The peroxisomal ATP binding cassette (ABC) transporter adrenoleukodystrophy-related protein, encoded by ABCD2, displays functional redundancy with the X-linked adrenoleukodystrophyassociated protein, making ABCD2 up-regulation of therapeutic value. Cholesterol lowering activates human ABCD2 in cultured cells. To investigate in vivo regulation by sterols, we first characterized a sterol regulatory element (SRE) in the murine Abcd2 promoter that is directly bound by SRE-binding proteins (SREBPs). Intriguingly, this element overlaps with a direct repeat 4, which serves as binding site for liver X receptor (LXR)/retinoid X receptor heterodimers, suggesting novel cross-talk between SREBP and LXR/retinoid X receptor in gene regulation. Using fasting-refeeding and cholesterol loading, SREBP accessibility to the SRE/direct repeat 4 was tested. Results suggest that adipose Abcd2 is induced by SREBP1c, whereas hepatic Abcd2 expression is down-regulated by concurrent activation of LXR␣ and SREBP1c. In cell culture, SREBP1c-mediated Abcd2 induction is counteracted by ligand-activated LXR␣. Finally, hepatic Abcd2 expression in LXR␣,-deficient mice is inducible to levels vastly exceeding wild type. Together, we identify LXR␣ as negative modulator of Abcd2, acting through a novel regulatory mechanism involving overlapping SREBP and LXR␣ binding sites.
X-linked adrenoleukodystrophy (X-ALD2 ; OMIM 300100) is a neurodegenerative disorder caused by mutations in the ABCD1 (ALD) gene, encoding the peroxisomal ATP binding cassette (ABC) half-transporter adrenoleukodystrophy protein (ALDP) (1). Currently, no satisfying therapy is available for X-ALD patients.Next to ALDP, three additional mammalian peroxisomal ABC halftransporters have been identified: adrenoleukodystrophy-related protein (ALDRP), 70-kDa peroxisomal membrane protein (PMP70), and PMP70-related protein (P70R), sharing 66, 39, and 25% amino acid identity with ALDP, respectively. Thus, the ABCD2-encoded ALDRP is the protein most closely related to ALDP and upon overexpression can functionally compensate for ALDP deficiency in X-ALD fibroblasts and Abcd1-deficient mice (2, 3). Therefore, pharmacological stimulation of ABCD2 expression has been targeted as an alternative therapeutic strategy for X-ALD (4), requiring detailed knowledge about how the ABCD2 gene is transcriptionally regulated.We recently showed that human ABCD2 is induced upon cholesterol depletion in cultured cells via a mechanism requiring the activation and binding of sterol regulatory element (SRE)-binding proteins (SREBPs) (5). SREBPs, which are synthesized as membrane-bound precursors and cleaved to generate the active nuclear form, are a class of transcription factors known to play a major role in regulating genes involved in fatty acid and cholesterol synthesis (reviewed in Ref. 6). To date, three SREBPs have been identified: SREBP1a and SREBP1c, which are produced from a single gene and preferentially regulate fatty acid synthesis, and SREBP2, encoded by a separate gene and controlling expression of ...