The Role of SCAP/SREBP as Central Regulators of Lipid Metabolism in Hepatic Steatosis

Abstract

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly increasing worldwide at an alarming pace, due to an increase in obesity, sedentary and unhealthy lifestyles, and unbalanced dietary habits. MASLD is a unique, multi-factorial condition with several phases of progression including steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Sterol element binding protein 1c (SREBP1c) is the main transcription factor involved in regulating hepatic de novo lipogenesis. This transcription factor is synthesized as an inactive precursor, and its proteolytic maturation is initiated in the membrane of the endoplasmic reticulum upon stimulation by insulin. SREBP cleavage activating protein (SCAP) is required as a chaperon protein to escort SREBP from the endoplasmic reticulum and to facilitate the proteolytic release of the N-terminal domain of SREBP into the Golgi. SCAP inhibition prevents activation of SREBP and inhibits the expression of genes involved in triglyceride and fatty acid synthesis, resulting in the inhibition of de novo lipogenesis. In line, previous studies have shown that SCAP inhibition can resolve hepatic steatosis in animal models and intensive research is going on to understand the effects of SCAP in the pathogenesis of human disease. This review focuses on the versatile roles of SCAP/SREBP regulation in de novo lipogenesis and the structure and molecular features of SCAP/SREBP in the progression of hepatic steatosis. In addition, recent studies that attempt to target the SCAP/SREBP axis as a therapeutic option to interfere with MASLD are discussed.

Keywords: MASLD; SCAP; SREBP1c; de novo lipogenesis; fatty acid synthesis; insulin resistance; lipid metabolism; liver; pathogenesis; therapy; triglycerides.

Figure 3

Domain structure of the three SREBP family members SREBP1a, SREBP1c, and SREBP2. (A) The precursors of the three members of the SREBP family are comprised of three domains, namely, an NH₂-terminal domain composed of an acidic domain, a proline and serine-rich stretch, and a basic helix-loop-helix-leucine zipper domain, two hydrophobic transmembrane segments separated by a short loop of 30 amino acids, and a carboxy-terminal regulatory region. This part of the figure was redrawn in modified and extended form from [26]. (B) The processed nuclear SREBP (nSREBP) contains only the N-terminal part of the precursor, composed of the acidic domain acting as a transcriptional activation domain and the basic helix-loop-helix-leucine zipper motif that binds sterol response elements (SREs) and acts as a DNA-binding domain. For more details see text.

Figure 1

Schematic structure of the sterol element binding protein cleavage activating protein (SCAP). The SCAP protein is composed of five functional subdomains that are relevant for the binding of cholesterol, insulin-induced genes (INSIGs), coat protein complex II (COPII), and SREBPs, or for sensitizing cholesterol concentrations. The sterol-sensing domain (SSD) mediates the responsiveness towards cholesterol. The eight transmembrane domains are numbered from the N-terminus to the C-terminus. CTD, carboxy-terminal domain.

Figure 2

Cryogenic electron microscopic structure of the transmembrane region of the human SCAP and INSIG2 complex formed in the presence of 25-hydroxycholesterol. The sterol is sandwiched in a hydrophobic central pocket formed between SCAP and INSIG2 in the luminal leaflet of the membrane. The transmembrane spanning domains of INSIG2 and SCAP anchor the complex in the endoplasmic reticulum membrane, while the COPII binding site, which includes the MELADL motif, is exposed to the cytosol. More details about the complex resolved at resolutions of 3.3 to 3.9 Å are given elsewhere [17]. The image was generated with Ribbons XP Version 3.0 using coordinates deposited in the RCSB Protein Data Base (access. no.: 6M49).

Figure 4

Sterol-mediated proteolytic activation of SREBPs. (A) In conditions with abundant sterol content, SREBP, SCAP, and INSIG are anchored in the membranes of the endoplasmic reticulum. Under these conditions, SREBP has a hairpin orientation in which both the amino-terminal basic helix loop helix transcription factor motif and the carboxy-terminal regulatory domain are faced to the cytoplasm, while SCAP and INSIG bind to each other and form a hydrophobic cavity for sterol. (B) In conditions in which the sterol concentrations are low, the binding of SCAP and INSIG gets lost, and SCAP undergoes a conformational change that exposes a MELADL motif which is recognized by COPII. This protein serves as an escort protein, moving SCAP and bound SREBPs to the surface of the Golgi apparatus. (C) There, SREBP is proteolytically cleaved by the site-1 protease in the 30 amino acid stretch that links the transmembrane domains. (D) The site-2 protease cleaves SREBP within the membrane-spanning helix. This leads to the release of the carboxyl-terminal part of SREBP which contains the bHLH-Zip motif that shuttles to the nucleus where it activates the transcription of genes that are necessary for cholesterol and fatty acid biosynthesis.

Figure 5

Sphingomyelin and polyunsaturated fatty acids (PUFAs) in the control of SREBP processing. In conditions with high concentrations of cholesterol and 25-hydrocholesterol, the sterol regulatory element-binding protein (SREBP) and the SREBP cleavage-activating protein (SCAP) form a complex and are retained in the endoplasmic reticulum along with insulin-induced gene proteins (INSIGs). However, when sterol concentrations are low, membrane-bound ubiquitin ligases, such as gp78, bind to INSIGs, leading to their rapid degradation through the ubiquitin pathway [48]. In turn, SREBPs are transported to the Golgi apparatus. The N-terminal domains of SREBPs are then released through the action of site-1 protease (S1P) and site-2 protease (S2P). These domains move to the nucleus, where they activate the expression of genes necessary for cholesterol and fatty acid synthesis. This proteolytic processing is triggered by high concentrations of glucose, insulin, and sphingomyelin, while it is inhibited by PUFAs.

Figure 6

Sources and cellular usage of fatty acids. De novo lipogenesis and cholesterol synthesis are driven by the SCAP/SREBP axis. The pool of fatty acids is further increased by dietary free fatty acids that are released by the hydrolysis of triglycerides. In the cell, fatty acid is used for the synthesis of phospholipids in membrane biogenesis, mitochondrial fatty acid β-oxidation to maintain cellular energy metabolisms, or the synthesis of triglycerides that, in excess of fatty acids, can be stored in the liver or in fat cells to supply the body with energy when it is required.

Figure 7

Small molecule inhibitors targeting the SCAP/SREBP axis. There are several small molecule inhibitors available that target the SCAP/SREBP axis and can be considered for the treatment of non-alcoholic fatty liver diseases. They either inhibit the translocation of the SCAP/SREBP complex from the endoplasmic reticulum to the Golgi, prevent Golgi-specific glycosylation, induce lysosomal degradation of SCAP, prevent phosphorylation of critical mediators driving lipogenic processes, inhibit SREBP expression, prevent binding of COPII to the preformed SCAP/SREBP complex, or target individual compounds of the pathways responsible for hepatic fat accumulation. Abbreviations used are: ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; PAQR3, progestin and adipoQ receptor 3; SCAP, SREBP cleavage activating protein; SREBP, sterol element binding protein.