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

Hepatocyte ABCA1 Deletion Impairs Liver Insulin Signaling and Lipogenesis.

Author information

1
Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
2
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
3
Department of Nutrition and Health Sciences, University of Nebraska, Lincoln, NE 68588, USA.
4
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
5
Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827, USA.
6
Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
7
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02062, USA.
8
Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. Electronic address: jparks@wakehealth.edu.

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.

KEYWORDS:

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

PMID:
28591582
PMCID:
PMC5512440
DOI:
10.1016/j.celrep.2017.05.032
[Indexed for MEDLINE]
Free PMC Article

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