**1.4 Interaction of cholesterol with other lipids**

Cholesterol plays a vital role in determining the physiochemical properties of cell membranes. However, the detailed nature of cholesterol–lipid interactions is a subject of ongoing debate. Cholesterol primarily serves as a structural component of cellular membranes. When incorporated into phospholipid bilayers, cholesterol aligns so that its polar hydroxyl group is near the interface with the aqueous environment while its hydrophobic body is buried in the bilayer (Ohvo-Rekila et al., 2002; Olsen et al., 2011a; Olsen et al., 2011b). The interaction of cholesterol with neighboring phospholipids alters membrane structure. The alignment and ordering of nearby phospholipid tails causes membrane condensation, decreasing the area of the membrane and increasing the thickness (Ohvo-Rekila et al., 2002). Cholesterol also broadens the liquid-to-solid phase transition, inducing an intermediate liquid-ordered phase that retains lateral mobility while increasing lipid order (Feigenson, 2007; Simons and Vaz, 2004; van Meer et al., 2008). These changes result in a mechanically stronger membrane with decreased permeability due to tighter packing among lipids (Ikonen, 2008; Simons and Vaz, 2004). The low activity pool consists of cholesterol that is sequestered within the phospholipids and relatively inaccessible to other molecules, while the high activity pool of cholesterol that is more accessible and mobile in the non-condensed phospholipids of the membrane (Olsen et al., 2011b). Distribution between the high and low activity pools is determined by the ability of the phospholipids to condense with cholesterol, which in turn is dependent on the phospholipid composition of the membrane. Thus, raising the plasma membrane cholesterol concentration can saturate the ability of the membrane to accommodate cholesterol in the condensed phospholipids, whereupon excess cholesterol transitions into the high activity pool where it is more available for trafficking to the ER. Sphingomyelin is other important lipid present in the biomembrane that interact with cholesterol (Garmy et al., 2005). Interaction between cholesterol and sphingomyelin has a very high biological significance as lipid-lipid interaction leads to the formation of ordered lipid domains in the plasma membrane of eukaryotic cells (Simons and Ikonen, 1997). Molecular association between cholesterol and sphingomyelin is very important as this constitute cholesterol enriched microdomains of plasma membrane and plays a very important role in cellular functions such as the control of signal transduction pathways. On the other hand, the formation of cholesterol-sphingomyelin molecular complexes in the intestinal lumen explains the mutual inhibitory effects of cholesterol and sphingomyelin on their intestinal absorption (Nyberg et al., 2000).

#### **1.5 Cholesterol homeostasis**

Every eukaryotic cell require cholesterol as its not only integral part of membrane as well as plays very important role in cell signalling pathways. That the reason, all eukaryotic cells, which have specialized methods of recruiting and synthesizing the cholesterol only when it is needed. While effectively maintaining intracellular cholesterol homeostasis, these processes leave excess circulating though the body, leading to atherosclerotic plaque development and subsequent coronary artery disease. Thus, levels of cholesterol and related lipids circulating in plasma are important predictive tools utilized clinically to diagnose the risk of a cardiovascular diseases (Daniels et al., 2009; Ikonen, 2008; Simons and Ikonen, 2000; Singh et al., 2007). Cholesterol is transported in the plasma predominantly as cholesteryl esters associated with lipoproteins and dietary cholesterol is transported from the small intestine to the liver in the form of chylomicrons. Cholesterol synthesized by the liver, as well as any dietary cholesterol in the liver that exceeds hepatic needs, is transported in the serum in the form of low density lipoproteins (LDLs). In the liver, VLDLs are biosyntheiszed and are converted to LDLs by endothelial cell-associated lipoprotein lipase. High density lipoproteins (HDLs)can extract Cholesterol found in plasma membranes and

