GSE157972
ß-carotene conversion to vitamin A delays atherosclerosis progression by decreasing hepatic lipid secretion in mice
Atherosclerosis is characterized by the pathological accumulation of cholesterol-laden macrophages in the arterial wall. Atherosclerosis is also the main underlying cause of cardiovascular diseases (CVDs), and its development is largely driven by elevated plasma cholesterol. Strong epidemiological data find an inverse association between plasma ß-carotene with atherosclerosis, and we recently showed that ß-carotene oxygenase 1 (BCO1) activity, responsible for ß-carotene cleavage to vitamin A, is associated with reduced plasma cholesterol in humans and mice. In this study, we explore whether intact ß-carotene or vitamin A affect atherosclerosis progression in the atheroprone low-density lipoprotein receptor (LDLR) - deficient mice. In comparison to control-fed Ldlr-/- mice, ß-carotene-supplemented mice showed reduced atherosclerotic lesion size at the level of the aortic root and plasma cholesterol levels (P = 0.0003). These changes were absent in Ldlr-/-/Bco1-/- mice, despite accumulating ß-carotene in plasma and atherosclerotic lesions. We discarded the implication of myeloid BCO1 in the development of atherosclerosis by performing bone marrow transplant experiments. Lipid production assays found that retinoic acid, the active form of vitamin A, reduced the secretion of newly synthetized triglyceride and cholesteryl ester in cell culture and mice. Overall, our findings provide insights into the role of BCO1 activity and vitamin A in atherosclerosis progression through the regulation of hepatic lipid metabolism. Overall design: CD68+ cells accumulated in atherosclerotic lesions at the level of the aortic root were isolated by laser capture microdisection. Briefly, Eight-week-old male and female Ldlr-/-/Bco1-/- mice were lethally irradiated with a double dose of 550 rads (5.5 GY) from a cesium source four hours apart. Ten hours later, mice were transplanted with freshly isolated bone marrow from donor wild-type or Bco1-/- (ko) mice.