摘要：SummaryLipids, such as cholesterol and fatty acids, influence cell signaling, energy storage, and membrane formation. Cholesterol is biosynthesized through the mevalonate pathway, and aberrant metabolism causes metabolic diseases. The genetic association of a transcription factor NRF3 with obesity has been suggested, although the molecular mechanisms remain unknown. Here, we show that NRF3 upregulates gene expression in SREBP2-dependent mevalonate pathway. We further reveal that NRF3 overexpression not only reduces lanosterol, a cholesterol precursor, but also induces the expression of theGGPS1gene encoding an enzyme in the production of GGPP from farnesyl pyrophosphate (FPP), a lanosterol precursor. NRF3 overexpression also enhances cholesterol uptake through RAB5-mediated macropinocytosis process, a bulk and fluid-phase endocytosis pathway. Moreover, we find that GGPP treatment abolishes NRF3 knockdown-mediated increase of neutral lipids. These results reveal the potential roles of NRF3 in the SREBP2-dependent mevalonate pathway for cholesterol uptake through macropinocytosis induction and for lipogenesis inhibition through GGPP production.Graphical abstractDisplay OmittedHighlights•NRF3 upregulates gene expression of enzymes in the mevalonate pathway•NRF3 inducesSREBP2gene expression and interacts with active SREBP2 proteins•NRF3 reduces neutral lipid levels through GGPS1-mediated GGPP production•NRF3 enhances cholesterol uptake through RAB5-mediated macropinocytosisBiochemistry; Biological sciences; Molecular biology
