Transcriptional Regulation of Lipid Metabolism Antibody Sampler Kit #82675

Sterol regulatory element–binding proteins (SREBPs) are basic-helix-loop-helix–leucine zipper (bHLH-Zip) transcription factors. Inactive precursor forms of SREBPs are bound to endoplasmic reticulum (ER) membranes. When cells are starved for sterols, SREBPs move from the ER to the Golgi apparatus with the help of SREBP cleavage-activating protein (SCAP). In the Golgi apparatus, precursor SREBPs are then sequentially cleaved by two proteases, site-1 protease (S1P) and site-2 protease (S2P). The released N-terminal domain, which contains the bHLH-Zip region, enters the nucleus and binds to sterol response elements (SREs) in the promoters of various genes responsible for the synthesis of cholesterol, fatty acids, and other lipids, activating their expression (1,2). Studies show that SREBP-1-dependent fatty acid homeostasis has a critical role in promoting the pro-tumor phenotype of M2-like tumor-associated macrophages (TAMs), and inhibition of SREBP-1 enhances the efficacy of immune checkpoint blockade (3). Studies show that, in the tumor microenvironment, the sterol metabolites known as oxysterols alter the activity of the SREBP-2 and LXR pathways and, therefore, cause T cell cholesterol deficiency, leading to T cell exhaustion and dysfunction (4).

Peroxisome proliferator-activated receptor δ (PPARδ), also known as PPARβ or PPARβ/δ, is a widely expressed member of the PPAR nuclear receptor family, which controls lipid homeostasis (5,6). In response to various ligands, PPAR proteins heterodimerize with retinoid X receptors (RXRs) to bind DNA and regulate target genes (7,8). PPARδ plays a role in many different biological functions, including cholesterol efflux, embryo implantation, preadipocyte proliferation, and wound healing (9-12).

Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the ligand-activated nuclear receptor superfamily and functions as a transcriptional activator (13). PPARγ is preferentially expressed in adipocytes as well as in vascular smooth muscle cells and macrophages (14). Besides its role in mediating adipogenesis and lipid metabolism (14), PPARγ also modulates insulin sensitivity, cell proliferation, and inflammation (15). PPARγ transcriptional activity is inhibited by MAP kinase phosphorylation of PPARγ at Ser84 (16,17).

Transcription factor EB (TFEB) is a member of the Myc-related, bHLH-Zip family of transcription factors that drives the expression of a network of genes known as the Coordinated Lysosomal Expression and Regulation (CLEAR) network (18,19). TFEB specifically recognizes and binds regulatory sequences within the CLEAR box (GTCACGTGAC) of lysosomal and autophagy genes, resulting in the upregulated expression of genes involved in lysosome biogenesis and function, and autophagy regulation (18,19). TFEB is activated in response to nutrient deprivation, stimulating translocation to the nucleus, where it forms homo- or heterooligomers with other members of the microphthalmia-associated transcription factor (MITF) subfamily, leading to upregulation of autophagosomes and lysosomes (20-22). Recently, it has been shown that TFEB is a component of mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which regulates TFEB phosphorylation and nuclear translocation in response to cellular starvation and stress (23-26).

Transcription factor E3 (TFE3) is a member of a family of bHLH-Zip transcription factors that include MITF, TFEB, TFE3, and TFEC. Members of this family form heterodimers with each other, bind the same DNA sequences, and undergo the same types of post-translational modifications, including sumoylation (27). Research studies indicate that TFE3 and other family members play roles in development, organelle biogenesis, nutrient sensing, autophagy, and energy metabolism (28,29).