Elsevier

Progress in Lipid Research

Volume 40, Issue 6, November 2001, Pages 439-452
Progress in Lipid Research

Review
Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes

https://doi.org/10.1016/S0163-7827(01)00010-8Get rights and content

Abstract

Roles of sterol regulatory element-binding proteins (SREBPs) have been established as lipid synthetic transcription factors especially for cholesterol and fatty acid synthesis. SREBPs have unique characteristics. Firstly, they are membrane-bound proteins and the N-terminal active portions enter nucleus to activate their target genes after proteolytic cleavage, which requires sterol-sensing molecule, SREBP-activating protein (SCAP) and is crucial for sterol-regulation. Secondly, they bind and activate sterol-regulatory (SREs) containing promoters as well as some E-boxes, which makes SREBPs eligible to regulate a wide range of lipid genes. Finally, three isoforms, SREBP-1a–1c, and have different roles in lipid synthesis. In vivo studies using transgsenic and knockout mice suggest that SREBP-1 seems to be involved in energy metabolism including fatty acid and glucose/insulin metabolism, whereas SREBP-2 is specific to cholesterol synthesis. Future studies will be focused on understanding molecular mechanisms sensing cellular sterol and energy states where SREBPs are deeply involved.

Introduction

Cholesterol and fatty acids are primary components of cellular membranes. Growing cells need to synthesize both cholesterol and fatty acids according to their demand for growth. In the differentiated tissues such as liver and endocrine organs, cholesterol biosynthetic pathway is linked to synthesis of bile acids and steroid hormones, respectively. Synthesis for fatty acids and triglycerides, often referred to as lipogenesis, is an energy storage system specialized to lipogenic organs such as liver and adipose tissues. In contrast to cholesterol synthesis, which is tightly regulated by a feedback system to maintain cellular cholesterol levels, fatty acid synthesis is driven primarily by the availability of carbohydrates and the actions of hormones such as insulin (reviewed in [1], [2]). Both pathways are nutritionally controlled at the transcriptional level. Recent evidence suggests that despite these different patterns of regulation, both biosynthetic pathways are controlled by a common family of transcription factors designated sterol regulatory element binding proteins (SREBPs) (reviewed in [3]). In this review, we focus on recent progress in understanding the molecular basis on physiological functions of SREBPs which have now been established as global lipid synthetic regulators.

Section snippets

Structure of SREBPs (Fig. 1)

SREBPs were purified as nuclear factors that bind to the sterol regulatory element (SRE) common to LDL receptor and HMG CoA synthase genes [4], [5]. Cloning and sequence of SREBP genes revealed their unique aspect as membrane-bound transcription factors (6). SREBPs are structurally composed of four domains with two membrane-spanning regions. Both amino- and carboxyl-terminal portions of the proteins project into the cytoplasm. The N-terminal domain of approximately 480 amino acids is a

SREBP-1a,-1c, and -2 (Fig. 1)

To date, three SREBPs have been identified; SREBP-1a and SREBP-1c produced from a single gene through the use of alternate promoters, and SREBP-2 from a separate gene [6], [64], [65], [66]. SREBP-1a and -1c are identical except the NH2-terminal transactivation domains. The rat homologue of SREBP-1c, named ADD1, was cloned independently as a protein which binds to E-boxes, and presumably promotes adipocyte differentiation [67]. All actively growing cultured cells so far studied produce

SREBP transgenic mice

To gain insight into the distinct roles of each SREBP isoform in vivo, transgenic mice that overexpress truncated, active nuclear forms of human SREBP-1a, -1c, or-2 in the liver, were produced and characterized [69], [74]. The different SREBP-overexpressing transgenic animals showed different patterns of increase in hepatic synthesis and accumulation of cholesterol and/or fatty acids. These data suggest that the SREBP-1c is more selective in activating fatty acid biosynthetic genes while

Presence of SRE and oxysterol-inducible region in SREBP-1c promoter

Transcriptional regulation of lipogenic enzymes is controlled by the amount of SREBP-1c mRNA. This notion prompted us to analyze the promoter of SREBP-1c to understand the regulation of SREBP-1c itself, and thus, that of lipogenic enzymes [55]. A cluster of putative binding sites of several transcription factors composed of NF-Y site, E-box, sterol-regulatory element, and Sp1 site were located at −90 bp of the SREBP-1c promoter. Luciferase reporter gene and gel shift assays indicated that the

ADD1/SREBP-1c in adipogenesis

SREBP-1c was also cloned as a transcription factor for genes involved in adipogenesis, and designated adipocyte determination and differentiation factor 1 (ADD1) [67]. ADD1/SREBP-1c has been suggested to be involved in adipogenesis by activating PPAR gamma, a master gene for adipogenesis [97]. It was reported that ADD1 activates promoters of PPAR gamma 1 and 3, and directly induces transcription of PPAR gamma [98]. More interestingly, ADD1 induces production or secretion of some lipid molecule

Transcriptional regulation of lipid synthesis by SREBP-2 and -1c in the liver (Fig. 4)

