Chronic alcohol consumption disrupted cholesterol homeostasis in rats: down-regulation of low-density lipoprotein receptor and enhancement of cholesterol biosynthesis pathway in the liver.
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
Long-term excessive alcohol feeding | increase | fatty liver and liver injury | rats | - | caused | #1 |
Long-term excessive alcohol feeding | increase | cholesterol homeostasis | rats | - | associated with disrupted | #2 |
Long-term excessive alcohol feeding | increase | hepatic cholesterol levels | rats | - | characterized by increased | #3 |
Long-term excessive alcohol feeding | increase | hypercholesterolemia | rats | - | characterized by | #4 |
Long-term excessive alcohol feeding | increase | sterol regulatory element-binding protein-2 (SREBP-2) | rats | - | concomitant with constantly activated | #5 |
Long-term excessive alcohol feeding | increase | 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase | rats | - | increased expression of | #6 |
Long-term excessive alcohol feeding | increase | cholesterol biosynthesis | rats | - | indicating enhanced | #7 |
Alcohol-induced hypercholesterolemia | decrease | LDL receptor (LDLr) levels | rats | - | was accompanied by decreased | #8 |
Chronic alcohol exposure | increase | hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) contents | rats | - | increased | #9 |
Chronic alcohol exposure | decrease | LDLr | rats | - | to down-regulate | #10 |
Alcohol feeding | decrease | extracellular signal-regulated kinase (ERK) activation | rats | - | suppressed | #11 |
Inhibition of ERK activation | decrease | LDLr expression | HepG2 cells | - | was associated with decreased | #12 |
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.