Dual functions of Insig proteins in cholesterol homeostasis

Abstract

The molecular mechanism of how cells maintain cholesterol homeostasis has become clearer for the understanding of complicated association between sterol regulatory element-binding proteins (SREBPs), SREBP cleavage-activating protein (SCAP), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) and Insuin induced-genes (Insigs). The pioneering researches suggested that SREBP activated the transcription of genes encoding HMG-CoA reductase and all of the other enzymes involved in the synthesis of cholesterol and lipids. However, SREBPs can not exert their activities alone, they must form a complex with another protein, SCAP in the endoplasmic reticulum (ER) and translocate to Golgi. Insigs are sensors and mediators that regulate cholesterol homeostasis through binding to SCAP and HMG-CoA reductase in diverse tissues such as adipose tissue and liver, as well as the cultured cells. In this article, we aim to review on the dual functions of Insig protein family in cholesterol homeostasis.

Figure 1

Feedback control of cholesterol synthesis through binding to Insigs. HMG-CoA reductase is subject to feedback inhibition by cholesterol, oxysterols and lanosterol. Cholesterol binding to SCAP causes a conformational change that induces SCAP to bind to Insigs. So, cholesterol inhibits reductase activity by suppressing the activation of SREBPs. Oxysterols binding to Insigs inhibit reductase by accelerating its degradation and by suppressing the activation of SREBPs. Lanosterol down-regulates reductase solely by accelerating degradation of the enzyme.

Figure 2

Dual functions of Insigs in cholesterol metabolism. Insig proteins exert their dual functions in cholesterol metabolism through binding to SCAP or HMG-CoA reductase. When sterols are over-accumulation, Insigs’ binding to SCAP prevents delivery of SCAP/SREBP complex to the Golgi. For this reason, transcriptional genes are needed for uptake and synthesis of cholesterol, fatty acids, phospholipids and triglycerides decline. Insigs’ binding to HMG-CoA reductase leads to the ubiquitination/degradation of the reductase. The degradation of HMG-CoA reductase inhibits cholesterol synthesis.