A theoretical model of dietary lipid variance as the origin of primary ciliary dysfunction in preeclampsia

Abstract

Serving as the cell’s key interface in communicating with the outside world, primary cilia have emerged as an area of multidisciplinary research interest over the last 2 decades. Although the term “ciliopathy” was first used to describe abnormal cilia caused by gene mutations, recent studies focus on abnormalities of cilia that are found in diseases without clear genetic antecedents, such as obesity, diabetes, cancer, and cardiovascular disease. Preeclampsia, a hypertensive disease of pregnancy, is intensely studied as a model for cardiovascular disease partially due to many shared pathophysiologic elements, but also because changes that develop over decades in cardiovascular disease arise in days with preeclampsia yet resolve rapidly after delivery, thus providing a time-lapse view of the development of cardiovascular pathology. As with genetic primary ciliopathies, preeclampsia affects multiple organ systems. While aspirin delays the onset of preeclampsia, there is no cure other than delivery. The primary etiology of preeclampsia is unknown; however, recent reviews emphasize the fundamental role of abnormal placentation. During normal embryonic development, trophoblastic cells, which arise from the outer layer of the 4-day-old blastocyst, invade the maternal endometrium and establish extensive placental vascular connections between mother and fetus. In primary cilia of trophoblasts, Hedgehog and Wnt/catenin signaling operate upstream of vascular endothelial growth factor to advance placental angiogenesis in a process that is promoted by accessible membrane cholesterol. In preeclampsia, impaired proangiogenic signaling combined with an increase in apoptotic signaling results in shallow invasion and inadequate placental function. Recent studies show primary cilia in preeclampsia to be fewer in number and shortened with functional signaling abnormalities. Presented here is a model that integrates preeclampsia lipidomics and physiology with the molecular mechanisms of liquid–liquid phase separation in model membrane studies and the known changes in human dietary lipids over the last century to explain how changes in dietary lipids might reduce accessible membrane cholesterol and give rise to shortened cilia and defects in angiogenic signaling, which underlie placental dysfunction of preeclampsia. This model offers a possible mechanism for non-genetic dysfunction in cilia and proposes a proof-of-concept study to treat preeclampsia with dietary lipids.

Paradoxes: Cholesterol and Hypoxia in Preeclampsia

“…However, it is not total cholesterol, but the availability of free or accessible membrane cholesterol which positively regulates Hh signaling [123] [124]. Low accessible cholesterol may also explain the shortening, reduction in number and impaired function of maternal endothelial cell cilia [125] .…”

Paradoxes: Cholesterol and Hypoxia in Preeclampsia

“…However, it is not total cholesterol, but the availability of free or accessible membrane cholesterol, that positively regulates Hh signaling [ 117 , 118 ]. Low accessible cholesterol may also explain the shortening, reduction in number, and impaired function of maternal endothelial cell cilia [ 87 ].…”

“…(Parts of figure used with permission from Hart NR. A theoretical model of dietary lipid variance as the origin of primary ciliary dysfunction in preeclampsia [ 87 ]).…”