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

Abstract

Sterol 27‐hydroxylase (CYP27A1) is involved in bile acid synthesis and cholesterol homoeostasis. Cyp27a1 (−/−) / Apolipoprotein E (−/−) double knockout mice (DKO) fed a western diet failed to develop atherosclerosis. Caveolin‐1 (CAV‐1), the main component of caveolae, is associated with lipid homoeostasis and has regulatory roles in vascular diseases. We hypothesized that liver CAV‐1 would contribute to the athero‐protective mechanism in DKO mice. Cyp27a1 (+/+) / ApoE (−/−) (ApoE KO), Cyp27a1 (+/−) / ApoE (−/−) (het), and DKO mice were fed a western diet for 2 months. Atherosclerotic plaque and CAV‐1 protein were quantified in aortas. Hepatic Cav‐1 mRNA was assessed using qPCR, CAV‐1 protein by immunohistochemistry and western blotting. Total hepatic and plasma cholesterol was measured using chemiluminescence. Cholesterol efflux was performed in RAW264.7 cells, using mice plasma as acceptor. CAV‐1 protein expression in aortas was increased in endothelial cells of DKO mice and negatively correlated with plaque surface ( P < 0.05). In the liver, both CAV‐1 protein and mRNA expression doubled in DKO, compared to ApoE KO and het mice ( P < 0.001 for both) and was negatively correlated with total hepatic cholesterol ( P < 0.05). Plasma from DKO, ApoE KO and het mice had the same efflux capacity. In the absence of CYP27A1, CAV‐1 overexpression might have an additional athero‐protective role by partly overcoming the defect in CYP27A1‐mediated cholesterol efflux.

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].…”