Hepatocyte ABCA1 Deletion Impairs Liver Insulin Signaling and Lipogenesis

Publication date: 6 June 2017
Source:Cell Reports, Volume 19, Issue 10
Author(s): 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
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.

Graphical abstract

Teaser

Key et al. find that deletion of hepatocyte ABCA1 leads to decreased lysosomal free-cholesterol trafficking to the plasma membrane and attenuated cholesterol biosynthesis, resulting in decreased insulin signaling to mTORC1 and attenuated lipogenesis. However, gluconeogenesis remains responsive. Mice lacking hepatocyte ABCA1 are resistant to high-fat-diet-induced hepatosteatosis.


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