ApoA-I deficiency in mice is associated with redistribution of apoA-II and aggravated AApoAII amyloidosis

Wang, Yaoyong; Sawashita, Jinko; Qian, Jin; Zhang, Beiru; Fu, Xiaoying; Tian, Geng; Chen, Lei; Mori, Masayuki; Higuchi, Kenichi

doi:10.1194/jlr.m013235

Cited by 15 publications

(25 citation statements)

References 42 publications

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“…Notably, in apoA-1 − / − cells, expression of apoA-2 was twice that seen in WT cells. This finding is in line with other studies 32 and possibly reflects an adaptation to loss of apoA-1.…”

Section: Discussionsupporting

confidence: 93%

Apolipoprotein A-1 regulates osteoblast and lipoblast precursor cells in mice

Blair

Kalyvioti

Papachristou

et al. 2016

Laboratory Investigation

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Imbalances in lipid metabolism affect bone homeostasis, altering bone mass and quality. A link between bone mass and high-density lipoprotein (HDL) has been proposed. Indeed, it has been recently shown that absence of the HDL receptor scavenger receptor class B type I (SR-B1) causes dense bone mediated by increased adrenocorticotropic hormone (ACTH). In the present study we aimed at further expanding the current knowledge as regards the fascinating bone-HDL connection studying bone turnover in apoA-1-deficient mice. Interestingly, we found that bone mass was greatly reduced in the apoA-1-deficient mice compared with their wild-type counterparts. More specifically, static and dynamic histomorphometry showed that the reduced bone mass in apoA-1 − / − mice reflect decreased bone formation. Biochemical composition and biomechanical properties of ApoA-1 − / − femora were significantly impaired. Mesenchymal stem cell (MSC) differentiation from the apoA-1 − / − mice showed reduced osteoblasts, and increased adipocytes, relative to wild type, in identical differentiation conditions. This suggests a shift in MSC subtypes toward adipocyte precursors, a result that is in line with our finding of increased bone marrow adiposity in apoA-1 − / − mouse femora. Notably, osteoclast differentiation in vitro and osteoclast surface in vivo were unaffected in the knock-out mice. In whole bone marrow, PPARγ was greatly increased, consistent with increased adipocytes and committed precursors. Further, in the apoA-1 − / − mice marrow, CXCL12 and ANXA2 levels were significantly decreased, whereas CXCR4 were increased, consistent with reduced signaling in a pathway that supports MSC homing and osteoblast generation. In keeping, in the apoA-1 − / − animals the osteoblast-related factors Runx2, osterix, and Col1a1 were also decreased. The apoA-1 − / − phenotype also included augmented CEPBa levels, suggesting complex changes in growth and differentiation that deserve further investigation. We conclude that the apoA-1 deficiency generates changes in the bone cell precursor population that increase adipoblast, and decrease osteoblast production resulting in reduced bone mass and impaired bone quality in mice.Laboratory Investigation (2016) 96, 763-772; doi:10.1038/labinvest.2016 published online 18 April 2016 Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone, resulting in bone fragility and fracture susceptibility. 1,2 It is a major public health problem worldwide; indeed, in the United States, more than 44 million people have osteoporosis or low bone mass. 3 The pathogenesis of osteoporosis is multifactorial. Age, sex, body size, metabolic factors, and genetic susceptibility are contributory factors. Interestingly, several studies have shown that there are strong links between bone, fat metabolism, and systemic energy metabolism, and that perturbations in lipid regulatory pathways may trigger both local and systemic phenomena that ultimately affect osteoblast and/or osteoclast function, resulting...

