Abstract
BackgroundThe 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.MethodYoung 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 6 weeks.ResultsWeight gain (~ 40 g) was observed only following 6 weeks of the obesogenic diets (P < 0.01). Compared to the 2-week treatment, obesogenic diets tripled fat pad weight (~ 20 vs 7 g) after 6 weeks. Hepatic triglyceride (TG) levels were greater in response to both the WD and HFD compared to the SD (P < 0.01) at 2 and 6 weeks and their concentrations were greater (P < 0.05) in WD than HFD at 2 weeks. Plasma total cholesterol levels were higher (P < 0.05) in animals submitted to WD. After 2 and 6 weeks, 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.ConclusionThese 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.
Highlights
Non-alcoholic fatty liver disease (NAFLD), referred to as hepatic steatosis is characterized by excessive fat accumulation (5 to 10% of liver weight) in absence of significant alcohol consumption [1]
These include cholesterol synthesis, uptake from chylomicron remnants, re-uptake from LDL and high-density lipoproteins (HDL) as well as the release of cholesterol under very-low density lipoproteins (VLDL), and biliary acids production. All of these pathways have a major influence on the regulation of plasma cholesterol levels and the subsequent proatherogenic profile associated with fat accumulation in the liver
The main finding of the present study is that animals fed a WD for only 2 weeks depicted lower gene expression of several key markers of liver cholesterol metabolism including low-density lipoprotein-receptor (LDL-R), PCSK9, sterol regulatory element binding protein 2 (SREBP2), and hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR) compared to animals fed a SD or a HFD
Summary
Non-alcoholic fatty liver disease (NAFLD), referred to as hepatic steatosis is characterized by excessive fat accumulation (5 to 10% of liver weight) in absence of significant alcohol consumption [1] This state is associated with several clinical and pathological manifestations. The liver is the master regulator of several biological pathways involved in the control of cholesterol metabolism These include cholesterol synthesis, uptake from chylomicron remnants, re-uptake from LDL and high-density lipoproteins (HDL) as well as the release of cholesterol under very-low density lipoproteins (VLDL), and biliary acids production. All of these pathways have a major influence on the regulation of plasma cholesterol levels and the subsequent proatherogenic profile associated with fat accumulation in the liver. 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
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