Inhibition of the synthesis of apolipoprotein B-containing lipoproteins.
Increased serum concentrations of low density lipoproteins represent a major cardiovascular risk factor. Low-density lipoproteins are derived from very low density lipoproteins secreted by the liver. Apolipoprotein (apo)B that constitutes the essential structural protein of these lipoproteins exists in two forms, the full length form apoB-100 and the carboxy-terminal truncated apoB-48. The generation of apoB-48 is due to editing of the apoB mRNA which generates a premature stop translation codon. The editing of apoB mRNA is an important regulatory event because apoB-48-containing lipoproteins cannot be converted into the atherogenic low density lipoproteins. The apoB gene is constitutively expressed in liver and intestine, and the rate of apoB secretion is regulated post-transcriptionally. The translocation of apoB into the endoplasmic reticulum is complicated by the hydrophobicity of the nascent polypeptide. The assembly and secretion of apoB-containing lipoproteins within the endoplasmic reticulum is strictly dependent on the microsomal tricylceride transfer protein which shuttles triglycerides onto the nascent lipoprotein particle. The overall synthesis of apoB lipoproteins is regulated by proteosomal and nonproteosomal degradation and is dependent on triglyceride availability. Noninsulin dependent diabetes mellitus, obesity and the metabolic syndrome are characterized by an increased hepatic synthesis of apoB-containing lipoproteins. Interventions aimed to reduce the hepatic secretion of apoB-containing lipoproteins are therefore of great clinical importance. Lead targets in these pathways are discussed.
Greeve
J
J
Klinik für Allgemeine Innere Medizin, Inselspital-Universitätsspital Bern, Switzerland. jobst.greeve@insel.ch
D000071479:APOBEC-1 Deaminase; D000818:Animals; D001055:Apolipoproteins B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D003564:Cytidine Deaminase / Q000235:genetics / Q000502:physiology; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology; D006801:Humans; D006995:Hypobetalipoproteinemias / Q000235:genetics; D007328:Insulin / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D047493:PPAR alpha / Q000819:agonists; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D014176:Protein Biosynthesis; D017393:RNA Editing; D014158:Transcription, Genetic
D001055:Apolipoproteins B; D002352:Carrier Proteins; D015525:Fatty Acids, Omega-3; D007328:Insulin; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D047493:PPAR alpha; C106092:microsomal triglyceride transfer protein; D046988:Proteasome Endopeptidase Complex; D000071479:APOBEC-1 Deaminase; C000605089:APOBEC1 protein, human; D003564:Cytidine Deaminase