Cholestasis-associated glucocorticoid overexposure does not increase atherogenesis

Area of Science:

• Cardiovascular Disease Research
• Hepatology
• Endocrinology

Background:

• Chronic glucocorticoid overexposure is linked to atherosclerotic cardiovascular disease.
• Cholestatic liver disease elevates plasma glucocorticoid levels.
• The impact of cholestasis-induced glucocorticoid changes on atherosclerosis is unknown.

Purpose of the Study:

• To investigate if cholestatic liver disease increases atherosclerosis susceptibility in a preclinical model.
• To examine the relationship between liver disease, glucocorticoid levels, and cardiovascular risk.

Main Methods:

• Atherosclerosis-susceptible apolipoprotein E (APOE)-knockout mice were fed a regular chow diet.
• Mice were treated with alpha-naphthylisothiocyanate (ANIT) for 8 weeks to induce cholestatic liver disease.
• Liver and plasma markers, adrenal weights, corticosterone levels, and atherosclerosis were assessed.

Main Results:

• ANIT induced fibrotic cholestatic liver disease with elevated bilirubin and bile acids.
• ANIT-treated mice showed increased adrenal weights and plasma corticosterone levels.
• Despite increased cholesterol and glucocorticoids, atherosclerosis susceptibility was not enhanced; immunosuppression was observed.

Conclusions:

• Cholestatic liver disease-associated glucocorticoid overexposure does not increase atherosclerosis susceptibility in APOE-knockout mice.
• The immunosuppressive effect of glucocorticoids is uncoupled from their metabolic effects in cholestasis.
• Preclinical data suggest cholestatic hypercholesterolemia may not translate to increased cardiovascular disease risk.