| First Author | Johnson LA | Year | 2011 |
| Journal | Diabetes | Volume | 60 |
| Issue | 9 | Pages | 2285-94 |
| PubMed ID | 21810592 | Mgi Jnum | J:189275 |
| Mgi Id | MGI:5444824 | Doi | 10.2337/db11-0466 |
| Citation | Johnson LA, et al. (2011) Apolipoprotein E4 exaggerates diabetic dyslipidemia and atherosclerosis in mice lacking the LDL receptor. Diabetes 60(9):2285-94 |
| abstractText | 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 E4LDLR(-/-) 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. |
