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Reprogramming of hepatic lipoprotein metabolism by small molecule inducers of TRIB1 expression (998.1)

Recent genome wide association studies have identified TRIB1 as a novel locus associated with the risk of CAD and myocardial infarction. Since increased expression of the TRIB1 gene is associated with lower plasma levels of LDL cholesterol and triglycerides and higher levels of HDL cholesterol, we set up a qRT‐PCR‐based phenotypic assay for inducers of TRIB1 expression in human HepG2 cells. In the screen of the diversity‐oriented synthesis (DOS) compound collection we identified a class of benzofuran‐based compounds that upregulate TRIB1 expression and phenocopy the effects of TRIB1 overexpression as they inhibit the triglyceride synthesis and ApoB secretion in cells. In addition, the compounds downregulate expression of MTTP and APOC3, encoding key proteins involved in lipoprotein assembly. Unexpectedly, active benzofurans ‐ as well as natural product TRIB1 inducers ‐ also modulate multiple components of hepatic cell cholesterol metabolism including elevating the expression of LDLR transcript and the level of LDL receptor while reducing the levels of PCSK9 transcript and secreted PCSK9 and stimulating the LDL uptake. The effects of the TRIB1 inducers are not masked by cholesterol depletion and are MAPKerk dependent. These chemically tractable compounds represent a novel type of modulators that reprogram cellular lipoprotein metabolism in HepG2 cells from lipogenesis to scavenging.