Familial type III

Familial type III hyperlipoproteinemia (broad beta disease, remnant removal disease, familial dysbetalipoproteinemia) Deficiency in remnant clearance by the liver is due to abnormality in apo E. Patients lack isoforms E3 and E4 and have only E2, which does not react with the E receptor. Increase in chylomicron and VLDL remnants of density < 1.019 (P-VLDL). Causes hypercholesterolemia, xanthomas, and atherosclerosis. 

Production of LDL from VLDL in the plasma With these modifications, the VLDL is converted in the plasma to LDL. An intermediate-sized particle, the intermediate-density lipoprotein (IDL) or VLDL remnant, is observed during this transition. IDLs can also be taken up by cells through receptor-mediated endocytosis that uses apo E as the ligand. [Note Apolipoprotein E is normally present in three isoforms, E2, E3, and E4. Apo E2 binds poorly to receptors, and patients who are homozygotic for apo E2 are deficient in the clearance of chylomicron remants and IDLs. The individuals have familial type III hyperlipoproteinemia (familial dysbetalipoproteinemia, or broad beta disease), with hypercholesterolemia and premature atherosclerosis. Not yet understood is the fact that the E4 isoform confers increased susceptibility to late-onset Alzheimer disease.]... 

Patients with familial type III hyperlipoproteinemia develop the following... 

III C T.TAG t /3-VLDL T Familial type III hyperlipidemia Defect in TAG-rich remnant clearance... 

Poly(L-malic acid) denotes a family of polyesters derived from L-malic acid as the building unit. By chemical synthesis, three kinds of poly(L-malic acid) have been obtained, depending on the molecular position of the ester bond the a-type(I) [1], the j8-type(II) [2], and the a,j8-mixed-type(III) [3). 

Hyperlipoproteinemia, Type III, is a rare hereditary disease (also called familial dysbetalipoproteinemia) manifested by the occurrence of an uncommon P-lipo-protein form. Cholesterol and triglyceride contents in the patients may occasion-ally be 2-5 times superior to the norm. 

Recently, a new polyketide biosynthetic pathway in bacteria that parallels the well studied plant PKSs has been discovered that can assemble small aromatic metabolites.8,9 These type III PKSs10 are members of the chalcone synthase (CHS) and stilbene synthase (STS) family of PKSs previously thought to be restricted to plants.11 The best studied type III PKS is CHS. Physiologically, CHS catalyzes the biosynthesis of 4,2, 4, 6 -tetrahydroxychalcone (chalcone). Moreover, in some organisms CHS works in concert with chalcone reductase (CHR) to produce 4,2 ,4 -trihydroxychalcone (deoxychalcone) (Fig. 12.1). Both natural products constitute plant secondary metabolites that are used as precursors for the biosynthesis of anthocyanin pigments, anti-microbial phytoalexins, and chemical inducers of Rhizobium nodulation genes.12... 

To resolve the issue of cyclization specificity, the x-ray crystal structure of the stilbene synthase from pine was determined to atomic resolution. This information allowed the mutagenic conversion of alfalfa CHS to a functional STS, and crystal structures of this engineered STS were solved, in the apo form and with resveratrol bound in the active site (Austin and Noel, unpublished). These experiments support a mechanistic proposal, which prompted further mutagenic and modeling experiments. This work has allowed the elucidation of the structural and mechanistic basis for cyclization specificity (aldol versus Claisen condensation) in the CHS family of type III PKSs. 

Adhesion proteins in this group contain an immunoglobulin domain that is composed of 90-100 amino acids arranged in a sandwich of two sheets of antiparallei strands. Some members of this family also contain fibronectin type III—like domains in addition to the immunoglobulin domain. Immunoglobulin-related adhesion proteins either can exist as transmembrane structures or can be attached to cell membranes via glycosyl phosphatidylinositol links (B4, R5). 

The fibrates are mainly used to treat two hyperlipi-demias, familial hypertriglyceridemia (type IV) and dysbetalipoproteinemia (type III). They are also useful in the treatment of hypertriglyceridemia associated with type II diabetes (secondary hyperlipidemia). The fibrates are the drugs of choice in treating hypertriglyceridemias, particularly those associated with low levels of HDL cholesterol. The fibrates additionally appear to... 

