Abstract
Plasma membrane (PM) free cholesterol (FC) is emerging as an important modulator of signal transduction. Here, we show that hepatocyte-specific knockout (HSKO) of the cellular FC exporter, ATP-binding cassette transporter A1 (ABCA1), leads to decreased PM FC content and defective trafficking of lysosomal FC to the PM. Compared with controls, chow-fed HSKO mice had reduced hepatic (1) insulin-stimulated Akt phosphorylation, (2) activation of the lipogenic transcription factor Sterol Regulatory Element Binding Protein (SREBP)-1c, and (3) lipogenic gene expression. Consequently, Western-type diet-fed HSKO mice were protected from steatosis. Surprisingly, HSKO mice had intact glucose metabolism; they showed normal gluconeogenic gene suppression in response to re-feeding and normal glucose and insulin tolerance. We conclude that: (1) ABCA1 maintains optimal hepatocyte PM FC, through intracellular FC trafficking, for efficient insulin signaling; and (2) hepatocyte ABCA1 deletion produces a form of selective insulin resistance so that lipogenesis is suppressed but glucose metabolism remains normal.
Original language | English (US) |
---|---|
Pages (from-to) | 2116-2129 |
Number of pages | 14 |
Journal | Cell Reports |
Volume | 19 |
Issue number | 10 |
DOIs | |
State | Published - Jun 6 2017 |
Keywords
- Western-type diet
- cholesterol
- hepatocyte
- hepatosteatosis
- lipid raft
- mTORC
- plasma membrane
- selective insulin resistance
- vesicle trafficking
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology