LDL receptor gene

Forty-four amino acid module characterized by three internal disulfide bridges and an octahedrical cage for a calcium ion. Complement-type repeats are found in many cell surface proteins and form the ligand-binding domain of receptors of the LDL receptor gene family. 

Much of our knowledge of the structure and function of endocytic receptors is based on the analysis of the LDL receptor gene family. Member s of this extended gene family can be found in a variety of species ranging from roundworms to insects, to vertebrates. Ten receptors exist in mammalian organisms, all of which share common structural motifs required for receptor-mediated... 

Transgenic animal models with spontaneous or induced receptor gene defects have been instrumental in elucidating the physiological roles of the LDL receptor gene family. In addition, a number of human diseases have been identified that are caused by sporadic or inherited forms of receptor deficiency (Table 1). 

Low-density Lipoprotein Receptor Gene Family. Table 1 Human diseases of the LDL receptor gene family... 

LRP4 is another receptor of the LDL receptor gene family involved in regulation of embryonic patterning, mainly controlling formation of limb structures. Loss of receptor activity in gene targeted mice or spontaneous mutation in bovine cause abnormal limb development and... 

Familial hypercholesterolaemia is characterized by a significant elevation in plasma LDL concentration. The basic metabolic defect appears to be abnormal LDL receptor function, arising from mutations in the LDL receptor gene. Several receptor mutations have been identified and hypercholesterolaemia severity as well as the age of onset of ischaemic heart disease has recently been demonstrated to vary according to the type of LDL receptor gene defect (Moorjani et al., 1993). 

Moorjani, S., Betard, C., Brun, D., Roy, M., Gagne, C., Davignon, J., Torres, A., Lambert, M. and Lupien, P. (1993). Mutations of the LDL receptor gene, variations in plasma cholesterol and expression of coronary heart disease in homozygous familial hypercholesterolaemia. Lancet 341, 1303-1306. 

Karayan L, Qiu S, Betard C, Dufour R, Roederer G, Minnich A, et al. Response to HMG CoA reductase inhibitors in heterozygous familial hypercholesterolemia due to the 10-kb deletion ( French Canadian mutation ) of the LDL receptor gene. Arteriosder Thromb 1994 14 1258-1263. 

Soutar, A. K., McCarthy, S. N., Seed, M., and Knight, B. L., Relationship between apopro-tein(a) phenotype, lipoprotein(a) concentration in plasma and low-density lipoprotein (LDL) receptor function in a large kindred with Familial Hypercholesterolemia due to the Pro Leu mutation in the LDL-receptor gene. J. Clin. Invest. 88, 483-492 (1991). 

Scientists studying a common mutation in the LDL receptor gene have inserted the defective gene into fertilized murine ova. The altered ova are implanted in a firster mother and the progeny are used to study the effects of the mutant allele. The mice produced in this procedure would be referred to as ... 

Heterozygotes for type 11 hypercholesterolemia have one normal and one mutant LDL receptor gene. Thus, they have just half the normal number of functional hepatic LDL receptors. They are, therefore, less than fully effective at eliminating cholesterol from the body. These individuals have substantially elevated plasma LDL cholesterol levels and frequently experience heart attacks in their 40s and 50s. 

The many different LDL receptor gene mutations that lead to FFI can be classified into five groups according to the functional defect in the receptor ... 

The lowered concentration of bile acids returning to the liver by the enterohepatic circulation results in derepression of 7-a-hydroxylase, the rate-limiting enzyme for conversion of cholesterol to bile acids. This results in increased use of cholesterol to replace the excreted bile acids and lowering of hepatic cholesterol (mechanism VI in Fig. 23.2). Thus, similar to the statins, the ultimate actions of the bile acid-sequestering resins are up-regulation of transcription of the LDL receptor gene, increased hepatic receptor activity, and lowering of plasma LDL cholesterol (mechanism VII in Fig. 23.2). 

