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Recent genome wide association studies have linked tribbles pseudokinase 1 ( TRIB1 ) to the risk of coronary artery disease (CAD). Based on the observations that increased expression of  TRIB1  reduces secretion of VLDL and is associated with lower plasma levels of LDL cholesterol and triglycerides, higher plasma levels of HDL cholesterol and reduced risk for myocardial infarction, we carried out a high throughput phenotypic screen based on quantitative RT-PCR assay to identify compounds that induce  TRIB1  expression in human HepG2 hepatoma cells. In a screen of a collection of diversity-oriented synthesis (DOS)-derived compounds, we identified a series of benzofuran-based compounds that upregulate  TRIB1  expression and phenocopy the effects of  TRIB1  cDNA overexpression, as they inhibit triglyceride synthesis and apoB secretion in cells. In addition, the compounds downregulate expression of  MTTP  and  APOC3 , key components of the lipoprotein assembly pathway. However, CRISPR-Cas9 induced chromosomal disruption of the  TRIB1  locus in HepG2 cells, while confirming its regulatory role in lipoprotein metabolism, demonstrated that the effects of benzofurans persist in  TRIB1 -null cells indicating that TRIB1 is sufficient but not necessary to transmit the effects of the drug. Remarkably, active benzofurans, as well as natural products capable of  TRIB1  upregulation, also modulate hepatic cell cholesterol metabolism by elevating the expression of  LDLR  transcript and LDL receptor protein, while reducing the levels of  PCSK9  transcript and secreted PCSK9 protein and stimulating LDL uptake. The effects of benzofurans are not masked by cholesterol depletion and are independent of the SREBP-2 regulatory circuit, indicating that these compounds represent a novel class of chemically tractable small-molecule modulators that shift cellular lipoprotein metabolism in HepG2 cells from lipogenesis to scavenging.

Modulators of Hepatic Lipoprotein Metabolism Identified in a Search for Small-Molecule Inducers of Tribbles Pseudokinase 1 Expression