Hepatocyte ABCA1 Deletion Impairs Liver Insulin Signaling and Lipogenesis

• DOI: 10.1016/j.celrep.2017.05.032
• Publication Date: 2017-06-06T16:19:34Z
• Authors: Chia-Chi C. Key; Mingxia Liu; C. Lisa Kurtz; Soonkyu Chung; Elena Boudyguina; Timothy A. Dinh; Alexander Bashore; Peter E. Phelan; Barry I. Freedman; Timothy F. Osborne; Xuewei Zhu; Lijun Ma; Praveen Sethupathy; Sudha B. Biddinger; John S. Parks
• Keywords: Lipogenesis

Plasma membrane (PM) free cholesterol (FC) is emerging as an important modulator of signal transduction. Here, we show that hepatocyte-specific knockout (HSKO) the cellular FC exporter, ATP-binding cassette transporter A1 (ABCA1), leads to decreased PM content and defective trafficking lysosomal PM. Compared with controls, chow-fed HSKO mice had reduced hepatic (1) insulin-stimulated Akt phosphorylation, (2) activation lipogenic transcription factor Sterol Regulatory Element Binding Protein (SREBP)-1c, (3) gene expression. Consequently, Western-type diet-fed were protected from steatosis. Surprisingly, intact glucose metabolism; they showed normal gluconeogenic suppression in response re-feeding insulin tolerance. We conclude that: ABCA1 maintains optimal hepatocyte FC, through intracellular trafficking, for efficient signaling; deletion produces a form selective resistance so lipogenesis suppressed but metabolism remains normal.