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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.

The liver plays a central role in metabolism and mediating insulin action. To dissect the effects of insulin on the liver in vivo, we have studied liver insulin receptor knockout (LIRKO) mice. Because LIRKO livers lack insulin receptors, they are unable to respond to insulin. Surprisingly, the most profound derangement observed in LIRKO livers by microarray analysis is a suppression of the cholesterologenic genes. Sterol regulatory element binding protein (SREBP)-2 promotes cholesterologenic gene transcription, and is inhibited by intracellular cholesterol. LIRKO livers show a slight increase in hepatic cholesterol, a 40% decrease in Srebp-2, and a 50–90% decrease in the cholesterologenic genes at the mRNA and protein levels. In control mice, SREBP-2 and cholesterologenic gene expression are suppressed by fasting and restored by refeeding; in LIRKO mice, this response is abolished. Similarly, the ability of statins to induce Srebp-2 and the cholesterologenic genes is lost in LIRKO livers. In contrast, ezetimibe treatment robustly induces Srepb-2 and its targets in LIRKO livers, raising the possibility that insulin may regulate SREBP-2 indirectly, by altering the accumulation or distribution of cholesterol within the hepatocyte. Taken together, these data indicate that cholesterol synthesis is a key target of insulin action in the liver.