Hepatocyte ABCA1 Deletion Impairs Liver Insulin Signaling and Lipogenesis

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

Research output: Contribution to journalArticle

10 Scopus citations

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 languageEnglish (US)
Pages (from-to)2116-2129
Number of pages14
JournalCell Reports
Volume19
Issue number10
DOIs
StatePublished - Jun 6 2017

Keywords

  • Western-type diet
  • cholesterol
  • hepatocyte
  • hepatosteatosis
  • lipid raft
  • mTORC
  • plasma membrane
  • selective insulin resistance
  • vesicle trafficking

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Key, C. C. C., Liu, M., Kurtz, C. L., Chung, S., Boudyguina, E., Dinh, T. A., Bashore, A., Phelan, P. E., Freedman, B. I., Osborne, T. F., Zhu, X., Ma, L., Sethupathy, P., Biddinger, S. B., & Parks, J. S. (2017). Hepatocyte ABCA1 Deletion Impairs Liver Insulin Signaling and Lipogenesis. Cell Reports, 19(10), 2116-2129. https://doi.org/10.1016/j.celrep.2017.05.032