BACKGROUND AND AIMS: Homozygous familial hypercholesterolemia (HoFH) is an autosomal genetic disorder that generates increased levels of low-density lipoproteins (LDL) in the serum. Elevated LDL results in hypercholesterolemia leading to potentially fatal cardiovascular disease. HoFH patients are often refractory to standard cholesterol-lowering treatments. Some available pharmaceuticals developed specifically for HoFH can elevate hepatic lipid levels and in other cases have limited accessibility. Previously, we identified a family of triazine thiol compounds that effectively reduce apolipoprotein B-100 (APOB) secretion by hepatocytes. In mice with humanized livers, triazine thiols effectively lowered serum cholesterol, triglycerides, low-density lipoproteins and lipoprotein(a) (Lp(a)). Despite their effectiveness, the mode of action of triazine thiols was unknown. METHODS AND RESULTS: induced human pluripotent stem cells have a significant reduction in APOB secretion, mimicking the effect of treating hepatocytes with triazine thiols. CONCLUSIONS: This study establishes triazine thiols as novel, highly specific CES1 inhibitors, providing insight into their mechanism and highlighting CES1 inhibition as an approach for treating hypercholesterolemia.
Blaszkiewicz et al. (Tue,) studied this question.