The SREBP-dependent regulation of bHLHE40 represents a novel pathway to control lipid metabolism. 

Abstract

Lipid metabolism is a highly regulated process which is essential for maintaining cellular and systematic homeostasis. Fatty acid, triglyceride, and cholesterol synthesis and metabolism are regulated by the sterol regulatory element-binding protein (SREBP) family of transcription factors, which takes place mainly in the liver. While SREBP1c drives fatty acid and triglyceride synthesis in response to insulin, SREBP2 regulates cholesterol metabolism based on cellular cholesterol levels. The protein SCAP (SREBP cleavage activating protein) is crucial for activating both SREBPs. Insulin signaling induces SREBP1c expression, controlled by various transcription factors, including BHLHE40, which has mainly been studied in the context of circadian rhythm and cellular stress, but its role in lipid regulation is not well understood. This study investigates how bHLHE40 interacts with the SREBP pathway. We show that insulin increases bHLHE40 expression in both liver and adipose-derived cells through a PI3K-AKT-dependent mechanism. This induction depends on SREBP2, but not SREBP1, indicating a specific regulatory role. Our findings also reveal that bHLHE40 positively regulates SCAP and SREBP1/2 expression, suggesting the presence of a feedback loop. Additionally, we show that FBW7 negatively regulates bHLHE40, and that in FBW7-deficient cells, the elevated bHLHE40 expression relies on active SCAP and SREBPs. Importantly, SCAP overexpression is able to partially rescue SREBP expression in bHLHE40 knockdown cells. Taken together, these results identify bHLHE40 as an insulin-responsive transcription factor involved in the regulation of the SREBP-SCAP axis, and point toward a new layer of transcriptional control in lipid metabolism.

Date of Award	2025
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences