The Regulation of Cholesterol Absorption: Nuclear Hormone Receptors and Niemann-Pick C1 Like 1

Cholesterol plays fundamental roles in cellular physiology, but it is also involved in many pathophysiological processes including atherosclerosis, cholelithiasis, and some forms of neurodegenerative disease. The ability of mammals to selectively absorb cholesterol from the diet while largely excluding plant sterols has been known for more than 75 years, but the precise repertoire of molecular events necessary for this process are just beginning to be elucidated. Recently, several candidates have been put forth as putative intestinal cholesterol "permeases" responsible for cholesterol transport across the intestinal brush border. In addition, members of the nuclear receptor superfamily of ligand-activated transcription factors are known to modulate expression of genes involved in cholesterol and bile acid homeostasis, and cholesterol absorption. Therefore, we wanted not only to clarify the essential molecular mechanisms by which cholesterol was absorbed, but also to investigate the potential role of nuclear receptors in regulating essential steps in this process. Here, we show that a candidate component of the cholesterol transport machinery, caveolin-1 (CAV1), is neither required for intestinal cholesterol transport or sensitivity to the novel cholesterol absorption blocking agent, ezetimibe. This rules out a critical role for caveolin-1 and lends further support to the contention that Niemann-Pick C1 like 1 (NPC1L1) is the bona fide intestinal cholesterol permease. Therefore to better understand new ways in which nuclear receptors could regulate cholesterol absorption, we studied nuclear receptor regulation of NPC1L1 and determined that several nuclear receptors could modulate its expression in small intestine, including peroxisome proliferator-activated receptor alpha (PPAR alpha ) and retinoid X receptor (RXR). Thus, cholesterol absorption can be regulated by nuclear receptor modulation of NPC1L1 expression.