Cholesin

You wouldn’t think that there was anything more to be said about cholesterol metabolism after decades of work by med school classmate Mike Brown and a host other researchers.  But there is.

The body can synthesize cholesterol starting from scratch and Mike found out how this is inhibited when cholesterol levels get too high.  Here is a brief summary of how this happens from a recent paper [ Cell vol. 187 pp. 1685 – 1700 ’24 ]

“Cholesterol biosynthesis and uptake are tightly regu-lated through a negative feedback mechanism that senses the cellular cholesterol levels. When cells are deficient in cholesterol, SREBP2, along with its escort protein SREBP cleavage-acti- vating protein (SCAP), is transported in coat protein complex II (COPII) vesicles from the endoplasmic reticulum (ER) to the Golgi apparatus. In the Golgi, SREBP2 is sequentially cleaved by site-1 and site-2 proteases. The N-terminal domain of SREBP2, released by this cleavage, travels to the nucleus, where it func- tions as a transcription factor to enhance the expression of genes involved in cholesterol synthesis and uptake. Conversely, when cellular cholesterol levels rise, cholesterol molecules bind to SCAP, triggering its interaction with insulin-induced gene (INSIG). This interaction retains SREBP in the ER and prevents the subsequent activation of SREBP and the expression of genes involved in cholesterol metabolism”.

 

Well now you can see why this took decades to figure out.

However a recently discovered protein cholesin cuts off cholesterol synthesis when you eat and absorb cholesterol, which is much more proactive as it doesn’t wait for cholesterol levels to increase.   Cholesin is secreted into the blood by the gut when cholesterol is absorbed (secretion into the blood is what makes it a hormone).   Human cholesin contains 195 amino acids and works its magic by binding to a G Protein Coupled Receptor (GPCR) called GPCR146 which shuts off signaling by protein kinase A (PKA). This prevents  SREPB2 from turn on cholesterol synthesis (primarily in the liver).

So obviously GPCR146 and cholesin do a biochemical dance together.  Amazingly, dance is more than a metaphor, and the two proteins are coded (and entwined) on opposite strands of the same genetic locus of chromosome #7 with the code for GPCR146 on one strand inside the code for cholesin on the other.

I find this both bizarre and fantastic.  The discoveries of molecular biology never cease to amaze (me at least, and you too if your molecular biological soul isn’t completely dead).