Overexpression of apolipoprotein A5 in mice is not protective against body weight gain and aberrant glucose homeostasis

Pamir, Nathalie; McMillen, Timothy S.; Li, Yu I.; Lai, Ching Mei; Wong, Howard; LeBoeuf, Renée C.

doi:10.1016/j.metabol.2008.11.018

Cited by 16 publications

(13 citation statements)

References 54 publications

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“…Shu et al ( 32 ) observed that both the hepatic TG content and the apoA-V lipid droplet association were increased in human apoA-V transgenic mice, whereas inactivation of the mouse apoA-V gene had little effect. Although the impact on plasma TG was not examined in that study, Pamir et al ( 45 ) found that when human apoA-V transgenic mice were fed a high-fat and high-sucrose diet, fasting plasma TG levels fell instead of increasing, suggesting that apoA-V gene expression had inhibited diet-induced hepatic VLDL-TG secretion. Werner et al ( 46 ) observed that hepatic steatosis induced by essential fatty acid defi ciency is accompanied by increased apoA-V gene expression; yet, Huang et al ( 47 ) found that plasma apoA-V levels were 45% lower in obese, insulin-resistant, dyslipidemic subjects, suggesting that hepatic steatosis, which is a concomitant condition of the metabolic syndrome, reduced hepatic apoA-V secretion.…”

Section: Discussionmentioning

confidence: 91%

Biogenesis of apolipoprotein A-V and its impact on VLDL triglyceride secretion

Blade

Fabritius

et al. 2011

Journal of Lipid Research

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triglyceride (TG) metabolism ( 1 ). When it is overexpressed in transgenic mice, apoA-V reduces plasma TG levels by 65%, whereas inactivation of the apoA-V gene increases plasma TG by 4-fold ( 2 ). The preponderance of current literature suggests that apoA-V affects plasma TG turnover by stimulating LPL-mediated lipolysis of TG-rich lipoproteins, either directly or indirectly ( 3-7 ). ApoA-V has also been found to serve as a ligand for LDL receptor family members and other potential lipoprotein receptors and may thus contribute to the clearance of TG-rich lipoproteins and their remnants ( 8-11 ). However, recent studies have revealed that the effects of apoA-V on plasma TG concentration are complex and variable. In humans, several loss-of-function and null apoA-V alleles are associated with both reduced plasma apoA-V levels and elevated plasma TG ( 12, 13 ), yet other studies have found both positive and negative associations between plasma apoA-V and TG concentrations ( 7,14,15 ). Moreover, recent studies in mice have found a positive correlation between plasma apoA-V and TG concentrations ( 16,17 ).Despite its apparent impact on intravascular TG-rich lipoprotein lipolysis and clearance, a peculiar characteristic of apoA-V is that its plasma concentration is in the range of 100-200 µg/l, which is ‫ف‬ 10,000-fold lower than apoA-I and ‫ف‬ 1,000-fold lower than apoA-IV and corresponds to ‫ف‬ 1 molecule of apoA-V for every 1,000 VLDL particles ( 18,19 ). This presents a conundrum as to how an apolipoprotein circulating at such low levels could exert such a potent effect on plasma TG metabolism and concentration. Although it is certainly possible that apoA-V could function in plasma at extreme substoichiometric concentrations relative to that of TG-rich lipoproteins, it has also been suggested that apoA-V might function within the hepatocyte to directly modulate Apolipoprotein A-V (apoA-V), a member of the exchangeable apolipoprotein family synthesized predominantly in the liver, is a potent regulator of intravascular and This work was supported by National Institutes of Health Grants

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Section: Discussionmentioning

confidence: 91%

Biogenesis of apolipoprotein A-V and its impact on VLDL triglyceride secretion

Blade

Fabritius

et al. 2011

Journal of Lipid Research

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“…Mice were then randomly assigned to one of two groups for another 3 weeks of either continued ad libitum HFD feeding or to caloric restriction. For caloric restriction, mice were individually housed and given 60% of the HFD food consumption as monitored during weeks 10-12 as described ( 43 ). At the end of all feeding studies, mice were fasted for 4 h in the morning, bled from the retro-orbital sinus into tubes containing 1 mM to our knowledge.…”

Section: Methodsmentioning

confidence: 99%

“…WT mice fed the HFD have been repeatedly shown to gain body weight and fat, accompanied by systemic and adipose tissue infl ammation ( 11,14,15,43,46,51,58 ). What is not known is whether alterations in myeloidderived Abcg1 Ϫ / Ϫ worsen obesity or alter the course of body weight and fat loss during caloric restriction.…”

Section: Abcg1 Myeloid Defi Ciency Does Not Modulate Body Weight or Gmentioning

confidence: 99%

ABCG1 regulates mouse adipose tissue macrophage cholesterol levels and ratio of M1 to M2 cells in obesity and caloric restriction

