Jose M Arbones-Mainar

Publications (30) View all

• Article: Apolipoprotein E4 exaggerates diabetic dyslipidemia and atherosclerosis in mice lacking the LDL receptor.

  Lance A Johnson, Jose M Arbones-Mainar, Raymond G Fox, Avani A Pendse, Michael K Altenburg, Hyung-Suk Kim, Nobuyo Maeda
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  ABSTRACT: We investigated the differential roles of apolipoprotein E (apoE) isoforms in modulating diabetic dyslipidemia-a potential cause of the increased cardiovascular disease risk of patients with diabetes. Diabetes was induced using streptozotocin (STZ) in human apoE3 (E3) or human apoE4 (E4) mice deficient in the LDL receptor (LDLR(-/-)). Diabetic E3LDLR(-/-) and E4LDLR(-/-) mice have indistinguishable levels of plasma glucose and insulin. Despite this, diabetes increased VLDL triglycerides and LDL cholesterol in E4LDLR(-/-) mice twice as much as in E3LDLR(-/-) mice. Diabetic E4LDLR(-/-) mice had similar lipoprotein fractional catabolic rates compared with diabetic E3LDLR(-/-) mice but had larger hepatic fat stores and increased VLDL secretion. Diabetic E4LDLR(-/-) mice demonstrated a decreased reliance on lipid as an energy source based on indirect calorimetry. Lower phosphorylated acetyl-CoA carboxylase content and higher gene expression of fatty acid synthase in the liver indicated reduced fatty acid oxidation and increased fatty acid synthesis. E4LDLR(-/-) primary hepatocytes cultured in high glucose accumulated more intracellular lipid than E3LDLR(-/-) hepatocytes concomitant with a 60% reduction in fatty acid oxidation. Finally, the exaggerated dyslipidemia in diabetic E4LDLR(-/-) mice was accompanied by a dramatic increase in atherosclerosis. ApoE4 causes severe dyslipidemia and atherosclerosis independent of its interaction with LDLR in a model of STZ-induced diabetes. ApoE4-expressing livers have reduced fatty acid oxidation, which contributes to the accumulation of tissue and plasma lipids.
  Diabetes 08/2011; 60(9):2285-94. · 8.29 Impact Factor
• Article: Impaired adipogenic response to thiazolidinediones in mice expressing human apolipoproteinE4.

  Jose M Arbones-Mainar, Lance A Johnson, Michael K Altenburg, Hyung-Suk Kim, Nobuyo Maeda
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  ABSTRACT: Thiazolidinediones (TZDs) are insulin sensitizers used to treat patients with insulin resistance. To assess potential gene-drug interactions, mice expressing human apolipoprotein E3 or E4 (APOE3 or APOE4) were fed a Western-type high-fat diet for 12 wk, at which time they developed similarly impaired glucose tolerance. Supplementing the diet with rosiglitazone (1.5 mg/g body weight) for an additional 4 wk improved plasma lipid profiles in both APOE3 and APOE4 mice. However, glucose tolerance improved only in APOE3 mice. Induction of adipogenesis and lipogenesis was severely blunted in adipose tissues, but not in the livers, of APOE4 mice. Consequently, lipids were channeled to the liver, causing marked steatosis in these mice. Impaired glucose tolerance was not a prerequisite for this adverse effect, and long-term treatment with rosiglitazone altered liver enzymes and caused hepatic fibrosis in APOE4 mice. Finally, TZDs failed to stimulate PPARγ activation and adipocyte differentiation in preadipocytes and embryonic fibroblasts isolated from APOE4 mice compared to those from APOE3 mice. We conclude that the effects of TZDs are APOE isoform dependent, and that the metabolic damage observed in APOE4 mice is rooted in an impaired activation of the adipogenic program in the adipose tissues expressing APOE4.
  The FASEB Journal 10/2010; 24(10):3809-18. · 5.71 Impact Factor
• Source

  Available from: Jesús Osada

  Article: Sex-dependent effect of liver growth factor on atherosclerotic lesions and fatty liver disease in apolipoprotein E knockout mice.

