Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP

Abstract

The liver is a central organ that controls systemic energy homeostasis and nutrient metabolism. Dietary carbohydrates and lipids, and fatty acids derived from adipose tissue are delivered to the liver, and utilized for gluconeogenesis, lipogenesis, and ketogenesis, which are tightly regulated by hormonal and neural signals. Hepatic lipogenesis is activated primarily by insulin that is secreted from the pancreas after a high-carbohydrate meal. Sterol regulatory element binding protein-1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP) are major transcriptional regulators that induce key lipogenic enzymes to promote lipogenesis in the liver. Sterol regulatory element binding protein-1c is activated by insulin through complex signaling cascades that control SREBP-1c at both transcriptional and posttranslational levels. Carbohydrate-responsive element-binding protein is activated by glucose independently of insulin. Here, the authors attempt to summarize the current understanding of the molecular mechanism for the transcriptional regulation of hepatic lipogenesis, focusing on recent studies that explore the signaling pathways controlling SREBPs and ChREBP.

Figure 1. Schematic illustration of the proteolytic activation SREBPs

SREBPs are synthesized as ER-anchored precursor forms. Low cellular sterol concentration triggers the release of SCAP-SREBP-2 complex from Insig. Insulin stimulates the transport of SREBP-1c to Golgi. SREBP is sequentially cleaved by S1P and S2P proteases in the Golgi apparatus. The processed SREBP enter the nucleus to activate the transcription of genes regulating fatty acid and cholesterol metabolism.

Figure 2. Insulin promotes SREBP-1c processing

Insulin induces AKT-mediated SREBP-1c phosphorylation, which stimulates the transport of SREBP-1c-SCAP complex to Golgi apparatus. Insulin also induces the degradation of Insig-2a mRNA to promote the Golgi transport and proteolytic processing of SREBP-1c.

Figure 3. Regulation of SREBP by insulin signaling pathway

Insulin activates SREBP-1 through multiple mechanisms. Insulin stimulates SREBP-1c transcription, promotes proteolytic processing, facilitates the nuclear import of the the processed protein, and suppresses the proteosomal degradation of SREBP-1.

Figure 4. Regulation of ChREBP activity

The phosphorylation/dephosphorylation of ChREBPα by PKA/protein phosphatase 2A (PP2A) is involved in ChREBPα nuclear translocation and activation. Acetylation by coactivator CBP/P300 and O-GlcNAcylation by O-GlcNAc transferase (OGT) also contribute to ChREBPα transcriptional activities. ChREBPα forms heterodimer with Max-like protein X (MLX) and binds to the Carbohydrate-response elements (ChoREs) in the nucleus to induce its target genes involved in glycolytic and lipogenic pathways. In the adipose tissue, active ChREBPα induces expression of ChREBPβ, a new ChREBP isoform which lacks the low glucose inhibitory domain (LID), and hence constitutively active regardless of glucose concentration.