Cellular and molecular gastroenterology and hepatology · 2026
Triazine Thiols Decrease Apolipoprotein B Secretion From Hepatocytes Through Inhibition of Human Carboxylesterase 1.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Blaszkiewicz Josef, Jiang Yu-Lin, Liu Jui-Tung, Martinez-Morant Carla, Dearth Troy, van Altena Casper, Lamprecht Mary Paige, Kappler Christiana, Lee Mi-Hye, Bethard Jennifer R, Ball Lauren E, Duncan Stephen A
Аннотация
BACKGROUND & AIMS: Homozygous familial hypercholesterolemia is an autosomal genetic disorder that generates increased levels of low-density lipoproteins in the serum. Elevated low-density lipoprotein results in hypercholesterolemia leading to potentially fatal cardiovascular disease. Patients with homozygous familial hypercholesterolemia are often refractory to standard cholesterol-lowering treatments. Some available pharmaceuticals developed specifically for homozygous familial hypercholesterolemia 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 secretion by hepatocytes. In mice with humanized livers, triazine thiols effectively lowered serum cholesterol, triglycerides, low-density lipoproteins and lipoprotein(a). Despite their effectiveness, the mode of action of triazine thiols was unknown.
METHODS: Affinity-based mass spectrometry, biochemical assays, molecular modeling, and gene-edited induced pluripotent stem cell-derived hepatocyte-like cells were used to identify and characterize the molecular target and mechanism of action of triazine thiols.
RESULTS: Using affinity-based mass spectrometry, we identified Carboxylesterase 1 (CES1) as a triazine thiol binding protein. Biochemical assays demonstrated that triazine thiols are slow-binding, allosteric, covalent CES1-specific inhibitors. Molecular modeling identified a predicted binding site within CES1 near cysteine 390, and loss of this cysteine conferred resistance to triazine thiol-mediated inhibition. Moreover, hepatocyte-like cells derived from CES1-/- induced human pluripotent stem cells exhibited a significant reduction in APOB secretion, mimicking the effect of triazine thiol treatment.
CONCLUSIONS: This study establishes triazine thiols as novel, highly specific carboxylesterase 1 inhibitors, providing insight into their mechanism and highlighting carboxylesterase 1 inhibition as an approach for treating hypercholesterolemia.
METHODS: Affinity-based mass spectrometry, biochemical assays, molecular modeling, and gene-edited induced pluripotent stem cell-derived hepatocyte-like cells were used to identify and characterize the molecular target and mechanism of action of triazine thiols.
RESULTS: Using affinity-based mass spectrometry, we identified Carboxylesterase 1 (CES1) as a triazine thiol binding protein. Biochemical assays demonstrated that triazine thiols are slow-binding, allosteric, covalent CES1-specific inhibitors. Molecular modeling identified a predicted binding site within CES1 near cysteine 390, and loss of this cysteine conferred resistance to triazine thiol-mediated inhibition. Moreover, hepatocyte-like cells derived from CES1-/- induced human pluripotent stem cells exhibited a significant reduction in APOB secretion, mimicking the effect of triazine thiol treatment.
CONCLUSIONS: This study establishes triazine thiols as novel, highly specific carboxylesterase 1 inhibitors, providing insight into their mechanism and highlighting carboxylesterase 1 inhibition as an approach for treating hypercholesterolemia.