membranes. When incorporated into phospholipid bilayers, cholesterol aligns so that its polar hydroxyl group is near the interface with the aqueous environment while its hydrophobic body is buried in the bilayer (Ohvo-Rekila et al., 2002; Olsen et al., 2011a; Olsen et al., 2011b). The interaction of cholesterol with neighboring phospholipids alters membrane structure. The alignment and ordering of nearby phospholipid tails causes membrane condensation, decreasing the area of the membrane and increasing the thickness (Ohvo-Rekila et al., 2002). Cholesterol also broadens the liquid-to-solid phase transition, inducing an intermediate liquid-ordered phase that retains lateral mobility while increasing lipid order (Feigenson, 2007; Simons and Vaz, 2004; van Meer et al., 2008). These changes result in a mechanically stronger membrane with decreased permeability due to tighter packing among lipids (Ikonen, 2008; Simons and Vaz, 2004). The low activity pool consists of cholesterol that is sequestered within the phospholipids and relatively inaccessible to other molecules, while the high activity pool of cholesterol that is more accessible and mobile in the non-condensed phospholipids of the membrane (Olsen et al., 2011b). Distribution between the high and low activity pools is determined by the ability of the phospholipids to condense with cholesterol, which in turn is dependent on the phospholipid composition of the membrane. Thus, raising the plasma membrane cholesterol concentration can saturate the ability of the membrane to accommodate cholesterol in the condensed phospholipids, whereupon excess cholesterol transitions into the high activity pool where it is more available for trafficking to the ER. Sphingomyelin is other important lipid present in the biomembrane that interact with cholesterol (Garmy et al., 2005). Interaction between cholesterol and sphingomyelin has a very high biological significance as lipid-lipid interaction leads to the formation of ordered lipid domains in the plasma membrane of eukaryotic cells (Simons and Ikonen, 1997). Molecular association between cholesterol and sphingomyelin is very important as this constitute cholesterol enriched microdomains of plasma membrane and plays a very important role in cellular functions such as the control of signal transduction pathways. On the other hand, the formation of cholesterol-sphingomyelin molecular complexes in the intestinal lumen explains the mutual inhibitory effects of cholesterol and

sphingomyelin on their intestinal absorption (Nyberg et al., 2000).

Every eukaryotic cell require cholesterol as its not only integral part of membrane as well as plays very important role in cell signalling pathways. That the reason, all eukaryotic cells, which have specialized methods of recruiting and synthesizing the cholesterol only when it is needed. While effectively maintaining intracellular cholesterol homeostasis, these processes leave excess circulating though the body, leading to atherosclerotic plaque development and subsequent coronary artery disease. Thus, levels of cholesterol and related lipids circulating in plasma are important predictive tools utilized clinically to diagnose the risk of a cardiovascular diseases (Daniels et al., 2009; Ikonen, 2008; Simons and Ikonen, 2000; Singh et al., 2007). Cholesterol is transported in the plasma predominantly as cholesteryl esters associated with lipoproteins and dietary cholesterol is transported from the small intestine to the liver in the form of chylomicrons. Cholesterol synthesized by the liver, as well as any dietary cholesterol in the liver that exceeds hepatic needs, is transported in the serum in the form of low density lipoproteins (LDLs). In the liver, VLDLs are biosyntheiszed and are converted to LDLs by endothelial cell-associated lipoprotein lipase. High density lipoproteins (HDLs)can extract Cholesterol found in plasma membranes and

**1.5 Cholesterol homeostasis** 

esterified by the HDL-associated enzyme LCAT. The cholesterol acquired from peripheral tissues by HDLs can then be transferred to VLDLs and LDLs via the action of cholesteryl ester transfer protein (apo-D) which is associated with HDLs. In humans, HDL levels are a very well known measurement of cardiac health due to their strong inverse relationship with coronary artery disease. Peripheral cholesterol is returned to the liver by the process called r**everse cholesterol transport by HDLs** and ultimately, cholesterol is excreted in the bile as free cholesterol or as bile salts following conversion to bile acids in the liver (Figure 4).

Fig. 4. Cholesterol homeostasis