  Joaquín C Surra, Natalia Guillén, Cristina Barranquero, José M Arbonés-Mainar, María A Navarro, Sonia Gascón, Carmen Arnal, Javier Godino, Mario A Guzmán, Juan J Díaz-Gil, Jesús Osada
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  ABSTRACT: Since the hepatic mitogen, liver growth factor (LGF), improves vascular structure and function in a hypertensive rat model and exhibits antioxidant activity, it may play a role in the development of atherosclerosis. To test this hypothesis, 14 male and 11 female apolipoprotein E (apoE)-deficient mice with a C57BL/6J genetic background were injected intraperitoneally twice a week with 1.7 microg of LGF per mouse for ten weeks. Plasma carbohydrates, inflammatory and lipid parameters, apolipoproteins A-I and A-II and paraoxonase activity were assessed at the end of the experimental period. Histological and chemical analyses of the livers and quantification of aortic atherosclerotic lesions were also carried out. LGF administration changed neither plasma lipid nor inflammatory parameters. ApoA-I and arylesterase activity were not affected by LGF either, while apoA-II decreased significantly in males but not in females. Plasma apoA-II correlated positively with liver fat in males but negatively in females. Atherosclerotic area lesions in males receiving LGF were 25% lower than in control mice. Likewise, a significant reduction of fatty liver disease was also observed in males in association with decreased levels of insulin, leptin and resistin. These results indicate that administration of LGF modulates atherosclerotic lesions in a sex-dependent manner. This effect is independent of plasma cholesterol, triglycerides, IL-6, MCP-1 and TNF-alpha and is related to a remodelling of HDL particles characterised by a decrease in apoA-II induced by changes in hepatic mRNA expression. Hence, LGF administration could be used as a safe alternative to control fatty liver disease and atherosclerosis in males.
  Histology and histopathology 05/2010; 25(5):609-18. · 2.48 Impact Factor
• Source

  Available from: Jesús Osada

  Article: Sex as a profound modifier of atherosclerotic lesion development in apolipoprotein E-deficient mice with different genetic backgrounds.

  Joaquín C Surra, Natalía Guillén, José M Arbonés-Mainar, Cristina Barranquero, María A Navarro, Carmen Arnal, Israel Orman, José C Segovia, Jesús Osada
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  ABSTRACT: Research suggests that sex may condition atherosclerosis development against different genetic backgrounds. This study addresses the hypothesis that this effect would be exerted by changes in the different apolipoproteins present in high-density lipoproteins. ApoE-deficient mice of both sexes with Ola 129 and C57BL/6J genetic backgrounds were fed a chow diet for 14 weeks. At the end of the dietary intervention, the development of atherosclerotic lesions, apolipoproteins, lipid metabolism, inflammation and paraoxonase were assessed. Differences between atherosclerotic lesions in Ola 129 and C57BL/6J strains of apoE-deficient mice were sex-dependent and were only statistically significant in females. Plasma levels of HDL cholesterol and apolipoproteins related to these lipoparticles, such as apoA-I, apoA-II, apoA-IV, apoA-V and apoJ, were significantly different between these two strains and there were sex-related differences in some of these apolipoproteins. Hepatic steatosis was also related to the strain and was independent of sex. In females, changes in HDL cholesterol and apolipoproteins A-I and A-II were important determinants of atherosclerosis, while this was not the case in males. Our results demonstrate that atherosclerosis-related differences between Ola129 and C57BL/6J genetic backgrounds in apoE-deficient mice are sex-dependent and that this finding is explained by the differences in HDL cholesterol and its apolipoprotein components, mainly apoA-I and A-II. Overall, our findings highlight the importance of taking sex into account in the analysis of atherosclerosis and lipid metabolism in animal models.
  Journal of atherosclerosis and thrombosis 05/2010; 17(7):712-21. · 2.69 Impact Factor
• Article: Apolipoprotein E knock-out and knock-in mice: atherosclerosis, metabolic syndrome, and beyond.

  Avani A Pendse, Jose M Arbones-Mainar, Lance A Johnson, Michael K Altenburg, Nobuyo Maeda
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  ABSTRACT: Given the multiple differences between mice and men, it was once thought that mice could not be used to model atherosclerosis, principally a human disease. Apolipoprotein E-deficient (apoEKO) mice have convincingly changed this view, and the ability to model human-like plaques in these mice has provided scientists a platform to study multiple facets of atherogenesis and to explore potential therapeutic interventions. In addition to its well-established role in lipoprotein metabolism, recent observations of reduced adiposity and improved glucose homeostasis in apoEKO mice suggest that apoE may also play a key role in energy metabolism in peripheral organs, including adipose tissue. Finally, along with apoEKO mice, knockin mice expressing human apoE isoforms in place of endogenous mouse apoE have provided insights into how quantitative and qualitative genetic alterations interact with the environment in the pathogenesis of complex human diseases.
  The Journal of Lipid Research 01/2009; 50 Suppl:S178-82. · 5.56 Impact Factor