Abstract 4906: Systemic Nrf2 Expression Enhances Atherosclerosis Partially by Effects on Plasma Lipoproteins
Background: Nrf2 has been shown to be an important transcription factor and “master” orchestrator of the cellular anti-oxidant and anti-inflammatory response by regulating the expression of a variety of antioxidant genes such as Heme oxygenase 1, superoxide dismutase, catalase among many others. We have previously developed Nrf2 KO mice on the apoE null background to assess the role of Nrf2 on atherogenesis, resulting in Nrf2 homozygous (KO), heterozygous (HET) and wild-type (WT) littermates. Unexpectedly, we found that 14-week-old chow-fed KO males exhibited 47% and 53% lower lesions than HET and WT mice respectively, in agreement with a recently published report. The purpose of this work was to determine mechanisms that could explain Nrf2 proatherogenic effects.
Methods: Male and female mice from all three genotypes underwent retroorbital bleeding at 14 weeks of age. Plasma lipoproteins were determined by enzymatic methods. Expression of lipid metabolic genes was assessed in the liver by qPCR. Atherosclerotic lesions were scored in the aortic root as μm2/section.
Results: KO mice exhibited markedly decreased levels of plasma total cholesterol at the expense of the non-HDL fractions, decreased free fatty acids, unesterified cholesterol and glucose in a manner akin to the aortic atherosclerotic outcomes and in a sex-dependent fashion. Atherosclerotic lesion scores correlated positively with plasma total cholesterol levels in males (r = 0.47, p = 0.008) but not in females (r = −0.005, p = 0.98). These metabolic effects could be partially explained by the regulation of hepatic genes involved in lipogenesis. We found that as compared with WT controls, KO male livers displayed significant reduction (p < 0.05) in the mRNA levels of Me1 (malic enzyme 1), lipin1 and trends toward decreased levels of fatty acyl synthase (FAS), glucose 6-phosphate dehydrogenase (G6PDH), diacylglycerol acyl transferase (DGAT1) and HMG-CoA reductase. In addition, hepatic Me1 levels in male mice correlated positively with the levels of total plasma cholesterol levels (r = 0.43, p = 0.02) and free fatty acids (r = 0.54, p = 0.003).
Conclusions: Nrf2 expression promotes atherosclerosis partly by effects on plasma lipoproteins, likely associated with increased hepatic lipogenesis.