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Chronic Alcohol Consumption Disrupted Cholesterol Homeostasis in Rats: Down‐Regulation of Low‐Density Lipoprotein Receptor and Enhancement of Cholesterol Biosynthesis Pathway in the Liver
Author(s) -
Wang Zhigang,
Yao Tong,
Song Zhenyuan
Publication year - 2010
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2009.01111.x
Subject(s) - medicine , endocrinology , ldl receptor , cholesterol , sterol regulatory element binding protein , fatty liver , hmg coa reductase , cholesterol 7 alpha hydroxylase , biology , liver x receptor , chemistry , lipoprotein , sterol , reductase , biochemistry , enzyme , nuclear receptor , disease , gene , transcription factor
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.