Disease relevance of Apoa2

• Age-associated decreases in the messenger ribonucleic acid level and the rate of synthesis of apolipoprotein A-II in murine senile amyloidosis [1].
• Dramatically decreased high density lipoprotein cholesterol, increased remnant clearance, and insulin hypersensitivity in apolipoprotein A-II knockout mice suggest a complex role for apolipoprotein A-II in atherosclerosis susceptibility [2].
• In this study, to investigate whether the type B apoA-II protein inhibits the extension of amyloid fibrils, we constructed an adenovirus vector bearing the Apoa2(b) cDNA (Adex1CATApoa2(b)), which is expressed under the control of a hepatocyte-specific promoter [3].

High impact information on Apoa2

• In contrast, eNOS is not activated by purified forms of the major HDL apolipoproteins ApoA-I and ApoA-II or by low-density lipoprotein [4].
• A locus on distal chromosome 1 containing the apolipoprotein AII gene was linked to HDL-cholesterol levels on both the chow and the atherogenic diets, but this locus did not contribute to the decrease in HDL-cholesterol in response to the diet [5].
• ApoA-II gene expression is unaffected [6].
• To test whether variations of the apoAII gene influence plasma lipid metabolism in humans, we studied 306 individuals in 25 families enriched for coronary artery disease [7].
• Ath-1 is clearly separable from Alp-2, and the distance between these genes is 6.0 centimorgans with a standard error of 4.2 centimorgans [8].

Biological context of Apoa2

• Herein, we report using a two-step process to identify Apoa2 as the gene underlying Hdlq5, a QTL for plasma high-density lipoprotein cholesterol (HDL) levels on mouse chromosome 1 [9].
• These findings support Apoa2 as the underlying Hdlq5 gene and suggest the Apoa2 polymorphisms responsible for the Hdlq5 phenotype [9].
• Three different Apoa2 alleles are known on the basis of amino acid substitutions at four residues [10].
• By testing all pairs of marker loci, I found a significant interaction between Cq3 and the Apoa2 locus, and F(2) mice with the Apoa2(KK)/Apoa2(KK); D3Mit102(B6)/D3Mit102(B6) genotype had significantly higher cholesterol levels than did F(2) mice with other genotypes [11].
• To identify additional HDL-C level quantitative trait loci (QTLs), while controlling for the effect of the Apoa2 locus, we performed linkage analysis in 179 standard diet-fed F(2) mice derived from strains BALB/cJ and B6.C-H25(c) (a congenic strain carrying the BALB/c Apoa2 allele) [12].

Anatomical context of Apoa2

• The structural gene for mouse apolipoprotein A-II, designated Alp-2, resides on mouse chromosome 1, tightly linked to Ly-m20, a lymphocyte alloantigen locus [13].
• This is consistent with a normal response of adipose tissue to the increased insulin levels in the apoA-II transgenic mice and may partially explain the increased fat deposition [14].
• Skeletal muscle isolated from fasted apoA-II transgenic mice exhibited reduced uptake of 2-deoxyglucose compared with muscles isolated from control mice [14].
• We also show that thawed and transduced hepatocytes engrafted and participated in liver growth after transplantation into newborn mice and that the apolipoprotein A-II promoter is functional [15].
• As expected, the SrtA knockout mutant was unable to anchor the C5a peptidase (ScpB) and Alp2 to the cell wall [16].

Associations of Apoa2 with chemical compounds

• Compared with control mice, apoA-II transgenic mice exhibited a delay in plasma clearance of a glucose bolus [14].
• Adipose tissue isolated from fasted apoA-II transgenic mice exhibited a 50% decrease in triglyceride hydrolysis compared with adipose tissue from control mice [14].
• Substitution of glutamine (ASSAM) for proline (apo A-II) at position 5 is distinct and may possibly be related to murine senile amyloid-ogenesis [17].
• Fluorometry using thioflavine T also revealed that AApoAII fibril extension was inhibited by the addition of type B apoA-II in vitro [3].
• N-terminal sequencing of the protein revealed that the pro-segment of five amino acid residues (Ala-Leu-Val-Lys-Arg) extended from the N-terminal glutamine residue of mature apoA-II protein [18].

Regulatory relationships of Apoa2

• Apolipoprotein AII enrichment of HDL enhances their affinity for class B type I scavenger receptor but inhibits specific cholesteryl ester uptake [19].
• The molecular structure of apolipoprotein A-II modulates the capacity of HDL to promote cell cholesterol efflux [20].

Other interactions of Apoa2

• The major candidate gene for Cq2 and Cq6 is Apoa2, and that for Cq4 and Cq5 is Apoa4 [21].
• BACKGROUND: Apolipoprotein A-II (apoA-II), an apoprotein of serum high density lipoprotein, is the serum precursor of murine senile amyloid protein fibril [1].
• For the phenotype of susceptibility to diet-induced atherosclerosis in the mouse, we have studied four quantitative traits: area of aortic fatty streaks and serum concentrations of high-density lipoprotein-bound cholesterol (HDL-cholesterol), apolipoprotein A-I, and apolipoprotein A-II (apo A-II) [22].
• The Cq6 was located over the gene for apolipoprotein A-Il (Apoa2), and the RR allele was associated with increased plasma cholesterol [10].
• ApoA-II transgenic mice have increased adipose mass and higher plasma leptin levels than C57BL/6J control mice [14].

Analytical, diagnostic and therapeutic context of Apoa2

• First, we performed a sequence analysis of the Apoa2 coding region in 46 genetically diverse mouse strains and found five different APOA2 protein variants, which we named APOA2a to APOA2e [9].
• Molecular cloning and nucleotide sequence of cDNA for murine senile amyloid protein: nucleotide substitutions found in apolipoprotein A-II cDNA of senescence accelerated mouse (SAM) [23].
• Each type was identifiable by digestion of amplified apoA-II DNA by PCR, using restriction-fragment-length polymorphism of the apoA-II gene for restriction enzymes Cfr13I and MspI [24].
• Senescence-accelerated mouse-prone (SAMP1; SAMP1@Umz) is an animal model of senile amyloidosis with apolipoprotein A-II (apoA-II) amyloid fibril (AApoAII) deposits [25].
• Expression of apoA-II mRNA in those tissues was also examined by RT-PCR analysis [26].

References