Etiology of disrupted cholesterol metabolism in the liver of young rats submitted to obesogenic diets

Abstract

The purpose of the study was to test the hypothesis that a short period (2 weeks) of a high fat (HFD) and a western (WD) diet leading to an increase in liver fat accumulation will disrupt key markers of liver cholesterol metabolism mainly targeting the LDL‐receptor (LDL‐R) pathway. Rats were submitted to either a standard (SD), HFD (60%) or a WD (40% fat + 35% sucrose) diet for 2 and 6 weeks. Body weight gain and body fat values were higher (p < 0.01) in rats fed the HFD and WD for 6 weeks although food intakes in kcal/d were not different for all groups throughout the experimental period. Liver fat accumulation was significantly (P < 0.01) higher in HFD and WD rats as compared to the SD diet for both feeding durations. On the other hand, liver fat accumulation was higher in WD rats (P < 0.05) than HFD animals after two weeks of treatment. In addition, WD animals displayed the highest plasma cholesterol levels. After 2 and 6 weeks of treatment, hepatic gene expression of LDL‐R, Pcsk9 and SREBP‐2 was lower (p < 0.01) in WD animals than in HFD and SD rats. In addition, mRNA levels of Lrp1 and Acat2 were lower (p < 0.01) in WD rats as compared to those fed with SD. Gene expression of HMGCoA‐r, the main enzyme involved in the regulation of cholesterol synthesis, was lower in HFD (2 weeks) and even more so in rats fed the WD diet (2 and 6 weeks). The WD was associated with a higher (p < 0.01) gene expression of markers involved in the mediation of de novo lipogenesis (ACC and ChREBP). It is concluded that a short‐term WD promptly increased fat accumulation while disrupting cholesterol metabolism in the liver. The present results provide new insights on the mechanisms through which westernized diets rapidly promote increases in plasma cholesterol levels.Support or Funding InformationNSERC, FRQS, CFI