Srebf1 (rat, P56720) - manual literature synthesis

No deep-research API was available for this review. This file was written by the
reviewer from cached publications in publications/ and the UniProt record
Srebf1-uniprot.txt. Every claim carries inline provenance.

Identity and architecture

• Rat Srebf1 encodes sterol regulatory element-binding protein 1 (SREBP-1), 1134 aa
  (isoform SREBP-1A displayed; SREBP-1C/ADD1 differs at the N-terminus).
  The precursor has a cytoplasmic N-terminal transactivation/bHLH-ZIP region (bHLH
  domain 317-367, leucine zipper 367-388), two transmembrane helices (482-502,
  537-557) separated by a short lumenal loop, and a cytoplasmic C-terminal regulatory
  domain [Srebf1-uniprot.txt FT TRANSMEM/DOMAIN].
• Rat ADD1 was first cloned from an adipocyte cDNA library as a bHLH-leucine zipper
  factor PMID:8336713 that "can function as a
  sequence-specific transcriptional activator" and activates through a binding site in
  the fatty acid synthase 5' flank PMID:8336713.

DNA binding and transcriptional activation

• ADD1/SREBP1 has dual DNA specificity PMID:7739539; it "activates transcription through both the carbohydrate
  response E-box element and SRE-1" PMID:7739539. An atypical tyrosine in the basic
  region controls SRE-1 recognition PMID:7739539.
• In rat adipocytes, a dominant-negative ADD1 showed that obesity-related FAS
  overexpression is ADD1/SREBP-dependent, and in vitro binding showed SREBP2 can
  displace ADD1/SREBP1 from the FAS SRE PMID:9786926.
• PCSK9 is an SREBP-1c target: a responsive element 335-355 bp upstream of the ATG was
  verified and dominant-negative SREBP-1c blunted insulin induction PMID:16407292.
• In rat H4IIEC3 cells, nuclear SREBP-1c binds SRE / SRE-related sequences of
  lipogenic target genes, which honokiol inhibits PMID:19371623.

Activation by regulated proteolysis

• Nascent SREBP-1c sits in the ER membrane and moves to the Golgi in COPII vesicles for
  two sequential cleavages PMID:19158095.
• In rat hepatocytes insulin selectively stimulates SREBP-1c (not SREBP-2) processing by
  Akt-dependent phosphorylation of the precursor, which increases binding of the
  SCAP-SREBP-1c complex to Sar1-Sec23/24 PMID:19158095.
• UniProt (by similarity to human/hamster): tight complex with SCAP in ER/Golgi;
  cleavage by MBTPS1 (lumenal loop) then MBTPS2 (first TM); nuclear form is
  proteasomally degraded [Srebf1-uniprot.txt CC SUBUNIT/PTM].
• PUFA suppress proteolytic release of SREBP-1 in rat liver PMID:12421847; DHA
  accelerates 26S-proteasome-dependent loss of nuclear SREBP-1 in rat hepatocytes
  PMID:16222032; central leptin impairs SREBP-1c maturation in rat WAT PMID:18801905;
  ethanol (via acetaldehyde) increases mature SREBP-1 in rat hepatoma cells
  PMID:12036955.

Physiological regulation and role

• Rat hepatocytes: SREBP-1c transcription is induced by insulin and repressed by
  glucagon/cAMP; dominant-negative ADD1/SREBP-1c abolishes glucose induction of L-PK,
  FAS, S14 and ACC PMID:10207099.
• LXR/RXR induce SREBP-1c transcription (mouse) PMID:11090130; insulin induces it via
  LXR and Sp1 (cultured hepatocytes) PMID:24458133.
• Expression responses reported in rat: fructose feeding PMID:11934685, progesterone
  in preadipocytes PMID:11278421, retinoic acid in osteoblastic cells PMID:9121491,
  fetal lung development PMID:12896875, HIV protease inhibitors in muscle/liver
  PMID:18171911, palmitate (down) in H4IIEC3 cells PMID:19332540, NDGA (down) in
  high-fructose rat liver PMID:26394137.
• Genetics: an SHR Srebf1 allele with reduced SREBP-1 expression protects against
  dietary hepatic cholesterol accumulation; congenic/transgenic correction restores it
  PMID:18071061.

Isoforms

• SREBP-1A: higher activity, cholesterogenic and lipogenic targets; SREBP-1C (ADD1):
  predominant, weaker, preferentially lipogenic [Srebf1-uniprot.txt CC FUNCTION, by
  similarity].