Activation of the Nuclear Receptor LXR by Oxysterols Defines a New Hormone Response Pathway

TLDR

Cholesterol accumulation suppresses genes for biosynthesis and uptake while inducing cholesterol 7α‑hydroxylase, promoting bile acid–mediated cholesterol removal. We show that the nuclear receptors LXRα and LXRβ are activated by physiological levels of 24(S),25‑epoxycholesterol and 24(S)-hydroxycholesterol, identify an LXR response element in the rat cholesterol 7α‑hydroxylase promoter, and provide evidence that this oxysterol‑responsive pathway regulates cholesterol homeostasis.

Abstract

Accumulation of cholesterol causes both repression of genes controlling cholesterol biosynthesis and cellular uptake and induction of cholesterol 7α-hydroxylase, which leads to the removal of cholesterol by increased metabolism to bile acids. Here, we report that LXRα and LXRβ, two orphan members of the nuclear receptor superfamily, are activated by 24(S),25-epoxycholesterol and 24(S)-hydroxycholesterol at physiologic concentrations. In addition, we have identified an LXR response element in the promoter region of the rat cholesterol 7α-hydroxylase gene. Our data provide evidence for a new hormonal signaling pathway that activates transcription in response to oxysterols and suggest that LXRs play a critical role in the regulation of cholesterol homeostasis. Accumulation of cholesterol causes both repression of genes controlling cholesterol biosynthesis and cellular uptake and induction of cholesterol 7α-hydroxylase, which leads to the removal of cholesterol by increased metabolism to bile acids. Here, we report that LXRα and LXRβ, two orphan members of the nuclear receptor superfamily, are activated by 24(S),25-epoxycholesterol and 24(S)-hydroxycholesterol at physiologic concentrations. In addition, we have identified an LXR response element in the promoter region of the rat cholesterol 7α-hydroxylase gene. Our data provide evidence for a new hormonal signaling pathway that activates transcription in response to oxysterols and suggest that LXRs play a critical role in the regulation of cholesterol homeostasis.