| Accompanyed by the changes of diet condition and diet composition, people begin to pay close attention to the fats and cholesterol in food. The liver is the critical organ of lipid metabolism. Atherosclerosis (AS) is a complex multifactorial disease. It is the pathological and physiological base of cardiovascular disease, such as hypercholesterolemia and hyperlipidemia. Hypercholesterolemia and hyperlipidemia induced by high dietary fat and cholesterol and the inherited defects in lipid metabolism by genetic modification are two major causative factors in atherogenesis, and high fat and high cholesterol diet play important roles in the regulation of genes involved in lipid metabolism. Intriguingly, peroxisome proliferater-activated receptors (PPARs), liver X receptors (LXRs), and other nuclear receptors not only in?uence lipid metabolism at the systemic level but also regulate lipid homeostasis and in?ammation within the artery wall. Activation of PPARs and LXRs leads to multiple changes in the expression of their responsive genes, some of which are predicted to be atherogenic or anti-atherogenic. PPARa, LXRa, and their responsive genes play central roles in the transcriptional control of lipid metabolism-related genes and are involved in atherogenesis.The results show:In apoE-/-/LDLR-/- mice fed with HF diet, the mRNA level of lipoprotein lipase (LPL) was significantly decreased compared with the mice fed with chow (P<0.01). In WT mice, however, it was increased after feeding with HF diet (P<0.01). From 4- to 12-week-old, the expression of angiopoietin-like 3 (Angptl3) was persistently increased in apoE-/-/LDLR-/- and WT mice fed with HF diet compared with the same genotype mice fed with chow diet (P<0.05). The mRNA levels of apolipoprotein AV (apoAV) remained unchanged in apoE-/-/LDLR-/- and WT mice either fed with HF or chow diet.In apoE-/-/LDLR-/- mice fed with HF diet, the mRNA level of scavenger receptor class B type I (SR-BI) was significantly decreased compared with the mice fed with chow (P<0.01). In WT mice, however, it was increased after feeding with HF diet (P<0.01). The mRNA level of apolipoprotein F (apoF) was upregulated in apoE-/-/LDLR-/- mice from 4 wees old fed with HF diet; however, the trend was reversed in age-matched WT mice. There was an obvious downregulation of apolipoprotein AI (apoAI) in AL mice fed with HF diet aswhen compared with the mice fed with chow (P<0.01). The same trend can be observed in WT group (P<0.05). Compared with apoE-/-/LDLR-/- mice fed with chow, the expression of apolipoprotein AIV (apoAIV) was decreased in AL mice fed with HF diet from 4-week-old (P<0.05).At the age of 12-week-old, the expression profiles of apolipoprotein B100 (apoB100) was significantly increased in apoE-/-/LDLR-/- mice fed with HF diet compared with the mice fed with chow. The expression of apoB100 had steady-state values in WT group from 3- to 12-week-old (P<0.01).With the aging, the expression levels of fatty acid translocase (FAT/CD36) displayed significant increases in apoE-/-/LDLR-/- mice fed with HF diet versus the mice fed with chow (P<0.05). A similar trend was also observed in WT mice (P<0.01). The mRNA levels of carnitine palmitoyl transferase 1 (CPT1) remained unchanged in apoE-/-/LDLR-/- mice fed with HF diet. In addition, CPT1 was highly increased (P<0.05) in WT mice fed with HF diet compared with the mice fed with chow. The mRNA level of acyl-coenzyme Aoxidase 1 (ACOX1) remained unchanged in apoE-/-/LDLR-/- mice, while it was upregulated in WT mice after fedfeeding with HF diet for 5 and 9 weeks (P<0.05). The expression level of FAS was significantly increased in apoE-/-/LDLR-/- mice fed with HF diet from 8- to 12-week-old (P<0.01). There was almost the same trend in WT mice (P<0.05). At the age of 12-week-old, the expression profiles of stearoyl-CoA desaturase-1 (SCD1) was significantly increased in apoE-/-/LDLR-/- mice fed with HF diet compared with the mice fed with chow (P<0.01). However, the expression of SCD1 had steady-state values in WT group from 3- to 12-week-old.At the age of 12 weeks old, the expression levels of PPARa displayed significant increases in apoE-/-/LDLR-/- mice fed with HF diet versus the mice fed with chow (P<0.01). A reverse trend can be observed in WT mice (P<0.01). The expression level of and LXRa was significantly increased in apoE-/-/LDLR-/- mice fed with HF diet from 8- to 12-week-old (P<0.01). There was almost the same trend in WT mice (P<0.05).The most revealing comparisons were that of TC, TG, LDL-C, and HDL-C levels between apoE-/-/LDLR-/- mice fed with HF and chow diet. The comparisons clearly showed that TC and LDL-C levels in AL mice fed with HF diet were remarkably increased (P<0.05) at any time point versus chow group. Average TG level displayed a significant increase in apoE-/-/LDLR-/- mice fed with HF diet compared to the mice fed with chow diet at 12-week-old (P<0.01). We also observed that HDL-C levels were elevated in AL mice fed with HF diet from 8- to 12-week-old (P<0.05). In WT group, feeding HF diet elevated TC and LDL-C from 8-week-old (P<0.05) and raised HDL-C from 4-week-old (P<0.05). After 9 weeks on HF diet, however,TG levels had equilibrated to steady-state values with no further significant changes inWT mice. We evaluated lesions development in the aortic sinus by cross-sectional proximal aortic sinus analysis. The atherosclerotic lesion area was significantly increased in apoE-/-/LDLR-/- mice fed with HF diet compared to those fed with chow. As expected from the increased lesion area in apoE-/-/LDLR-/- mice fed with HF diet, the average lesion area was increased compared with apoE-/-/LDLR-/- mice fed with chow (0.338±0.1 mm2 vs. 0.158±0.07 mm2) at 12-week-old. In contrast, from 3- to 12-week-old, WT mice developed no notable lesion in sinus regardless of feeding HF diet.From 4-week-old, lipid deposition was observed in the liver of apoE-/-/LDLR-/- mice. The lipid deposition in the liver of apoE-/-/LDLR-/- mice fed with HF diet was more extensive than those fed with chow at the age of 12 weeks. Further more, WT mice showed no lipid deposition in the liver on chow diet, while on HF diet, 12-week-old WT mice showed scarcely any lipid deposition.Since lipid metabolic system defected genetically in apoE-/-/LDLR-/- mice, we suggest that the changes of PPARα, LXRα, and their target genes aggravated lipid metabolic disorder in the liver and further accelerated the development of atherosclerosis on a stress of HF diet feeding in apoE-/-/LDLR-/- mice. Further more detail and long term study using molecular and pathological analysis is underway.In conclusion, the experiments reported here show that fat- and cholesterol- enriched diets demonstrate di?erent e?ects on the expression of PPARa, LXRa, and their responsive genes in the liver of mutant and intact mice. These factors play key roles in the pathogenesis of atherogenesis in apoE-/-/LDLR-/- mice fed with HF diet.The varieties of expression level of the genes in?uence the further development of pathological changes in the early period of atherosclerosis. But the regulation being transcriptional or posttranscriptional levels remains further to be investigated. In order to further understand the contribution of HF diet to lipid metabolism disorder in apoE-/-/LDLR-/- mice and mechanism of atherosclerosis development systematically, these genes should be tested in di?erent tissues in vivo, such as aorta and fatty tissues.
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