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

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

OBJECTIVE - 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. RESEARCH DESIGN AND METHODS - Diabetes was induced using streptozotocin (STZ) in human apoE3 (E3) or human apoE4 (E4) mice deficient in the LDL receptor (LDLR -/-). RESULTS - 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 E4LDLR2/2 mice was accompanied by a dramatic increase in atherosclerosis. CONCLUSIONS - 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.

Original languageEnglish
Pages (from-to)2285-2294
Number of pages10
JournalDiabetes
Volume60
Issue number9
DOIs
StatePublished - Sep 2011

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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