Researchers at UT Southwestern Medical Center have identified a previously unknown regulatory protein in the liver, called HELZ2, that plays a central role in controlling how much cholesterol is released into the bloodstream.

The study, published in the journal Circulation, reveals that HELZ2 influences cholesterol levels by regulating the stability of APOB messenger RNA (mRNA), which contains the genetic instructions needed to produce apolipoprotein B (apoB).

ApoB is a key structural component of lipoproteins such as LDL, which transport cholesterol and fats through the body and are strongly associated with cardiovascular disease when present in excess.The researchers found that when HELZ2 activity increases, it accelerates the breakdown of APOB mRNA inside liver cells.This leads to reduced production of apoB proteins and fewer cholesterol-carrying lipoproteins entering the bloodstream.

In animal studies, mice with a gain-of-function mutation in HELZ2 showed lower levels of LDL cholesterol and triglycerides, as well as a reduced risk of atherosclerosis, the artery-clogging condition responsible for many heart attacks and strokes.

However, this protective effect came with a trade-off: increased fat accumulation in the liver, suggesting a balance between circulating cholesterol and liver fat storage.

Importantly, mice lacking the mutation showed the opposite effect, highlighting HELZ2 as a biological “dial” that shifts fat distribution between the bloodstream and the liver.Researchers believe this discovery could open a new therapeutic pathway for treating high cholesterol and fatty liver disease.

Unlike statins, which reduce cholesterol after it is produced, targeting HELZ2 would intervene earlier in the process by controlling gene expression at the RNA level.

This represents a potentially new class of treatments aimed at fine-tuning lipid metabolism and reducing cardiovascular risk while carefully managing liver health.