Familial dysbetalipoproteinemia (type III) is characterized by the accumulation of chylomicron and VLDL remnants, which are enriched in cholesterol compared to their precursors. The primary molecular cause of familial dysbetalipoproteinemia (type III) is the homozygous presence of the apolipoprotein E2 (apoE2) isoform, which is associated with recessive inheritance of the disorder [62]. However, only 1 in 50 homozygotes for apoE2 will develop type III hyperlipoproteinemia, which is clinically characterized by palmar and tuberous xanthomas, arcus lipoides, and premature atherosclerosis of coronary, peripheral, and cerebral arteries. Precipitating factors include diabetes mellitus, renal disease, hemochromatosis, but also familial hypercholesterolemia. In addition, some rare mutations in the apoE gene have been found to cause dominant and more penetrant forms of type III hyperlipoproteinemia. 

Interpretation of the lipoprotein pattern is done according to Fredrickson and Lees [31]. Familial dysbetalipoproteinemia (type III) will result in one intense band, the so-called broad /i-band, encompassing bands with ji- and pre /i-mobilily (Fig. 5.2.3) and consisting mainly of chylomicron and VLDL remnants. This broad /i-band is... 

Familial dysbetalipoproteinemia (type III) will result in a highly elevated single fraction in the / -mobility to the pre-/ -mobility region, and a reduced a-fraction (HDL). 

The results of the lipoprotein electrophoresis have to be interpreted in the context of other lipid parameters, like plasma total cholesterol and triglyceride levels. Patients with normal cholesterol and triglyceride values may sometimes show electrophoresis patterns that resemble pathologic patterns but should not be classified as such. For untreated type III patients, plasma total cholesterol levels should range from 7.5 to 13.0 mmol/1 and triglycerides from 3.5 to 10.5 mmol/1. The presence of a broad-ji-band in the absence of hyperlipidemia excludes familial dysbetalipoproteinemia (type III). 

Cholestasis can lead to a similar occurrence of a broad-/l-band. This results from the presence of lipoprotein X [Lp(X)], which migrates slightly closer to the application point than LDL but cannot be separated from it. Lp(X) is derived from bile lipids including free cholesterol and phospholipids that acquired apolipoproteins after they were released into the blood. However, this Lp(X)-derived broad-jS-band migrates closer to the application point than LDL and can be distinguished from the broad-/l-band of familial dysbetalipoproteinemia (type III). 

Familial dysbetalipoproteinemia (type III) is characterized by the accumulation of chylomicron and VLDL remnants that are enriched in cholesterol compared to their native lipoproteins. Hazard et al. [38] observed that the VLDL cholesterokplasma triglyceride ratio was increased in patients with familial dysbetalipoproteinemia (type... 

Indication Adjunct to diet for the reduction of elevated total cholesterol. LDL. apo B. and TG levels in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial). mixed dyslipidemia (Fredrickson types Ila and 1 lb), elevated TG (type IV) and primary dysbetali-poproteinemia (type III) Adjunct to other lipid lowering treatments for homozygous familial hypercholesterolemia ... 

Fate of the remaining chylomicron components After most of tt triacylglycerol has been removed, the chylomicron remnan (which contain cholesteryl esters, phospholipids, apolipoprotein and some triacylglycerol) bind to receptors on the liver (seej 228) and are then endocytosed. The remnants are the hydrolyzed to their component parts. Cholesterol and the nitrogf nous bases of phopholipids (for example, choline) can be req cled by the body. [Note If removal of chylomicron remnants by th liver is defective, they accumulate in the plasma. This is seen i type III hyperlipoproteinemia (also called familial dysbetalipopro teinemia, see p. 229). 

Likewise, irradiation of an n-Si electrode in an aqueous electrolyte efficiently forms an insulating SiOx interface [3]. Reductive decomposition of semiconductors is rarely observed, although it has been claimed that certain p-type III-V semiconductors in the phosphide family decompose to form PH3. 

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