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Section: Discussionsupporting

confidence: 93%

Apolipoprotein A-1 regulates osteoblast and lipoblast precursor cells in mice

Blair

Kalyvioti

Papachristou

et al. 2016

Laboratory Investigation

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“…The guanidine-HCl (Gnd-HCl) denaturation experiments were performed as in ( 36 ). Midpoints of denaturation (D 1/2 ) were calculated by fi tting the experimental data points with sigmoidal curves generated by a four-parameter logistic Overexpression of human apoA-II in mice yielded different, and in many cases opposite, results in terms of plasma lipoprotein profi le, cholesterol effl ux effi ciency, and atherosclerosis development (reviewed in References 16,[28][29][30]. The applicability of these studies to human disease is signifi cantly complicated by the fundamentally different lipid metabolism of rodents versus humans and by major differences in regulation and structure of their apoA-II.…”

Section: Circular Dichroism Analysismentioning

confidence: 99%

High yield expression and purification of recombinant human apolipoprotein A-II in Escherichia coli

Smith

Yang

Goodman³

et al. 2012

Journal of Lipid Research

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“…ApoA-II proteins in plasma are primarily distributed in HDL 3 particles (15,32). To determine the effects of the polymorphism of apoA-II protein on lipoprotein distribution, we examined the properties of HDL and levels of ApoAs and cholesterols in B6.SPRET-Apoa2 f mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Aliquots were thawed on ice. To detect the levels of apoA-I and apoA-II in HDL, we collected the HDL fraction from plasma using the standard method of density gradient ultracentrifugation (15,32,34). HDL samples were loaded on a Tris-Tricine SDS polyacrylamide gel [16.5% (wt/vol) acrylamide] for electrophoresis (SDS/PAGE).…”

Section: Animals B6spret-apoa2mentioning

confidence: 99%

“…To determine the HDL particle size, plasma was prestained by Sudan Black B dye and followed by electrophoresis on a nondenaturing PAGE gel containing a 5-15% (wt/vol) linear polyacrylamide gradient. Plasma total and HDL cholesterol levels in 2-mo-old mice were determined using quantitative assay kits based on an enzymatic procedure or by a modified heparinmanganese precipitation procedure, respectively (15,32).…”

Section: Animals B6spret-apoa2mentioning

confidence: 99%

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C-terminal sequence of amyloid-resistant type F apolipoprotein A-II inhibits amyloid fibril formation of apolipoprotein A-II in mice

Sawashita

Zhang

Hara

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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In murine senile amyloidosis, misfolded serum apolipoprotein (apo) A-II deposits as amyloid fibrils (AApoAII) in a process associated with aging. Mouse strains carrying type C apoA-II (APOA2C) protein exhibit a high incidence of severe systemic amyloidosis. Previously, we showed that N-and C-terminal sequences of apoA-II protein are critical for polymerization into amyloid fibrils in vitro. Here, we demonstrate that congenic mouse strains carrying type F apoA-II (APOA2F) protein, which contains four amino acid substitutions in the amyloidogenic regions of APOA2C, were absolutely resistant to amyloidosis, even after induction of amyloidosis by injection of AApoAII. In vitro fibril formation tests showed that N-and C-terminal APOA2F peptides did not polymerize into amyloid fibrils. Moreover, a C-terminal APOA2F peptide was a strong inhibitor of nucleation and extension of amyloid fibrils during polymerization. Importantly, after the induction of amyloidosis, we succeeded in suppressing amyloid deposition in senile amyloidosis-susceptible mice by treatment with the C-terminal APOA2F peptide. We suggest that the C-terminal APOA2F peptide might inhibit further extension of amyloid fibrils by blocking the active ends of nuclei (seeds). We present a previously unidentified model system for investigating inhibitory mechanisms against amyloidosis in vivo and in vitro and believe that this system will be useful for the development of novel therapies. amyloid fibril formation | apolipoprotein A-II | inhibitory peptide | mouse | senile amyloidosis

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ApoA-I deficiency in mice is associated with redistribution of apoA-II and aggravated AApoAII amyloidosis

Cited by 15 publications

References 42 publications

Apolipoprotein A-1 regulates osteoblast and lipoblast precursor cells in mice

Apolipoprotein A-1 regulates osteoblast and lipoblast precursor cells in mice

High yield expression and purification of recombinant human apolipoprotein A-II in Escherichia coli

C-terminal sequence of amyloid-resistant type F apolipoprotein A-II inhibits amyloid fibril formation of apolipoprotein A-II in mice

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