Abstract
To investigate the effects of abolished cholic acid (CA) synthesis in the ApoE knockout model [apolipoprotein E (apoE) KO],a double-knockout (DKO) mouse model was created by crossbreeding Cyp8b1 knockout mice (Cyp8b1 KO), unable to synthesize the primary bile acid CA, with apoE KO mice. After 5 months of cholesterol feeding, the development of atherosclerotic plaques in the proximal aorta was 50% less in the DKO mice compared with the apoE KO mice. This effect was associated with reduced intestinal cholesterol absorption, decreased levels of apoB-containing lipoproteins in the plasma, enhanced bile acid synthesis, reduced hepatic cholesteryl esters, and decreased hepatic activity of ACAT2. The upregulation of Cyp7a1 in DKO mice seemed primarily caused by reduced expression of the intestinal peptide FGF15. Treatment of DKO mice with the farnesoid X receptor (FXR) agonist GW4064 did not alter the intestinal cholesterol absorption, suggesting that the action of CA in this process is confined mainly to formation of intraluminal micelles and less to its ability to activate the nuclear receptor FXR. Inhibition of CA synthesis may offer a therapeutic strategy for the treatment of hyperlipidemic conditions that lead to atherosclerosis.
Highlights
To investigate the effects of abolished cholic acid (CA) synthesis in the ApoE knockout model [apolipoprotein E KO],a double-knockout (DKO) mouse model was created by crossbreeding Cyp8b1 knockout mice (Cyp8b1 KO), unable to synthesize the primary bile acid CA, with apoE KO mice
No statistically significant difference could be found for the percentage of cells positive for the markers CD3 and I-Ab when comparing the plaques in the Double knockouts (DKOs) mice to those in the apoE KO mice (Table 1)
This particular fraction consists mainly of chylomicron remnants, inasmuch as the deficiency of apoE seriously hampers their receptor-mediated uptake into the liver, and it is reported that the hepatic release of VLDL particles in those mice is decreased [16]
Summary
To investigate the effects of abolished cholic acid (CA) synthesis in the ApoE knockout model [apolipoprotein E (apoE) KO],a double-knockout (DKO) mouse model was created by crossbreeding Cyp8b1 knockout mice (Cyp8b1 KO), unable to synthesize the primary bile acid CA, with apoE KO mice. After 5 months of cholesterol feeding, the development of atherosclerotic plaques in the proximal aorta was 50% less in the DKO mice compared with the apoE KO mice This effect was associated with reduced intestinal cholesterol absorption, decreased levels of apoBcontaining lipoproteins in the plasma, enhanced bile acid synthesis, reduced hepatic cholesteryl esters, and decreased hepatic activity of ACAT2. Intestinal absorption of cholesterol is promoted by CA, which in its role as a specific ligand for the nuclear farnesoid X receptor (FXR), regulates the expression of a large number of genes within the lipid metabolism and the carbohydrate metabolism [for a review, see Lefebvre et al [2]]. CA-depleted mice show other effects on cholesterol metabolism: they do not accumulate cholesteryl esters (CEs) in the Abbreviations: apoE, apolipoprotein E; CA, cholic acid; CE, cholesteryl ester; DKO, double knockout; FC, free cholesterol; FXR, farnesoid X receptor; KO, knockout
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