Targeting the gut-liver axis in cardiovascular disease

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ABSTRACT Cardiovascular Disease (CVD) is the leading cause of death in the United States. Atherosclerosis is a hallmark of CVD and underlies many adverse events. Increased dietary lipid intake is a major contributor to the increased CVD disease burden. Elevated plasma lipids, particularly in the form of LDL cholesterol, accelerate atherosclerosis, the major cause of CVD. Emerging evidence suggests that other lipids, such as triglycerides (TAG), play a role in the development of CVD, independent of LDL cholesterol. To date, lipid lowering therapies have mostly focused on lowering LDL cholesterol, yet adverse events continue to rise. In this application we put forth the framework and hypothesis that modulating bile acids, the body’s natural detergents, can be protective against the onset of atherosclerosis. Dietary lipids such as TAG and cholesterol ester (CE) are insoluble and require detergents (bile acids) for absorption. Bile acids are synthesized from cholesterol in the liver. There are many different bile acids which differ in their chemical structure which results in different properties as detergents and also as signaling molecules. Therefore, the liver is a central hub that coordinately regulates the bile acids, and by extension, the metabolism of many nutrients, including lipids. We have developed a central hypothesis that lipid absorption is regulated by the type and amount of bile acid that is secreted into the intestine following a meal. We hypothesize that bile acids are the key conduits that drive a gut-liver communication axis to regulate lipid absorption. We have selectively targeted enzymes in the bile acid synthetic pathway to elicit specific changes to bile acid levels, allowing us to study how changes in bile acid levels and composition alter lipid absorption in vivo. While much has been studied in recent years about bile acid signaling, the role of bile acids as detergents that facilitate the absorption of different dietary lipid species has been less well studied. To determine how bile acids alter the absorption of different lipids, we have developed and validated a novel AAV- CRISPR strategy to disrupt specific bile acid metabolism genes exclusively in the liver of adult mice. We have also established a non-invasive and quantitative mass spectrometry approach to measure the absorption of different dietary fatty acids in the intestine. Using these tools, we show that specific modulations in the total amount and/or composition of bile acids have profound effects on fatty acid absorption and atherosclerosis progression. Furthermore, we show that specific changes in bile acids can further accelerate and exacerbate atherosclerosis. We have designed two specific aims to test the hypothesis that defined changes in bile acids, mediated by specific disruption of enzymes of the bile acid synthesis pathway are protective against atherosclerosis. Completion of these studies will further our understanding of the role of bile acids as detergents and implicate bile acid metabolism as an important contributor in the pathogenesis atherosclerosis and CVD.