The efficient lipoprotein secretion by the liver is crucial to prevent liver steatosis that has been reported to predisposes to chronic liver diseases. New LDL-cholesterol lowering medications that inhibits the secretion of very low-density lipoproteins (VLDL) by the liver have recently become available to treat hypercholesterolemia and reduce the cardiovascular risk. These drugs, namely Lomitapide and Evolocumab, block the synthesis of apolipoprotein B (ApoB) and triglycerides targeting microsomal triglyceride transfer protein (MTP) and Angiopoietin-like 3 (ANGPTL3), respectively. A still unanswered question is whether these drugs may have long-term detrimental consequences on the liver.
There are three rare genetic conditions that mimic the lowering LDL-C effect of these drugs, e.g., abetalipoproteinemia (ABL) due to loss-of-function mutations (LOF) in MTTP gene, familial hypobetalipoproteinemia (FHBL1) due to LOF mutations in APOB gene and familial combined hypolipidemia (FHBL2) due to LOF mutations in ANGPTL3 gene. We speculate that studying humans who have inherited naturally occurring mutations in these genes may provide a unique opportunity to evaluate the lifelong effect of low cholesterol induced by the new LDL-C lowering drugs.
To this aim, the present project will use two different experimental approaches. First, the hepatic triglyceride content will be quantified by using magnetic resonance spectroscopy (MRS) in members from eight families with LOF mutations in ANGPTL3 gene. Second, the risk of adverse liver outcomes will be evaluated by employing a Mendelian randomization analysis, where carriers and non-carriers of LOF mutations in ANGPTL3 as well as in APOB and MTTP genes, selected across 500.000 individuals with genetic and clinical data included into the UK Biobank, will be compared.
MTP, APOB and ANGPTL3 are promising new therapeutic targets. Thus, further research is needed to better establish the full spectrum of mechanisms involved in their metabolic pathways.
We think that the identification of a large number of individuals carrying genetic variants in these genes that mirror the biological effects of new low cholesterol therapies could be useful to understand the effect of long-term exposure to lipid-lowering drugs perturbing the VLDL assembly and secretion by the liver. Previous investigations examining the relation between LOF mutations in these genes and risk of chronic liver disease, were limited by their small sample size. Similarly, clinical trials have shown the same limitations due to the rarity of patients who can benefit from these medications. Thus, we speculate that the Mendelian randomization approach may be useful in unrevealing the long-term liver implication of their effects which is at present unknown.
The confirmation that different LDL-C lowering mechanisms could affect liver at differing degrees may be useful to indicate need for pharmacovigilance for recently introduced drug classes. Moreover, the confirmation of the hepatic beneficial effect of ANGPTL3 inhibition, which we speculate, might shed light into the potential of Evinacumab as a therapeutic option to lower elevated LDL cholesterol levels without liver implication.
We believe that the following proposal has the potential to unveil that the possible harmful consequences on the liver are highly dependent on the way in which plasma cholesterol levels are reduced.