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Updated: Jun 10, 2026
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Abolished synthesis of cholic acid reduces atherosclerotic development in apolipoprotein E knockout mice
Katharina Slätis1, Mats Gåfvels, Kristina Kannisto
1Unit for Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
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.
Insights
Abolishing cholic acid synthesis in ApoE knockout mice reduced atherosclerosis by 50%. This involved lower cholesterol absorption and altered lipoproteins, suggesting bile acid inhibition as a therapeutic strategy for hyperlipidemia.
Area of Science:
- Biochemistry
- Cardiovascular Biology
- Metabolic Diseases
Background:
- Atherosclerosis is a complex disease influenced by lipid metabolism.
- Apolipoprotein E (apoE) knockout mice are a model for studying atherosclerosis.
- Cholic acid (CA) is a primary bile acid involved in lipid digestion and absorption.
Purpose of the Study:
- To investigate the impact of abrogated cholic acid synthesis on atherosclerosis development.
- To elucidate the mechanisms linking bile acid synthesis, cholesterol absorption, and lipoprotein metabolism in a mouse model.
Main Methods:
- Creation of a double-knockout (DKO) mouse model by crossbreeding Cyp8b1 knockout and apoE knockout mice.
- Cholesterol feeding of DKO and apoE knockout mice for 5 months.
- Analysis of atherosclerotic plaque development, intestinal cholesterol absorption, plasma lipoproteins, and hepatic lipid metabolism.
Main Results:
- DKO mice exhibited a 50% reduction in atherosclerotic plaques compared to apoE KO mice.
- This reduction was associated with decreased intestinal cholesterol absorption and lower apoB-lipoproteins.
- Enhanced bile acid synthesis, reduced hepatic cholesteryl esters, and decreased ACAT2 activity were observed in DKO mice.
Conclusions:
- Inhibition of cholic acid synthesis significantly ameliorates atherosclerosis in apoE knockout mice.
- The protective effect is linked to reduced cholesterol absorption and altered lipoprotein profiles.
- Targeting bile acid synthesis presents a potential therapeutic avenue for hyperlipidemic conditions and atherosclerosis.
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