Consequences of low cholesterol syndromes due to truncated ApoB or MTP and ANGPTL3 inactivation on chronic liver and cardiovascular diseases: a Mendelian randomization study.
Approved Research ID: 70790
Approval date: January 28th 2022
New medications to lower cholesterol in the blood have been developed. These new therapies are able to inhibit the production of a lipoprotein called very low-density lipoprotein (VLDL), which is made by the liver and carry triglycerides (TG). This effect is obtained by blocking three proteins called microsomal transfer protein (MTP), apolipoprotein B (ApoB) and angiopoietin like 3 protein (ANGPTL3). The MTP protein is responsible for putting together TG and ApoB to form the VLDL. The ANGPTL3 protein blocks the degradation of VLDL so that getting it out of the way we may expect to accelerate the elimination of VLDL.
Several studies in humans have demonstrated that these new drugs can bring plasma cholesterol and triglycerides at very low levels, which is a good thing for the people who must be cured because they have high lipids in the blood. However, one potential problem we may encounter if we block these proteins, is that people might accumulate TG in the liver. This condition is called hepatic steatosis and can predispose to more severe diseases, such as liver cirrhosis or liver cancer.
Three rare genetic disorders due to mutations in genes that reduce the production of MTP, ApoB and ANGPTL3 proteins can be taken as examples of what can happen to the liver if we block these proteins. Indeed, individuals with mutations in MTTP and APOB genes are prone to develop steatosis, while those with mutations in ANGPTL3 did not show any fat in the liver. In any case, patients affected by these rare diseases appear to be naturally protected against cardiovascular disease (CVD), probably due to the strong reduction of blood cholesterol.
Then, in order to elucidate the possible harmful effects on the liver of pharmacological blockage of MTP, ApoB, and ANGPTL3 proteins, we have planned to employ the experimental procedure called Mendelian Randomization. Following this procedure, we aim to compare the health status of the liver in individuals carrying mutations in APOB, MTTP, and ANGPTL3 genes vs. those not carrying any mutations. As a secondary objective, we will evaluate whether these mutations may determine a reduced risk of CVD. To achieve this aim, we will need 3-years. Our results may be useful for guiding the safety monitoring of the new upcoming cholesterol-lowering drugs.