Lipid ciliology: specialized ciliary membrane lipids in physiology and disease

Primary cilia are the microtubule-based sensory organelles. The unique lipid makeup of the ciliary membrane strictly controls their signaling ability, to orchestrate tissue formation and homeostasis. Emerging evidence has demonstrated that lipids play important roles in cilia formation and cilia-related signaling, solidifying the previously proposed concept of "lipid ciliology." The ciliary membrane exhibits a highly specialized lipid composition, including enrichment in cholesterol, sphingolipids, and specific phosphoinositides, compared with the surrounding plasma membrane. Recent studies have revealed that cholesterol and phosphoinositides function together to regulate ciliary homeostasis, protein trafficking, and signal transduction. A growing spectrum of ciliopathies, including polycystic kidney disease, retinal degeneration, cerebellar hypoplasia, and metabolic disorders, can be caused by dysregulation of lipid metabolism and lipid-modifying enzymes through impaired cilia-related signaling. Moreover, defects in cholesterol biosynthesis or intracellular lipid transport contribute to various ciliopathies, such as Smith-Lemli-Opitz syndrome and Zellweger spectrum disorders. In this review, we summarize recent advances in lipid ciliology, focusing on the underlying molecular mechanisms of ciliary cholesterol-dependent signaling in ciliopathies for emerging therapeutic strategies.