Tarling

McMillen

et al. 2015

Journal of Lipid Research

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Supplemental Material can be found at: 2338 Journal of Lipid Research Volume 56, 2015ATMs and that Abcg1 plays a key role in modulating ATM cholesterol levels in obesity and acute weight loss.ATMs were collected from mice for which the myeloid cells had been replaced by bone marrow transplantation (BMT) from Abcg1 Ϫ / Ϫ mice and from WT mice undergoing autologous BMT. We found that Abcg1 expression affected the steady-state cholesterol levels of ATMs, with Abcg1ATMs having the highest total cholesterol content. Other sterol species were not evaluated due to limitations in ATM cell quantities. We found that the ratio of M1 to M2 ATMs was altered with loss of Abcg1 expression, and that Abcg1 was most highly expressed by M2 rather than proinfl ammatory M1 macrophages suggesting that M2 cells have a unique role in adipose tissue sterol homeostasis. Overall, this study identifi es ABCG1 as an important protein determining the relative levels of ATMs and cholesterol metabolism especially in M2 macrophages. Understanding the contribution of ABCG1 to ATM cholesterol homeostasis may provide new information for controlling obesity, weight loss, and related disorders such as lung, liver, and gallbladder diseases ( 38-40 ). MATERIALS AND METHODS MiceIsogenic WT C57BL/6 mice were purchased from the Jackson Laboratory (Bar Harbor, ME; #000664). ABCG1 knockout ( Abcg1 Ϫ / Ϫ ) mice on a C57BL/6 background were generated as previously described ( 41 ). BMT was conducted using C57BL/6 male mice as acceptors of either C57BL/6 bone marrow cells (WT-BMT) or cells from Abcg1 Ϫ / Ϫ mice ( Abcg1 Ϫ / Ϫ BMT) using procedures as described below. Femurs taken from Abcg1Ϫ / Ϫ mice were placed in PBS and sent overnight on ice from the University of California, Los Angeles to the University of Washington where bone marrow cells were isolated. In addition, C57BL/6 male mice raised at the University of Washington (three to four generations from the Jackson Laboratory) were used as a reference strain for measures of body composition. All mice were housed in pathogen-free conditions, in a temperature-and humidity-controlled environment (12 h light/dark cycle). Animal procedures were reviewed and approved by the Institutional Animal Care and Use Committee of University of Washington. Study designBMT was performed essentially as described ( 42 ). Briefl y, male C57BL/6 mice (WT) at 13 weeks of age were irradiated (950 rads) and then engrafted with either WT or Abcg1 Ϫ / Ϫ bone marrow cells (5 × 10 6 cells/mouse; n = 20 in each group) by retroorbital injection. Mice were maintained on pelleted rodent chow (LabDiet 5053; Purina Mills, St. Louis, MO) and acidifi ed water with neomycin (X-gen Pharmaceuticals, Big Flats, NY) for 4 weeks of recovery. Mice were then fed a high-fat diet (HFD) [D12492; Research Diets Inc., New Brunswick, NJ; 60% kcal (primarily lard) and 20% kcal carbohydrate (maltodextrin 10 and sucrose)] for 13 weeks. Mice were then randomly assigned to one of two groups for another 3 weeks of either continued ad libitum HFD feeding or to...

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“…Whether increased levels of intracellular apoA-V affects LD formation, stability or residence time remains to be determined. However, the observation of Pamir et al [29] that APOA5 transgenic mice fed a diet high in fat and sucrose secrete lower amounts of TG is consistent with high apoA-V expression fostering cellular TG accumulation.…”

Section: Apoa-v As a Potential Regulator Of Tg Secretion Via Lipidmentioning

confidence: 97%

Apolipoprotein A-V dependent modulation of plasma triacylglycerol: A puzzlement

Sharma¹,

Ryan²,

Forte³

2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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The discovery of apolipoprotein A-V (apoA-V) in 2001 has raised a number of intriguing questions about role in lipid transport and triglyceride (TG) homeostasis. Genome wide association studies (GWAS) have consistently identified APOA5 as a contributor to plasma TG levels. Single nucleotide polymorphisms (SNP) with-in the APOA5 gene locus have been shown to correlate with elevated plasma TG. Furthermore, transgenic and knockout mouse models support the view that apoA-V plays a critical role in maintenance of plasma TG levels. The present review describes recent concepts pertaining to apoA-V SNP analysis and their association with elevated plasma TG. The interaction of apoA-V with glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) is discussed relative to its postulated role in TG-rich lipoprotein catabolism. The potential role of intracellular apoA-V in regulation of TG homeostasis, as a function of its ability to associate with cytosolic lipid droplets, is reviewed. While some answers are emerging, numerous mysteries remain with regard to this low abundance, yet potent, modulator of TG homeostasis. Given the strong correlation between elevated plasma TG and heart disease, there is great scientific and public interest in deciphering the numerous biological riddles presented by apoA-V. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.

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Overexpression of apolipoprotein A5 in mice is not protective against body weight gain and aberrant glucose homeostasis

Cited by 16 publications

References 54 publications

Biogenesis of apolipoprotein A-V and its impact on VLDL triglyceride secretion

Biogenesis of apolipoprotein A-V and its impact on VLDL triglyceride secretion

ABCG1 regulates mouse adipose tissue macrophage cholesterol levels and ratio of M1 to M2 cells in obesity and caloric restriction

Apolipoprotein A-V dependent modulation of plasma triacylglycerol: A puzzlement

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