Systemic metabolite profiling reveals sexual dimorphism of AIBP control of metabolism in mice

Abstract

Emerging studies indicate that APOA-I binding protein (AIBP) is a secreted protein and functions extracellularly to promote cellular cholesterol efflux, thereby disrupting lipid rafts on the plasma membrane. AIBP is also present in the mitochondria and acts as an epimerase, facilitating the repair of dysfunctional hydrated NAD(P)H, known as NAD(P)H(X). Importantly, AIBP deficiency contributes to lethal neurometabolic disorder, reminiscent of the Leigh syndrome in humans. Whereas cyclic NADPHX production is proposed to be the underlying cause, we hypothesize that an unbiased metabolic profiling may: 1) reveal new clues for the lethality, e.g., changes of mitochondrial metabolites., and 2) identify metabolites associated with new AIBP functions. To this end, we performed unbiased and profound metabolic studies of plasma obtained from adult AIBP knockout mice and control littermates of both genders. Our systemic metabolite profiling, encompassing 9 super pathways, identified a total of 640 compounds. Our studies demonstrate a surprising sexual dimorphism of metabolites affected by AIBP deletion, with more statistically significant changes in the AIBP knockout female vs male when compared with the corresponding controls. AIBP knockout trends to reduce cholesterol but increase the bile acid precursor 7-HOCA in female but not male. Complex lipids, phospholipids, sphingomyelin and plasmalogens were reduced, while monoacylglycerol, fatty acids and the lipid soluble vitamins E and carotene diol were elevated in AIBP knockout female but not male. NAD metabolites were not significantly different in AIBP knockout vs control mice but differed for male vs female mice. Metabolites associated with glycolysis and the Krebs cycle were unchanged by AIBP knockout. Importantly, polyamine spermidine, critical for many cellular functions including cerebral cortex synapses, was reduced in male but not female AIBP knockout. This is the first report of a systemic metabolite profile of plasma samples from AIBP knockout mice, and provides a metabolic basis for future studies of AIBP regulation of cellular metabolism and the pathophysiological presentation of AIBP deficiency in patients.

AIBP Regulates Metabolism of Ketone and Lipids but Not Mitochondrial Respiration

“…NAD levels are also reduced in the NAXE knockout heart, which is consistent with our findings of metabolites in the plasma [ 30 ]. The reduced NAD levels are probably the cause of the red, flaky skin of Pellagra disease in patients with NAXE mutation [ 13 , 40 ].…”

“…Thus, in contrast to human fibroblasts or other organisms, absence of NAXE in murine cardiac tissues appears to selectively perturb NADHX but not NADPHX repair. While NAXE knockout does not significantly change cardiac NAD or NADH levels, the NAD levels trend lower, which is consistent with the NAD content in plasma [ 30 ]. We further assessed the effect of NAXE on NAD levels in HUVECs.…”

Mitochondrial apolipoprotein A-I binding protein alleviates atherosclerosis by regulating mitophagy and macrophage polarization

“…Schneider et al [ 36 ] found that AIBP −/− /LDLR −/− mice fed a high-cholesterol, high-fat diet exhibited exacerbated weight gain, liver steatosis, glucose intolerance, hypercholesterolemia, hypertriglyceridemia, and larger atherosclerotic lesions compared to LDLR −/− mice. In addition, a report examining systemic metabolites in plasma samples from AIBP knockout mice indicated that AIBP may play an important role in regulating cellular metabolism [ 39 ]. In the present study, we used bone marrow transplantation (BMT) to transplant bone marrow from AIBP knockout mice or their wild-type littermate controls into LDL receptor knockout mice to construct AIBP WT /LDLR −/− and AIBP ΔBMK /LDLR −/− mouse models.…”

Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency

“…The similarities in the clinical presentation between patients with NAXE or NAXD deficiency provide robust evidence in support of NAD(P)HX accumulation and/or NAD(P)H depletion being the common causal factor involved in the pathogenesis and of a minor implication, if any, for a secondary role reported for NAXE as a secreted Apolipoprotein A‐1 binding protein that is involved in cholesterol efflux, angiogenesis, and atherosclerosis. Naxe knockout mice have so far been analysed mostly with a focus on these latter secondary functions, 7 , 8 , 32 and it is unclear whether these mice have any neurological impairment. Given the moonlighting functions of NAXE and the essential function of NAXD in NAD(P)HX repair, developing a Naxd deficient mouse model seems like an inevitable next step to progress in whole organism disease modelling of NAD(P)HX repair deficiency and ongoing work is under way to reach this goal.…”