Mechanism of the Regulation of Plasma Cholesterol Levels by PI(4,5)P.

Elevated low-density lipoprotein (LDL) cholesterol (LDLc) is one of the most well-established risk factors for cardiovascular disease, while high levels of high-density lipoprotein (HDL) cholesterol (HDLc) have been associated with protection from cardiovascular disease. Cardiovascular disease remains one of the leading causes of death worldwide; thus it is important to understand mechanisms that impact LDLc and HDLc metabolism. In this chapter, we will discuss molecular processes by which phosphatidylinositol-(4,5)-bisphosphate, PI(4,5)P, is thought to modulate LDLc or HDLc. Section 1 will provide an overview of cholesterol in the circulation, discussing processes that modulate the various forms of lipoproteins (LDL and HDL) carrying cholesterol. Section 2 will describe how a PI(4,5)P phosphatase, transmembrane protein 55B (TMEM55B), impacts circulating LDLc levels through its ability to regulate lysosomal decay of the low-density lipoprotein receptor (LDLR), the primary receptor for hepatic LDL uptake. Section 3 will discuss how PI(4,5)P interacts with apolipoprotein A-I (apoA1), the key apolipoprotein on HDL. In addition to direct mechanisms of PI(4,5)P action on circulating cholesterol, Sect. 4 will review how PI(4,5)P may indirectly impact LDLc and HDLc by affecting insulin action. Last, as cholesterol is controlled through intricate negative feedback loops, Sect. 5 will describe how PI(4,5)P is regulated by cholesterol.