ABCA1 deficiency causes tissue-specific dysregulation of the SREBP2 pathway in mice

The ATP-binding cassette transporter ABCA1 plays an essential role in the formation of high-density lipoprotein (HDL) by mediating phospholipid and cholesterol efflux to apolipoprotein A-I. In humans, loss-of-function mutations in the ABCA1 gene cause Tangier disease (TD), a familial HDL deficiency. In addition to the disappearance of HDL, TD patients and Abca1-/- mice exhibit the cholesterol deposition in peripheral tissues through a mechanism poorly understood, which may contribute to the development of premature atherosclerosis. We and others have shown that ABCA1 deficiency causes hyperactivation of the sterol regulatory element-binding protein 2 (SREBP2) pathway in vitro. In this work, we investigate whether ABCA1 deficiency affects SREBP2-dependent cholesterol homeostatic responses in vivo. We show that SREBP2 response gene expression is partly downregulated in the liver of Abca1-/- mice compared to wild-type mouse livers in the steady-state condition. In contrast, we find that in fasted or refed condition, the expression of SREBP2 target genes is upregulated in multiple tissues of Abca1-/- mice. Correspondently, SREBP2 processing is also increased in select tissues of these mice. Altogether, our results suggest that ABCA1 deficiency is associated with the tissue-specific dysregulation of the SREBP2 pathway in a manner dependent on nutritional status. Lack of ABCA1 thus causes not only HDL deficiency but also dysregulation of the SREBP2 pathway in multiple tissues, which may underlie the pathophysiology of TD.