Hepatocyte ABCA1 Deletion Impairs Liver Insulin Signaling and Lipogenesis

Cell Rep. 2017 Jun 6;19(10):2116-2129. doi: 10.1016/j.celrep.2017.05.032.


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.

Keywords: Western-type diet; cholesterol; hepatocyte; hepatosteatosis; lipid raft; mTORC; plasma membrane; selective insulin resistance; vesicle trafficking.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP Binding Cassette Transporter 1 / genetics
  • ATP Binding Cassette Transporter 1 / metabolism*
  • Animals
  • Cholesterol / genetics
  • Cholesterol / metabolism*
  • Gene Deletion
  • Hepatocytes / metabolism*
  • Insulin Resistance / genetics
  • Lipogenesis*
  • Liver / metabolism*
  • Mice
  • Mice, Knockout
  • Signal Transduction*


  • ABCA1 protein, mouse
  • ATP Binding Cassette Transporter 1
  • Cholesterol