Integrated physiological model of the molecular and metabolic networking between PCSK members. The figure illustrates the role of PCSK1, PCSK3, PCSK5, PCSK6, and PCSK9 in the lipoprotein triad (HDL, LDL and VLDL). HDL level and function are synergistically regulated by those metabolic factors: glucose, triglyceride (TG) and BA metabolism. Arrows with 2 different types of lines indicate the relationship between factors: dotted lines with arrow indicate a “negative influence.” For example, LDLR decreases HDL cholesterol concentration (Figure 3(4)). In contrast, solid lines with arrow indicate a “positive influence.” For example, CCK secreted from the small intestine stimulates BA secretion (Figure 3(5)). Solid lines without arrow indicate two major ways of reverse cholesterol transport (RCT). First, cholesteryl ester transfer protein (CETP) exchanges cholesterol in LDL by TG in HDL (Figure 3(9)). Second, HDL takes up cholesterol that is accumulated in macrophage foam cells inside the blood vessel wall (Figure 3(10)). Cholesterol-carrying HDL returns to the liver to recycle or excrete the cholesterol.