Sterol 27-hydroxylase gene dosage and the antiatherosclerotic effect of Rifampicin in mice

Abstract

Sterol 27-hydroxylase (CYP27A1) catalyzes the hydroxylation of cholesterol to 27-hydroxycholesterol (27-OHC) and regulates cholesterol homeostasis. In Cyp27a1/ Apolipoprotein E (ApoE) double knockout (KO) mice fed with Western diet (WD), the atherosclerotic phenotype found in ApoE KO mice was reversed. As protective mechanism, up-regulation of Cyp3a11 and Cyp7a1 was proposed. Cyp27a1 heterozygote/ApoE KO (het) mice, with reduced Cyp27a1 expression and normal levels of Cyp7a1 and Cyp3a11, developed more severe lesions than ApoE KO mice. To analyze the contribution of Cyp3a11 to the protection of atherosclerosis development, Cyp3a11 was induced by Rifampicin (RIF) in ApoE KO and het mice. Males were fed with WD and treated daily with RIF (10 mg/kg ip) or vehicle for 4 weeks. Atherosclerosis was quantified in the aortic valve. Plasma lipids and 27-hydroxycholesterol (27-OHC), expression of cytochromes P450 and genes involved in cholesterol transport and bile acids (BAs) signaling in liver and intestine, and intestinal cholesterol absorption were analyzed. RIF increased expression of hepatic but not intestinal Cyp3a11 4-fold in both genotypes. In ApoE KO mice treated with RIF, we found a 2-fold decrease in plasma cholesterol, and a 2-fold increase in high-density lipoprotein/low-density lipoprotein ratio and CY27A1 activity. Intestinal cholesterol absorption remained unchanged and atherosclerotic lesions decreased approximately 3-fold. In het mice, RIF had no effect on plasma lipids composition, CYP27A1 activity, and atherosclerotic plaque development, despite a reduction in cholesterol absorption. In conclusion, the antiatherogenic effect of Cyp3a11 induction by RIF was also dependent on Cyp27a1 expression.

27-Hydroxycholesterol-Induced Dysregulation of Cholesterol Metabolism Impairs Learning and Memory Ability in ApoE ε4 Transgenic Mice

“…Cholesterol metabolism has been identified as a modulator of AD that is involved in maintaining synaptic plasticity, neural development, and brain function [ 5 ]. Evidence suggests that 27-OHC plays an essential role in AD [ 11 , 12 , 29 , 30 ]. Moreover, our previous studies have shown that 27-OHC could inhibit cholesterol synthesis in C6 glioma cells [ 18 ] and facilitate the transport of cholesterol from astrocytes to neurons [ 16 ].…”

“…The sterol 27-hydroxylase (CYP27A1) can catalyze the hydroxylation of cholesterol to form 27-OHC mainly in the liver, which is initially released into the blood. 27-OHC is an abundant oxysterol in the blood with an ability to cross the BBB and it plays an essential role in AD pathogenesis [ 10 , 11 , 12 ]. An increasing amount of evidence has demonstrated that the plasma level of 27-OHC in patients with mild cognitive impairment and AD is higher than average [ 13 , 14 ].…”

Mitochondrial Cholesterol Metabolites in a Bile Acid Synthetic Pathway Drive Nonalcoholic Fatty Liver Disease: A Revised “Two-Hit” Hypothesis

“…Although not in all cases, most adult CTX patients have normal liver function despite their high cholesterol and 5α-cholestanol [50,51]. Similarly, in an atherogenic mouse model with Cyp27a1 deficiency, Zurkinden et al [92,93] reported that Cyp27a1/ApoE double-knockout mice were resistant to WD-induced liver inflammation, as demonstrated by their lowered hepatic inflammatory and oxidative stress gene expressions (i.e., Tnfα and Il1b). Another study in a goose model reported that hepatic Cyp27a1 mRNA expression can be significantly inhibited in goose fatty livers [94].…”

“…Based on the observations from CTX patients [50,51], Cyp27a1 −/− mice [92,93], and goose fatty liver models [94], it is also reasonable to consider Cyp27a1 inhibition for reducing NASH inflammatory responses. Although no such studies have been reported for NASH intervention, Cyp27a1 inhibition is now being explored for the treatment of breast cancer [128,129] and toxic retinol accumulation in the eye [130].…”