Fig. 4 depicts a current diagram for different functions of SREBP-2 and SREBP-1c in the regulation of lipid synthesis in the liver. Both SREBP-2 and -1c are subjected to the cleavage-system by SCAP, S1P, and S2P. If SCAP is disrupted, no cleavage of SREBP-1 or -2 occurs in the cultured cells [17], suggesting that there is no other cleavage system at least in the cultured system. Then, in the presence of sufficient amount of cholesterol, is lipogenesis shut down because cleavage of SREBP-1 is

Future aspects of SREBPs; crosstalk of transcription factors for lipid metabolism

The list of SREBP target genes is expanding. More detailed analysis on unknown target genes using DNA microarray or DNA chip technology will help our understanding of SREBP functions. It is necessary to elucidate a sterol-sensing system and identify signaling molecules for cellular cholesterol amount. The SCAP–SREBP-2 complex should play a key role in this mechanism. Identification of energy sensing molecules is another interesting topic. SREBP-1 should be involved in this mechanism and play a

Acknowledgements

I greatly thank my co-workers: Naoya Yahagi, Michiyo Amemiya-Kudo, Alyssa H. Hasty, and Tomohiro Yoshikawa for the main contribution to our work presented in this review, and Nobuhiro Yamada, Shun Ishibashi, J.L. Goldstein and M.S. Brown for continuous support.

References (111)

  • M.S. Brown et al.

    Cell

    (1997)
  • M.R. Briggs et al.

    J Biol Chem.

    (1993)
  • X. Wang et al.

    J Biol Chem.

    (1993)
  • C. Yokoyama et al.

    Cell

    (1993)
  • R. Sato et al.

    J Biol Chem.

    (1994)
  • X. Hua et al.

    Cell

    (1996)
  • J. Sakai et al.

    J Biol Chem.

    (1997)
  • X. Wang et al.

    Cell

    (1994)
  • J. Sakai et al.

    Cell

    (1996)
  • M.S. Brown et al.

    Cell

    (2000)
  • J. Sakai et al.

    J Biol Chem.

    (1998)
  • R.B. Rawson et al.

    J Biol Chem.

    (1999)
  • E.A. Duncan et al.

    J Biol Chem.

    (1997)
  • P.J. Espenshade et al.

    J Biol Chem.

    (1999)
  • E.A. Duncan et al.

    J Biol Chem.

    (1998)
  • R.B. Rawson et al.

    Mol Cell

    (1997)
  • J.F. Lawler et al.

    J Biol Chem.

    (1998)
  • A. Parraga et al.

    Structure

    (1998)
  • M.K. Mater et al.

    J Biol Chem.

    (1999)
  • M.K. Bennett et al.

    J Biol Chem.

    (1995)
  • H.B. Sanchez et al.

    J Biol Chem.

    (1995)
  • R. Sato et al.

    J Biol Chem.

    (1996)
  • J. Ericsson et al.

    J Biol Chem.

    (1996)
  • J. Ericsson et al.

    J Biol Chem.

    (1997)
  • M.M. Magana et al.

    J Lipid Res.

    (1997)
  • W.S. Yang et al.

    J Lipid Res.

    (1998)
  • K.A. Dooley et al.

    J Biol Chem.

    (1998)
  • R. Natarajan et al.

    Biochem. Biophys. Res. Commun.

    (1998)
  • S.M. Jackson et al.

    J Lipid Res.

    (1998)
  • J.V. Swinnen et al.

    J Biol Chem.

    (1998)
  • K.A. Dooley et al.

    J Biol Chem.

    (1999)
  • M.K. Bennett et al.

    J Biol Chem.

    (1999)
  • D.E. Tabor et al.

    J Biol Chem.

    (1999)
  • R. Sato et al.

    J Biol Chem.

    (2000)
  • M. Amemiya-Kudo et al.

    J Biol Chem.

    (2000)
  • Y.A. Moon et al.

    J Biol Chem.

    (2000)
  • M.M. Magana et al.

    J Biol Chem.

    (2000)
  • J. Ericsson et al.

    J Biol Chem.

    (1999)
  • R. Sato et al.

    J Biol Chem.

    (1999)
  • X. Hua et al.

    Genomics

    (1995)
  • A.R. Miserez et al.

    Genomics

    (1997)
  • J.T. Pai et al.

    J Biol Chem.

    (1998)
  • H. Shimano et al.

    J Biol Chem.

    (1999)
  • T.S. Worgall et al.

    J Biol Chem.

    (1998)
  • D.P. Thewke et al.

    J Biol Chem.

    (1998)
  • H.J. Kim et al.

    J Biol Chem.

    (1999)
  • N. Yahagi et al.

    J Biol Chem.

    (1999)
  • J.B. Kim et al.

    J Clin Invest.

    (1998)
  • A.H. Hasty et al.

    J Biol Chem.

    (2000)
  • B. Doiron et al.

    J Biol Chem.

    (1994)
  • Cited by (615)

    View all citing articles on Scopus
    View full text