Regulation of intestinal apolipoprotein A-IV synthesis

Abstract Apolipoprotein (apo) A-IV is a protein synthesized, in humans, only by the small intestine. It has a molecular weight of 46 000 Da. This paper summarizes the evidence supporting its role as a satiety factor following the ingestion of fat. This function of apo A-IV is unique and not shared by other apolipoproteins, including apo A-I. The satiety effect of apo A-IV is centrally mediated. The mechanism of how apo A-IV inhibits food intake is not clear but it probably acts by inhibiting both gastric acid secretion as well as gastric motility. Lipid absorption stimulates apo A-IV synthesis and secretion by the jejunum. In addition to lipid feeding, there is evidence that a factor which is released as a result of lipid absorption in the distal small intestine also stimulates the synthesis and release of apo A-IV by the jejunum. This factor is probably PYY.     

Haplotype and interspersion analysis of the FMR1 CGG repeat identifies two different mutational pathways for the origin of the fragile X syndrome

To understand the origins of the fragile X syndrome and factors predisposing alleles to instability and hyperexpansion, we have compared the haplotype (using markers FRAXAC1, FRAXAC2, and DXS548) and AGG interspersion patterns of the FMR1 CGG repeat for 214 normal and 16 premutation chromosomes. Association testing between interspersion pattern and haplotype reveals a highly significant (P < 0.002) non- random distribution, indicating that all three markers are useful in phylogenetic reconstruction of mutational change. Parsimony analysis of the FMR1 CGG repeat substructure predicts that loss of AGG interruptions has occurred independently on many haplotypes associated with the fragile X syndrome, partially explaining the haplotype diversity of this disease. Among haplotypes found in linkage disequilibrium with the fragile X mutation, two different modes of mutation and predisposition to instability have been identified. One pathway has involved the frequent and recurrent loss of AGG interruptions from rare asymmetrical ancestral array structures. Intergenerational transmission studies suggest that these predisposed chromosomes progress relatively rapidly to the disease state. In contrast, the second mutational pathway involves a single haplotype which has maintained two AGG interruptions. Parsimony analysis of CGG repeat substructure within this haplotype suggests that larger alleles have been generated by gradual increments of CGG repeats distal to the most 3' interruption. Pedigree analysis of the intergenerational stability of alleles of this haplotype confirms a gradual progression toward instability thresholds. As a result, a large reservoir of chromosomes carrying large repeats on this haplotype exists. These chromosomes are predisposed to disease. The present data support a model in which there are at least two different mutational pathways predisposing alleles to instability and hyperexpansion associated with the fragile X syndrome.