Kim SH, Bae JH, Chae JJ, Kim UK, Choe SJ, Namkoong Y, HS, Park YB, Lee CC (1999) Long-distance PCR-based screening for large rearrangements of the LDL receptor gene in Korean patients with familial hypercholesterolemia. Clin Chem 45 1424-1430... 

Effect of endocytosed cholesterol on cellular cholesterol homeostasis The chylomicron remnant-, IDL-, and LDL-derived cholesterol affects cellular cholesterol content in several ways (see Figure 18.20). First, HMG CoA reductase is inhibited by ttfi cholesterol, as a result of which, de novo cholesterol synthesis decreases. Second, synthesis of new LDL receptor protein is reduced by decreasing the expression of the LDL receptor gene, thus limiting further entry of LDL cholestrol into cells. [Note ... 

Regulation of the LDL receptor gene involves a hormone-response element (HRE, see p. 238).] Third, if the cholesterol is not required immediately for some structural or synthetic purpose, it is esterified by acyl CoA cholesterol acyltransferase (ACAT, AC AT transfers a fatty acid from a fatty acyl CoA derivative to cholesterol, producing a cholesteryl ester that can be stored in the cell (Figure 18.21). The activity of ACAT is enhanced in the presence of increased intracellular cholesterol. 

The LDL and related receptors. The LDL receptor gene extends over 50 kb of DNA and appears to be a mosaic of exons shared by several other genes that seem to have nothing to do with cholesterol metabolism.201 211 The 839-residue receptor protein consists of five structural domains. The N-terminal domain that binds the LDL consists of seven repeated 40-residue... 

Shichiti M, Tanaka A, Hirata Y. 2003. Intravenous gene therapy for familial hypercholesterolemia using ligand facilitated transfer of liposomes LDL receptor gene complex. Gene Ther. 10 827-831. 

LRP is a member of the LDL receptor gene family (ref. 649) and, like the LDL receptor, performs an essential role in the removal of certain lipoprotein particles from the bloodstream. As Heeren et al. (ref. 650) explain, triglycerides are transported mainly by two distinct classes of lipoproteins, the chylomicrons and the very-low-density lipoproteins (VLDL). After assembly in the intestine, chylomicrons are carried via lymph into the bloodstream, where they are transformed at the endothelial surface to remnant lipoproteins through the catalytic action of lipoprotein lipase (for review, see ref. 651,652). After lipolysis, the lipoprotein lipase remains associated with the chylomicron remnants and, in conjunction with apolipoprotein E (apo E) (ref. 653-655), facilitates their clearance by the liver into hepatocytes (ref. 656) via LDL receptors and the LRP (ref. 657-660). (The essential role for both receptors in chylomicron remnant removal in vivo has been demonstrated in gene knockout and gene transfer experiments (ref. 661,662 for review, see ref. 663).)... 

B.W. Howell and J. Herz, The LDL receptor gene family signaling functions during development, Curr. Opin. Neurobiol. 11 (2001)74-81. 

Three months later, her cholesterol levels were about 20% lower than prior to the gene therapy protocol. Repeat LDL metabolism studies showed that she cleared LDL from her blood significantly faster than prior to the gene therapy, consistent with some liver expression of the LDL receptor. A liver biopsy was done and demonstrated clusters of fiver cells that were expressing the normal LDL receptor gene. 

Members of a family of nuclear transcription factors called sterol regulatory element-binding proteins (SREBP) are responsible for the regulation of these cholesterol feedback mechanisms. SREBP are able to activate a number of genes encoding for proteins involved in the homeostasis of cholesterol and other lipids, including the LDL receptor gene itself. 

The promoter region of the LDL receptor gene contains several regulatory elements that control its expression. One in particular, sterol regulatory element 1, is the binding site for SREBP. Under baseline conditions, SREBP are inactive proteins bound to the endoplasmic... 

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