Editors' ChoiceMetabolism

Disrupting protein trafficking to reduce hepatic lipogenesis

Sci. Signal.  18 Aug 2015:
Vol. 8, Issue 390, pp. ec230
DOI: 10.1126/scisignal.aad2445

Sterol regulatory element–binding protein 1 (SREBP1) is a transcription factor that promotes the expression of genes involved in hepatic lipogenesis. In response to insulin signaling, amino acid stimulation, or sterol depletion, SREBP1 translocates from the endoplasmic reticulum (ER) to the Golgi, where it is proteolytically processed. Translocation of SREBP1 from the ER to the Golgi requires Sec23A and Sec31A, which are components of the COPII vesicle coat complex. Han et al. found that CRTC2 [cAMP response element binding protein (CREB)–regulated transcription coactivator 2], which is primarily known as a transcriptional regulator of glucose homeostasis, also contributes to lipid homeostasis by inhibiting intracellular trafficking of SREBP1. Compared with wild-type mice, Crtc2 –/– mice had increased hepatic lipids, increased nuclear abundance of SREBP1, and increased expression of SREBP1 target genes. A mutant version of CRTC2 that is constitutively localized to the nucleus did not rescue these phenotypes. In vitro assays and experiments in cultured cells and in vivo indicated that CRTC2 inhibited trafficking of SREBP1 by competing with Sec23A for binding to Sec31A. Treating primary mouse hepatocytes with insulin or amino acids stimulated phosphorylation of CRTC2, reduced the interaction between CRTC2 and Sec31A, and increased the interaction between Sec31A and Sec23A. The presence of a chemical inhibitor of the mechanistic target of rapamycin (mTOR), which is activated by both insulin and amino acids, prevented these effects. mTOR phosphorylated CRTC2 on Ser136 in vitro and in primary mouse hepatocytes. Fasting followed by refeeding or feeding of a high-fat diet (HFD) stimulated CRTC2 phosphorylation, reduced the interaction between CRTC2 and Sec31A, and promoted the interaction between Sec31A and Sec23A in the livers of wild-type mice, but had no effect on the interaction between Sec31A and Sec23A in Crtc2 –/– mice. Hepatic overexpression of CRTC2S136A, a form of CRTC2 that cannot be phosphorylated by mTOR, in the liver inhibited SREBP1 processing, reduced lipogenesis and hepatic steatosis, and improved insulin sensitivity in HFD-fed mice. Thus, cytosolic CRTC2 inhibits transport and processing of SREBP1, and the presence of nutrients or insulin relieves this inhibition by stimulating the mTOR-dependent phosphorylation of CRTC2.

J. Han, E. Li, L. Chen, Y. Zhang, F. Wei, J. Liu, H. Deng, Y. Wang, The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1. Nature 524, 243–246 (2015). [PubMed]