Two weeks of western diet disrupts liver molecular markers of cholesterol metabolism in rats

Background: The present study was designed to test the hypothesis that in the liver, excessive fat accumulation impairs cholesterol metabolism mainly by altering the low-density lipoprotein-receptor (LDL-R) pathway. Method: Young male Wistar rats were fed standard (SD), high fat (HFD; 60% kcal) or Western (WD; 40% fat +35% sucrose (17.5% fructose)) diets for 2 or 6weeks. Results: Weight gain (similar to 40g) was observed only following 6weeks of the obesogenic diets (P<0.01). Compared to the 2-week treatment, obesogenic diets tripled fat pad weight (similar to 20 vs 7g) after 6weeks. Hepatic triglyceride (TG) levels were greater in response to both the WD and HFD compared to the SD (P<0.01) at 2 and 6weeks and their concentrations were greater (P<0.05) in WD than HFD at 2weeks. Plasma total cholesterol levels were higher (P<0.05) in animals submitted to WD. After 2 and 6weeks, liver expression of LDL-R, proprotein convertase subtilisin/kexin 9 (PCSKk9) and sterol regulatory element binding protein 2 (SREBP2), involved in LDL-cholesterol uptake, was lower in animals submitted to WD than in others treated with HFD or SD (P<0.01). Similarly, low-density lipoprotein-receptor-related protein 1 (LRP1) and acyl-CoA cholesterol acyltransferase-2 (ACAT-2) mRNA levels were lower (P<0.01) among WD compared to SD-fed rats. Expression of the gene coding the main regulator of endogenous cholesterol synthesis, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR) was reduced in response to WD compared to SD and HFD at 2 (P<0.001) and 6 (P<0.05) weeks. Being enriched in fructose, the WD strongly promoted the expression of carbohydrate-response element binding protein (ChREBP) and acetyl-CoA carboxylase (ACC), two key regulators of de novo lipogenesis. Conclusion: These results show that the WD promptly increased TG levels in the liver by potentiating fat storage. This impaired the pathway of hepatic cholesterol uptake via the LDL-R axis, promoting a rapid increase in plasma total cholesterol levels. These results indicate that liver fat content is a factor involved in the regulation of plasma cholesterol.