Abstract Body: Hypercholesterolemia is a key risk factor for atherosclerosis development in men and women, making avenues of cholesterol disposal attractive for therapeutic development. Cholesterol is catabolized in the liver through the production of bile acids, which also facilitate the absorption of cholesterol and other lipids in the intestine. This is a finely regulated process that directly impacts cholesterol levels. We hypothesized that manipulating bile acid metabolism to reduce cholesterol absorption would decrease plasma cholesterol levels and protect from atherosclerosis.

To alter the bile acid pool, we used liver-directed AAV-CRISPR to disrupt Cyp7a1, which catalyzes the rate-limiting step of bile acid synthesis. Consequently, we show that loss of CYP7A1 in adult male mice reduces the size of the bile acid pool. To study atherosclerosis, we co-disrupted Cyp7a1 with Low Density Lipoprotein Receptor (Ldlr) to induce hypercholesterolemia during Western diet feeding for 20 weeks. Loss of hepatic CYP7A1 and LDLR in males reduced atherosclerosis and reduced cholesterol absorption.

In stark contrast to what we observed in male mice, the absence of CYP7A1 in female mice resulted in only a modest reduction of the bile acid pool. This blunted reduction was not sufficient to decrease cholesterol absorption, consequently resulting in the accumulation of cholesterol and markedly increased atherosclerosis in females. Atherosclerosis could only be reduced in female Cyp7a1/Ldlr CRISPR animals by the pharmacological lowering of cholesterol absorption with ezetimibe. Thus, we hypothesize that there is a female-specific mechanism to preserve bile acid production that is independent of CYP7A1.

These data indicate new avenues by which female bile acid and cholesterol metabolism differs from than that of males and may identify new pathways which could be targeted to regulate cholesterol. The resulting differences in cardiovascular risk highlight the essential need for male- and female-specific personalized medicine approaches for cardiovascular disease prevention.