LDLR Biosynthesis and Transport
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LDLR Biosynthesis and Transport
Cholesterol is an important component of cell membrane, and a precursor of Steroid hormones, vitamin D3, and Biliairy Acids. Cell Cholesterol homeostasis is under the control of endogenous Cholesterol synthesis, Cholesterol secretion, and of Lipoprotein Receptor activities that enrich the cell in Cholesterol. Lipoprotein Receptors play an important role in Lipoprotein metabolism and in Cellular Cholesterol homeostasis. LDLs (Low Density Lipoproteins) are the major carriers of Cholesterol as CE (Cholesteryl Esters) in humans. Elevated LDL Cholesterol (>130-160 mg/dl) is one of the major risk factors for CHD (Coronary Heart Disease). For every 1% increase in LDL-Cholesterol, the risk for CHD is increased by 1%-2%. Furthermore, reduction of LDL-Cholesterol dramatically reduces the risk of CHD by the same amount. Thus, the LDL Cholesterol level has to be taken care of in order to minimize the risk of CHD. Between 60 and 70% of circulating LDL is removed from the circulation by LDLR (LDL Receptor)-mediated endocytosis in the Liver, in which LDL is internalized and delivered to Lysosomes for degradation. Reduction in LDLR activity results in elevations in plasma LDL-Cholesterol and deposition of Cholesterol in body tissues. The critical importance of the LDLR pathway in preventing the accumulation of LDL is illustrated by the very high Plasma levels of LDL and severe premature Atherosclerosis that characterizes the two known Autosomal dominant forms of severe Hypercholesterolemia, FH (Familial Hypercholesterolemia) and FDB (Familial Defective Apolipoprotein-B) (Ref.1 & 2).

LDLR is a cell surface glycoprotein of 160 kDa that binds and internalizes LDL, and thus, regulates Cholesterol homeostasis. The binding of LDL to LDLR is followed by internalization via an endosomal pathway. The LDLR has several domains. The ligand-binding domain contains seven imperfect repeats, each with three disulfide bonds and a coordinated Ca2+ ion. Extracellularly, it binds the ApoB (Apolipoprotein-B) of LDL. LDL is produced in the circulation from its precursor, VLDL (Very Low Density Lipoprotein). ApoB is the major protein component of LDL. Besides ApoB , LDL contains Triacylglycerols, CE, and Phospholipids. The expression of LDLR on Liver cells is regulated by cholesterol levels inside the cell. The LDLR gene promoter contains SRE (Sterol Response Element) that is required for regulating transcription of the gene encoding LDLR in response to cellular sterol content. Two SRE-binding proteins, SREBP1 (Sterol Regulatory Element-Binding Protein-1) and SREBP2, are localized to the ER. Another protein, termed SCAP (SREBP-Cleavage Activating Protein), acts as a chaperone protein that transports the precursor SREBPs from the ER (Endoplasmic Reticulum) to the Golgi, where two proteases, S1P (Site-1 Protease) and S2P (Site-2 Protease), sequentially cleave the SREBPs. The cleavage liberates the NH2-terminal bHLH-Zip domains of the SREBP proteins which are capable of nuclear entry, and DNA binding. The NH2-terminal domains then travel to the nucleus, where they bind to the SREs of target genes such as that for LDLR, and activate gene transcription. The LDLR is synthesized at the ribosomes of the RER (Rough Endoplasmic Reticulum), transported to the Golgi apparatus and intercalated into cell membrane. After clustering at the cell surface, LDLR binds to LDL via ApoB , and associates with CCPs (Clathrin Coated Pits). The receptor-ligand complexes are internalized as CCVs (Clathrin Coated Vesicles). They are then converted into Endosomes. Here, a more acidic pH (4.5 to 5) exists, which leads to the dissociation of the ligand-receptor complex. The LDLR is recycled to the surface of the cell, and the Endosomes combine with Lysosomes. LDL is degraded in Lysosomes (Ref.3, 4 & 5).

In Lysosomes, LDL-ApoB is degraded to Amino Acids and LDL-CE is hydrolysed to free Cholesterol and Fatty Acids, and Triacylglycerols are cleaved into Glycerols. Lysosomal degradation of LDL results in an increase of the level of free Cholesterol in the cytosol. This resulting increase of the Cholesterol pool has several consequences. Freshly arrived free Cholesterol modulates the activity of the enzymes that ensure cell cholesterol homeostasis: HMGCoA Reductase (3-Hydroxy-3-Methylglutaryl Coenzyme-A Reductase), and ACAT (Acyl Coenzyme A: Cholesterol Acyltransferase). HMGCoA Reductase is associated with the ER and is the key enzyme in Cell Cholesterol synthesis; suppression of HMGCoA Reductase activity occurs by oversupply of Cholesterol due to Lysosomal degradation of LDL, and it adversely affects the cell’s inherent process of Cholesterol synthesis. ACAT is an integral membrane protein of the ER; when the cellular free Cholesterol level reaches a threshold, ACAT is activated and conjugates excess free Cholesterol with long chain fatty acid into CE. The Cholesterol can also enter into the intracellular Cholesterol pool important for incorporation into cell membrane, steroid hormones, and bile acids. The increase in the level of free Cholesterol also slows down the rate of LDLR synthesis by lowering the concentration of mRNA coding for LDLR. This reduces the number of LDLR at the cell surface, to slow LDL uptake. As a consequence, plasma LDL rises. High plasma LDL leads to cholesterol deposits in skin and tendons, and especially in Arteries (plaques), thus, increasing the risk of Atherosclerosis (Ref.2 & 5).

Reduced expression, altered ligand binding, or defective transport to the cell surface all lead to a reduction in the functionally effective population of LDLRs at the cell surface. Mutations in LDLR cause Hypercholesterolemia because of inefficient LDL clearance from the circulation. Defects in the LDLR cause FH, a condition associated with elevated plasma LDL-cholesterol levels. Thus, the LDLR protein has to find its way to the cell membrane; bind to the LDL; and it has to enter the cell. If this process works well, the receptor would bring Cholesterol into the Cell (in the form of LDL Cholesterol), and process it. However, if the LDLR does not function well and the Cholesterol is not brought into the cell, the cells get prepared to synthesize the required Cholesterol for themselves and this increases the risk of Hypercholesterolemia (Ref.2 & 6).