precursor for steroid hormones like androgens,
estrogens, and glucocorticoids, as well as for bile acids. Fatty
acids are linear polymers ranging in length from 16 to 24 carbons.
Also synthesized from acetyl-CoA, fatty acids are incorporated into
the bulk phospholipids of cell membranes, and they are the precursors
of many signaling molecules, including prostaglandins. When animals
ingest excess calories in the form of carbohydrate or protein, these
substrates are converted into fatty acids in the liver. The fatty
acids are esterified with glycerol to form triglycerides, which
are transported to adipose tissue for storage.
Recently, our laboratory discovered a family of transcription
factors called sterol regulatory element-binding proteins (SREBPs)
that control cholesterol and fatty acid synthesis. Unlike other
transcription factors, the SREBPs are synthesized as intrinsic
membrane-bound proteins of the endoplasmic reticulum (ER). After
synthesis, the SREBPs form a complex with a membrane-embedded
escort protein called SCAP. In lipid-depleted cells, SCAP facilitates
the incorporation of SREBPs into vesicles that bud from the ER
and move to the Golgi apparatus, where the SREBPs are processed
sequentially by two membrane-bound proteases. The second protease
cuts the SREBPs within a membrane-spanning helix in a process
called Regulated Intramembrane Proteolysis (RIP). This liberates
the active transcription factor domain of the SREBPs so that they
can enter the nucleus and activate genes encoding enzymes required
for synthesis of cholesterol and fatty acids. When cholesterol
accumulates in ER membranes, SCAP undergoes a conformational change
that causes it to bind to one of two ER retention proteins called
Insig-1 and Insig-2. This binding prevents SCAP from escorting
SREBPs to the Golgi, thereby abrogating the proteolytic processing
of SREBPs. This feedback inhibition is essential to the prevention
of cholesterol overproduction in animals.
