Intestinal apoB-containing lipoprotein

In chylomicron retention disease (Anderson s disease) the secretory defect is restricted to intestinal apoB-containing lipoproteins (i.e., chylomicrons). This very rare recessively inherited disorder results from defects in a GTPase, Sarlb, which plays a critical role in the intracellular assembly and trafficking of chylomicrons. The affected patients present with fat malabsorption resulting in steatorrhea and deficiency of fat-soluble vitamins [46, 52, 54]. 

Without the enzyme microsomal triglyceride transfer protein (MTP), hepatic triglycerides cannot be transferred to apoB-100. Patients with dysfunctional MTP fail to make any of the apoB-containing lipoproteins (VLDL, IDL, or LDL). MTP also plays a key role in the synthesis of chylomicrons in the intestine, and mutations of MTP that result in the inability of triglycerides to he transferred to either apoB-100 in the liver or apoB-48 in the intestine prevent VLDL and chylomicron production and cause the genetic disorder abetalipoproteinemia. 

The metabolism of HDL involves several different enzymes and transfer proteins but is not completely understood [7]. The major apolipoprotein of HDL is apoA-I. The liver and intestine are the sources of apoA-I, which interacts with peripheral cells to remove excess cellular cholesterol via the ATP-binding cassette protein A1 (ABCAl). Unesterified cholesterol associated with nascent HDL is a substrate for the plasma enzyme lecithin cholesterol acyltransferase (LCAT), resulting in the formation of cholesteryl ester and enlargement of the HDL particle. Genetic defects in apoA-I, ABCAl and LCAT can cause low levels of HDL, termed hypoalphalipopro-teinemia. HDL cholesteryl ester is transferred to apoB-containing lipoproteins (such as LDL) by the cholesteryl ester transfer protein (CETP) and can be returned to the liver via the LDL receptor. HDL may also deliver some cholesterol directly to the liver via the scavenger receptor class BI (SR-BI). The removal of excess cholesterol from peripheral cells and delivery to the liver for excretion in the bile is a process that has been termed reverse cholesterol transport . 

Figure 21-1 Movement of triacylglycerols from liver and intestine to body cells and lipid carriers of blood. VLDL very low density lipoprotein which contains triacylglycerols, phospholipids, cholesterol, and apolipoproteins B, and C. IDL intermediate density lipoproteins found in human plasma. LDL low density lipoproteins which have lost most of their triacylglycerols. ApoB-100, etc., are apolipoproteins listed in Table 21-2. LCAT, lecithin cholesterol acyltransferase CETP, cholesteryl ester transfer protein (see Chapter 22).

Although its role in lipoprotein metabolism has not been delineated fully, recent studies clearly imply that LRP is responsible for the clearance of a significant percentage of chylomicron remnants (Hussain et al., 1991 Mahley and Hussain, 1991). The interaction of apoE with the LRP has been most extensively studied using rabbit jS-VLDLs (Kowal et al., 1989, 1990). These cholesterol-enriched lipoproteins represent chylomicron remnants derived from the intestine and VLDL remnants from the liver. They contain multiple apoE molecules in addition to apoB and the low molecular weight apoC molecules. Interestingly, for rabbit )8-VLDLs to interact effectively with the LRP receptor, the apoE content of these lipoproteins must be first enriched by incuba-... 

An Important example of RNA editing in mammals involves the apoB gene, which encodes two alternative forms of the serum protein apollpoprotein B (apoB) apoB-100 expressed in hepatocytes and apoB-48 expressed in intestinal epithelial cells. The 240-kDa apoB-48 corresponds to the N-terminal region of the 500-kDa apoB-100. As we detail in Chapter 18, both apoB proteins are components of large lipoprotein complexes that transport lipids in the serum. However, only low-density lipoprotein (LDL) complexes, which contain apoB-100 on their surface, deliver cholesterol to body tissues by binding to the LDL receptor present on all cells. 

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