kinase (ERK) activation in the liver. In vitro studies showed that inhibition of ERK activation was associated with decreased LDLr expression in HepG2 cells.
  
  
  CONCLUSIONS
  Our study provides the first evidence that both increased PCSK9 expression and suppressed ERK activation in the liver contributes to alcohol-induced hypercholesterolemia in rats.
authors.affiliation: Department of Human Nutrition, University of Illinois at Chicago, Illinois 60612, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Wang
authors.forename: Tong
authors.initials: T
authors.lastname: Yao
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Song
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism; D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis*; D015536:Down-Regulation; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006706:Homeostasis; D006937:Hypercholesterolemia / Q000139:chemically induced; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000209:etiology / Q000378:metabolism*; D008297:Male; D000071449:Proprotein Convertase 9; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism
chemical_list: D002492:Central Nervous System Depressants; D011973:Receptors, LDL; D000431:Ethanol; D002784:Cholesterol; D048049:Extracellular Signal-Regulated MAP Kinases; C510804:PCSK9 protein, rat; D000071449:Proprotein Convertase 9; D012697:Serine Endopeptidases