Effect of Cyp27A1 gene dosage on atherosclerosis development in ApoE‐knockout mice

Abstract

In humans, sterol 27-hydroxylase (CYP27A1) deficiency leads to cholesterol deposition in tendons and vasculature. Thus, in addition to its role in bile acid synthesis, where it converts cholesterol to 27-hydroxycholesterol (27-OHC), CYP27A1 may also be atheroprotective. Cyp27A1-deficient (Cyp27A1(-/-)) mice were crossed with apolipoprotein E (apoE)-deficient mice. Cyp27A1(+/+)/apoE(-/-) [ApoE-knockout (KO)], Cyp27A1(+/-)/apoE(-/-) heterozygous (het), and Cyp27A1(-/-)/apoE(-/-) [double-knockout (DKO)] mice were challenged with a Western diet (WD) for 3 and 6 mo. ApoE-KO mice fed a chow diet or a WD were used as the control. The severity of atherosclerosis in DKO mice was reduced 10-fold. Compared with the control, the DKO mice had no 27-OHC, total plasma cholesterol and low-density lipoprotein and very low density lipoprotein (LDL/VLDL) concentrations were reduced 2-fold, and HDL was elevated 2-fold. Expression of hepatic CYP7A1, CYP3A, and CYP8B1 were 5- to 10-fold higher. 3-Hydroxy-3-methyl-glutaryl-CoA reductase (HMGR) activity increased 4-fold. Fecal cholesterol was increased. In contrast, het mice fed a WD developed accelerated atherosclerosis and severe skin lesions, possibly because of reduced reverse cholesterol transport due to diminished 27-OHC production. CYP27A1 activity is involved in the control of cholesterol homeostasis and development of atherosclerosis with a distinct gene dose-dependent effect.

27-Hydroxycholesterol, an endogenous selective estrogen receptor modulator

“…Subsequently, in the setting of hypercholesterolemia (apoe −/− mice), they found that elevation of 27HC by CYP7B1 deletion (apoe −/− ; cyp7b1 −/− mice) or exogenous 27HC administration resulted in increased lipid deposition and greater atherosclerotic lesions [61]. This is consistent with observations from Zurkinden et al that under hypercholesterolemia, complete 27HC inhibition via cyp27a1 deletion (apoe −/− ;cyp27a1 −/− mice) is atheroprotective [62]. …”

“…In addition, 27HC leads to the activation of the NF-κB pathway through ERα by stimulating Erk1,2 and JNK-dependent IκBα degradation. Conversely, complete 27HC inhibition via cyp27a1 deletion is associated with decreased macrophage infiltration in the aortic root [62]. …”

The interaction between metabolism, cancer and cardiovascular disease, connected by 27-hydroxycholesterol

“…In contrast, 27HC is also important for cholesterol elimination from macrophages, and this works as an atheroprotective effect [13]. Furthermore, in mice CYP27A1 shows gene dose-dependent effect which is likely due to affected reverse cholesterol transport, and atherosclerosis is accelerated in cyp27a1 +/− , but reduced in cyp27a1 −/− mice [51]. As described above, plasma 27HC concentration is strongly correlated with the concentration of cholesterol.…”

Hepatic caveolin‐1 is enhanced in Cyp27a1/ApoE double knockout mice

“…Cyp27a1 (+/+) / ApoE (−/−) (ApoE KO), Cyp27a1 (+/−) / ApoE (−/−) (het) and Cyp27a1 (−/−) / ApoE (−/−) (DKO) mice were bred/genotyped as previously published . Mice were maintained under a standard 12 : 12‐h light–dark cycle and fed ad libitum .…”

“…To study the athero‐protective role of CYP27A1 in vivo , Cyp27a1 KO mice were crossed with ApoE KO mice known for their propensity to spontaneously develop atherosclerosis, and the resulting offspring were fed a western diet (WD) for 3 and 6 months . The atherosclerosis observed in ApoE KO was abolished in Cyp27a1/ApoE double knockout (DKO) mice.…”