In recent years, cholesteryl ester transfer protein (CETP) has emerged as an important plasma component for HDL cholesterol metabolism. CETP facilitates the exchange of neutral lipids among plasma lipoproteins and induces a transfer of cholesteryl ester from HDL to triglyceride-rich lipoprotein in exchange for triglyceride.[27], [28] Humans with high activity of cholesteryl ester transfer protein (which account for all transfer of cholesteryl ester from HDL to VLDL and LDL particles in plasma) might have low HDL cholesterol as well as high VLDL-triglyceride levels, a pattern of plasma lipids that has been shown to cause increased risk of gallstones in case control studies.
Members of LDL-receptor gene family participate in diverse biological processes including lipoprotein metabolism.[29] Receptor-associated protein (RAP) serves as a molecular chaperone within the endoplasmic reticulum to assist the folding of certain LDL receptor members of the family. Till date, at least 23 mutations and polymor-phisms in the LRPAP1 gene coding for RAP have been reported. There is a large deletion polymorphism in intron 5, which has been linked to the regulation of cholesterol metabolism in coronary artery disease.[30] It remains to be investigated whether it has any association with gallstone disease or not.
The risk of atherosclerosis is inversely related to plasma levels of HDL cholesterol. Kozarsky et al[31] observed the disappearance of plasma HDL and substantial increase in biliary cholesterol of hepatocytes over-expressing SR-B1, a well-defined HDL receptor.[32]Whether low HDL is also a risk factor for gallstone formation, is yet to be determined.
In the above discussion, certain polymorphisms in apo E, apo- B and many other genes involved in lipid metabolism have been associated with increased risk of gallstone formation. Various proteins encoded by these genes may act by different mechanisms. Some of them may enhance the hepatic uptake of chylomicron remnants while others might cause increased absorption of intestinal cholesterol or decrease the synthesis of bile. All these alterations result in supersaturation of cholesterol in the bile that ultimately lead to gallstone formation. Although the individual risk associated with each allele may be small, it considerably increases in conjunction with other susceptibility genes and/or environ-mental factors.
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