**3. Acknowledgment**

436 Biochemistry

maintain a steady level in circulation. Additionally, the synthesis of LDL receptors increases to allow increased cholesterol uptake for bile acid synthesis, and the overall effect is a reduction in plasma cholesterol. This treatment is ineffective in homozygous FH patients

This drug is sold under the trade names Zetia® or Ezetrol® and is also combined with the statin drug simvastatin and sold as Vytorin® or Inegy®. Ezetimibe functions to reduce intestinal absorption of cholesterol, thus effecting a reduction in circulating cholesterol. The drug functions by inhibiting the intestinal brush border transporter involved in absorption of cholesterol. This transporter is known as Niemann-Pick type C1-like 1 (NPC1L1). NPC1L1 is also highly expressed in human liver. The hepatic function of NPC1L1 is presumed to limit excessive biliary cholesterol loss. NPC1L1-dependent sterol uptake is regulated by cellular cholesterol content. In addition to the cholesterol lowering effects that result from inhibition of NPC1L1, its' inhibition has been shown to have beneficial effects on components of the metabolic syndrome, such as obesity, insulin resistance, and fatty liver, in addition to atherosclerosis. Ezetimibe is usually prescribed for patients who cannot tolerate a statin drug or a high dose statin regimen. There is some controversy as to the efficacy of ezetimibe at lowering serum cholesterol and reducing the production of fatty plaques on arterial walls. The combination drug of ezetimibe and simvastatin has shown efficacy equal to or slightly greater

In the last decade, a number of epidemiological and clinical studies have demonstrated a direct correlation between the circulating levels of HDL cholesterol and a reduction in the potential for atherosclerosis and coronary heart disease (CHD). Individuals with low levels of HDL (below 40mg/dL) are at higher risk of coronary heart disease CHD) then individual with level above 50mg/dL. Clinical studies have demonstrated that infusion of HDL component, apolipoprotein A-1 (apoA-1) in patients, significantly increases the level of HDL. The newest strategies are targeted to up regulate the level of HDL cholesterol instead of decreasing the level of total cholesterol. Cholesterol ester transfer protein (CETP) is secreted primarily from the liver and plays a critical role in HDL metabolism by facilitating the exchange of cholesteryl esters (CE) from HDL for triglycerides (TG) in apoB containing lipoproteins, such as LDL and VLDL. The activity of CETP directly lowers the cholesterol levels of HDLs and enhances HDL catabolism by providing HDLs with the TG substrate of hepatic lipase. Thus, CETP plays a critical role in the regulation of circulating levels of HDL, LDL, and apoA-I. It has also been shown that in mice naturally lacking CETP most of their cholesterol is found in HDL and these mice are relatively resistant to atherosclerosis. CETP inhibitors have failed in the clinical trials as their use has increased negative cardiovascular

Cholesterol is an essential component in cell membrane, as a precursor for the synthesis of steroid hormones vitamin D, and bile acids that aid in digestion and cellular signal transduction. Half of the cholesterol is *de novo* synthesized in liver and is transported through various lipoprotein. Dysfunction in cholesterol metabolism can lead to

than atorvastatin (Lipitor®) alone at reducing circulating cholesterol levels.

**1.10.2.5 New approaches for the treatment of hypercholesterolemia** 

events and death rates in test subjects.

**2. Conclusion** 

since they are completely deficient in LDL receptors.

**1.10.2.4 Ezetimibe** 

We thank Professor (Dr) Papasani V. Subbaiah, Associate Professor (Dr) Irena Levitan, Professor (Dr) Todd Porter and Assistant Professor (Dr) Ramachandran Ramaswamy for their multiple critical discussions. Special thanks are to Software Professional, Mr Ravi Kesavarapu, for help in making the figures for the manuscript.
